DOCSLIB.ORG

Multi-Discipline Review

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Multi-Discipline Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211801Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multidisciplinary Review and Evaluation NDA 211801 IBSRELA (tenapanor) NDA/BLA Multidisciplinary Review and Evaluation Application Type New Drug Application (NDA) Application Number(s) 211801 (IND #108,732) Priority or Standard Standard Submit Date(s) 09/12/2018 Received Date(s) 09/12/2018 PDUFA Goal Date 09/12/2019 Division/Office Division of Gastroenterology and Inborn Errors Products (DGIEP)/ Office of Drug Evaluation III (ODE III) Review Completion Date 09/10/2019 Established/Proper Name Tenapanor (RDX5791; AZD1722) (Proposed) Trade Name Ibsrela Pharmacologic Class Sodium/hydrogen exchanger 3 (NHE3) inhibitor Code name Applicant Ardelyx, Inc. Dosage form Oral tablets Applicant proposed Dosing 50 mg orally twice daily Regimen Applicant Proposed Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Indication(s)/Population(s) Adults Applicant Proposed 440630006 SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Indication(s)/Population(s) Adults (if applicable) Recommended Dosing 50 mg orally twice daily Regimen i Version date: September 12, 2018 Reference ID: 4490899 NDA/BLA Multidisciplinary Review and Evaluation NDA 211801 IBSRELA (tenapanor) Table of Contents Table of Tables ..................................................................................................................... v Table of Figures .................................................................................................................... x Reviewers of Multidisciplinary Review and Evaluation ...................................................... 1 Glossary ............................................................................................................................... 3 1. Executive Summary ......................................................................................................... 5 1.1. Product Introduction ................................................................................................ 5 1.2. Conclusions on the Substantial Evidence of Effectiveness ...................................... 5 1.3. Benefit-Risk Assessment .......................................................................................... 7 1.4. Patient Experience Data ......................................................................................... 10 2. Therapeutic Context ..................................................................................................... 11 2.1. Analysis of Condition .............................................................................................. 11 2.2. Analysis of Current Treatment Options ................................................................. 12 3. Regulatory Background ................................................................................................. 15 3.1. U.S. Regulatory Actions and Marketing History ..................................................... 15 3.2. Summary of Presubmission/Submission Regulatory Activity ................................ 15 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 19 4.1. Office of Scientific Investigations ........................................................................... 19 4.2. Product Quality....................................................................................................... 19 4.3. Clinical Outcomes Assessment ............................................................................... 20 5. Nonclinical Pharmacology/Toxicology .......................................................................... 21 5.1. Executive Summary ................................................................................................ 21 5.2. Referenced NDAs, BLAs, DMFs ............................................................................... 24 5.3. Pharmacology ......................................................................................................... 24 5.3.1. Secondary Pharmacology ................................................................................ 26 5.3.2. Safety Pharmacology ....................................................................................... 26 5.4. ADME/PK ................................................................................................................ 27 5.5. Toxicology ............................................................................................................... 27 5.5.1. General Toxicology .......................................................................................... 27 5.5.2. Genetic Toxicology ........................................................................................... 31 5.5.3. Carcinogenicity ................................................................................................ 31 5.5.4. Reproductive and Developmental Toxicology ................................................. 31 5.5.5. Juvenile Toxicology Studies ............................................................................. 39 6. Clinical Pharmacology ................................................................................................... 41 6.1. Executive Summary ................................................................................................ 41 6.1.1. Recommendations ........................................................................................... 41 ii Version date: September 12, 2018 Reference ID: 4490899 NDA/BLA Multidisciplinary Review and Evaluation NDA 211801 IBSRELA (tenapanor) 6.2. Summary of Clinical Pharmacology Assessment .................................................... 41 6.2.1. Pharmacology and Clinical Pharmacokinetics ................................................. 41 6.2.2. General Dosing and Therapeutic Individualization ......................................... 42 6.3. Comprehensive Clinical Pharmacology Review ..................................................... 43 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ......................... 43 6.3.2. Clinical Pharmacology Questions .................................................................... 44 7. Sources of Clinical Data and Review Strategy ............................................................... 48 7.1. Table of Clinical Studies .......................................................................................... 48 7.2. Review Approach .................................................................................................... 50 7.3. Data Integrity .......................................................................................................... 50 8. Review of Relevant Individual Trials Used to Support Efficacy and Safety .................. 51 8.1. Study Design of Key Studies That Support Approval ............................................. 51 8.1.1. Phase 3 Studies: TEN-01-301 (Study 301) and TEN-01-302 (Study 302) ......... 51 8.1.2. Safety Extension: TEN-01-303 (Study 303) ...................................................... 56 9. Review of Efficacy ......................................................................................................... 56 9.1.1. TEN-01-301 (Study 301) Results ...................................................................... 57 9.1.2. TEN-01-302 (Study 302) Results ...................................................................... 66 10. Review of Safety .......................................................................................................... 75 10.1. Safety Review Approach....................................................................................... 75 10.1.1. Overall Exposure ............................................................................................ 78 10.1.2. Demographics / Adequacy of the Safety Population .................................... 79 10.1.3. Categorization of Adverse Events .................................................................. 80 10.2. Safety Result ......................................................................................................... 82 10.2.1. Overall Rates of Adverse Events .................................................................... 82 10.2.2. Dropouts and/or Discontinuations Due to Adverse Effects .......................... 82 10.2.3. Deaths ............................................................................................................ 83 10.2.4. Serious Adverse Events .................................................................................. 83 10.2.5. Common Adverse Events ............................................................................... 83 10.2.6. Adverse Events of “Severe” Intensity ............................................................ 85 10.2.7. Laboratory Findings ....................................................................................... 85 10.2.8. Adverse Events of Special Interest ................................................................ 95 10.2.9. Other Safety Evaluation (Vital Signs, Cardiovascular safety) ...................... 100 10.2.10.
Load more

Recommended publications
  • Review Article: Diagnosis, Management and Patient Perspectives of the Spectrum of Constipation Disorders
    Thomas Jefferson University Jefferson Digital Commons Department of Pharmacology and Experimental Department of Pharmacology and Experimental Therapeutics Faculty Papers Therapeutics 6-1-2021 Review article: diagnosis, management and patient perspectives of the spectrum of constipation disorders. Amol Sharma Satish S C Rao Kimberly Kearns Kimberly D Orleck Scott A Waldman Follow this and additional works at: https://jdc.jefferson.edu/petfp Part of the Gastroenterology Commons Let us know how access to this document benefits ouy This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Pharmacology and Experimental Therapeutics Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Received: 8 December 2020 | First decision: 24 December 2020 | Accepted: 31 March 2021 DOI: 10.1111/apt.16369 Review article: diagnosis, management and patient perspectives of the spectrum of constipation disorders Amol Sharma1 | Satish S. C. Rao1 | Kimberly Kearns2 | Kimberly D. Orleck3 | Scott A. Waldman4 1Division of Gastroenterology/Hepatology, Medical College of Georgia, Augusta Summary University, Augusta, GA, USA Background: Chronic constipation is a common, heterogeneous disorder with multi- 2 DuPage Medical Group, Hoffman Estates, ple symptoms and pathophysiological mechanisms.
    [Show full text]
  • Pinoresinol Reductase 1 Impacts Lignin Distribution During Secondary Cell Wall Biosynthesis in Arabidopsis
    Phytochemistry xxx (2014) xxx–xxx Contents lists available at ScienceDirect Phytochemistry journal homepage: www.elsevier.com/locate/phytochem Pinoresinol reductase 1 impacts lignin distribution during secondary cell wall biosynthesis in Arabidopsis Qiao Zhao a, Yining Zeng b,e, Yanbin Yin c, Yunqiao Pu d,e, Lisa A. Jackson a,e, Nancy L. Engle e,f, Madhavi Z. Martin e,f, Timothy J. Tschaplinski e,f, Shi-You Ding b,e, Arthur J. Ragauskas d,e, ⇑ Richard A. Dixon a,e,g, a Plant Biology Division, Samuel Roberts Noble Foundation, 2510 Sam Noble Parkway, Ardmore, OK 73401, USA b Biosciences Center, National Renewable Energy Laboratory, Golden, CO 80401, USA c Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, USA d Institute of Paper Science and Technology, Georgia Institute of Technology, Atlanta, GA, USA e BioEnergy Science Center (BESC), Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA f Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA g Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA article info abstract Article history: Pinoresinol reductase (PrR) catalyzes the conversion of the lignan (À)-pinoresinol to (À)-lariciresinol in Available online xxxx Arabidopsis thaliana, where it is encoded by two genes, PrR1 and PrR2, that appear to act redundantly. PrR1 is highly expressed in lignified inflorescence stem tissue, whereas PrR2 expression is barely detect- Keywords: able in stems. Co-expression analysis has indicated that PrR1 is co-expressed with many characterized Lignan genes involved in secondary cell wall biosynthesis, whereas PrR2 expression clusters with a different Lignin set of genes.
    [Show full text]
  • Nutraceuticals Brian Lockwood
    CjigVXZji^XVah HZXdcYZY^i^dc 7g^VcAdX`lddY 00 Prelim 2/3/07 18:51 Page i Nutraceuticals 00 Prelim 2/3/07 18:51 Page ii 00 Prelim 2/3/07 18:51 Page iii Nutraceuticals A guide for healthcare professionals Second edition Brian Lockwood BPharm, PhD, MRPharmS Senior Lecturer in Pharmacy, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK London • Chicago 00 Prelim 2/3/07 18:51 Page iv Published by the Pharmaceutical Press An imprint of RPS Publishing 1 Lambeth High Street, London SE1 7JN, UK 100 South Atkinson Road, Suite 200, Grayslake, IL 60030–7820, USA © Pharmaceutical Press 2007 is a trade mark of RPS Publishing RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain First edition published 2002 Second edition published 2007 Typeset by Type Study, Scarborough, North Yorkshire Printed in Great Britain by TJ International, Padstow, Cornwall ISBN 978 0 85369 659 9 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made. The right of Brian Lockwood to be identified as the author of this work has been asserted by him in accordance with sections 77 and 78 and subject to section 79(6) of the Copyright, Designs and Patents Act, 1988.
    [Show full text]
  • Chronic Constipation: Update on Management
    REVIEW CME LEARNING OBJECTIVE: Readers will differentiate the types of chronic constipation and apply traditional CREDIT and newer treatments to best advantage UMAR HAYAT, MD MOHANNAD DUGUM, MD SAMITA GARG, MD Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Department of Gastroenterology and Hepatol- Medicine Institute, Cleveland Clinic Nutrition, Department of Medicine, University of ogy, Digestive Disease Institute, Cleveland Clinic; Pittsburgh, PA Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH Chronic constipation: Update on management ABSTRACT hronic constipation has a variety of pos- C sible causes and mechanisms. Although Managing chronic constipation involves identifying and traditional conservative treatments are still treating secondary causes, instituting lifestyle changes, valid and first-line, if these fail, clinicians can prescribing pharmacologic and nonpharmacologic thera- choose from a growing list of new treatments, pies, and, occasionally, referring for surgery. Several new tailored to the cause in the individual patient. drugs have been approved, and others are in the pipeline. This article discusses how defecation works (or doesn’t), the types of chronic constipation, KEY POINTS the available diagnostic tools, and traditional Although newer drugs are available, lifestyle modifica- and newer treatments, including some still in tions and laxatives continue to be the treatments of development. choice for chronic constipation, as they have high re- ■ THE EPIDEMIOLOGY OF CONSTIPATION sponse rates and few adverse effects and are relatively affordable. Chronic constipation is one of the most com- mon gastrointestinal disorders, affecting about 15% of all adults and 30% of those over the Chronic constipation requires different management age of 60.1 It can be a primary disorder or sec- approaches depending on whether colonic transit time ondary to other factors.
    [Show full text]
  • Medicinal Properties of Selected Asparagus Species: a Review Polo-Ma-Abiele Hildah Mfengwana and Samson Sitheni Mashele
    Chapter Medicinal Properties of Selected Asparagus Species: A Review Polo-Ma-Abiele Hildah Mfengwana and Samson Sitheni Mashele Abstract Asparagus species are naturally distributed along Asia, Africa, and Europe and are known to have numerous biological properties. This review article was aimed to provide an organized summary of current studies on the traditional uses, phy- tochemistry, and pharmacological and toxicological studies of Asparagus laricinus Burch., Asparagus africanus Lam., Asparagus officinalis L., Asparagus racemosus Willd., and Asparagus densiflorus (Kunth) Jessop to attain and establish new insights for further researches. Information used in this review was obtained from electronic database including PubMed central, Google scholars, Science direct, Scopus, and Sabinet. Based on the present findings, the existing literature still presents some breaches about the mechanism of action of various constituents of these plants, and their relation to other plant compounds in poly-herbal formulations, as well as their long-term use and safety. More in-depth studies are still needed for active compounds and biological activities of Asparagus laricinus, Asparagus africanus, and Asparagus densiflorus. Therefore, innumerable opportunities and possibilities for investigation are still available in novel areas of these plants for future research stud¬ies. It can be concluded that all selected Asparagus species have tremendous potential to improve human health and the pharmacological activities of these plants can be attributed to bioactive phytochemicals they possess. Keywords: Asparagaceae, Asparagus africanus lam., Asparagus densiflorus (kunth) Jessop, Asparagus laricinus Burch., Asparagus officinalis L., Asparagus racemosus Willd., pharmacological actions, phytochemistry 1. Introduction Historically, plants were used for numerous purposes for mankind in general, inter alia, feeding and catering, culinary spices, medicine, various forms of cosmetics, symbols in worship and for a variety of ornamental goods.
    [Show full text]
  • Anticancer Activity of Lignan from the Aerial Parts of Saussurea Salicifolia (L.) DC
    Vol. 27, 2009, Special Issue Czech J. Food Sci. Anticancer Activity of Lignan from the Aerial Parts of Saussurea salicifolia (L.) DC. G. CHUNSRiiMYATAV1, 2*, I. HOZA1, P. VALÁšEK1, S. SKROVANKOVÁ1, D. BANZRAgcH2 and N. TsEVEgsUREN3 1Department of Food Engineering, Tomas Bata University in Zlin, 760 01 Zlín, Czech Republic; 2 Institute of Chemistry and Chemical Technology, Mongolian Academy Sciences, Ulaanbaatar, MON 51 Mongolia; 3Department of Organic Chemistry, Faculty of Chemistry, National University of Mongolia, Ulaanbaatar, Mongolia, *E-mail: [email protected] Abstract: Aerial parts of Saussurea salicifolia (L.) DC were studied for their lignan and flavonoids in solvent chloroform and n-butanol of ethanolic extract. Isolation and identification of phenolic compounds of the chloroform and n-butanol fractions were performed with Dionex HPLC-DAD system with water-methanol gradients in 4 different wave lengths (235 nm, 254 nm, 280 nm and 340 nm), using online UV and LC-MS as described previously. 9-OH-pinoresinol which is a lignan with anticancer activity was dominated in the chloroform fraction, whereas mainly flavonoid glycosides like quercetin-3-O-galactoside, apigenin-7-O-rhamnoside with anti-inflammatory effect were detected in the n-butanol fraction. Additionally, 9-OH-pinoresinol was also found in the n-butanol fraction. Anticancer tests were conducted in leukemia mouse lymphoma cells L5178Y at a concentration of 10 μg/ml of test compound. Crude ethanol extract of S. salicifolia reduced the growth of leukemia mouse lymphoma cells L5178Y to 23.8%. Keywords: flavonoids; Saussurea salicifolia; anticancer activity; Dionex HPLC-DAD system INTRODUCTION several species of Saussurea by other scientists in the world have revealed the presence of interest- Saussurea salicifolia is a medicinal plant belong- ing bioactive compounds like flavonoids (Jiang ing to genus of Saussurea of Asteraceae family.
    [Show full text]
  • Relative Efficacy of Tegaserod in a Systematic Review and Network Meta-Analysis of Licensed Therapies for Irritable Bowel Syndrome with Constipation
    This is a repository copy of Relative Efficacy of Tegaserod in a Systematic Review and Network Meta-analysis of Licensed Therapies for Irritable Bowel Syndrome with Constipation.. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/149160/ Version: Accepted Version Article: Black, CJ, Burr, NE orcid.org/0000-0003-1988-2982 and Ford, AC orcid.org/0000-0001-6371-4359 (2020) Relative Efficacy of Tegaserod in a Systematic Review and Network Meta-analysis of Licensed Therapies for Irritable Bowel Syndrome with Constipation. Clinical Gastroenterology and Hepatology, 18 (5). 1238-1239.E1. ISSN 1542-3565 https://doi.org/10.1016/j.cgh.2019.07.007 © 2019 by the AGA Institute. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/). Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Black et al. Page 1 of 9 Accepted for publication 3rd July 2019 TITLE PAGE Title: Relative Efficacy of Tegaserod in a Systematic Review and Network Meta- analysis of Licensed Therapies for Irritable Bowel Syndrome with Constipation.
    [Show full text]
  • A Cytotoxic C-Glycosylated Derivative of Apigenin from the Leaves Of
    Revista Brasileira de Farmacognosia 26 (2016) 763–766 ww w.elsevier.com/locate/bjp Short communication A cytotoxic C-glycosylated derivative of apigenin from the leaves of Ocimum basilicum var. thyrsiflorum a,b,∗ c,d Mohamed I.S. Abdelhady , Amira Abdel Motaal a Pharmacognosy Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt b Pharmacognosy Department, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia c Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt d Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo, Egypt a b s t r a c t a r t i c l e i n f o Article history: The standardized 80% ethanolic extract of the leaves of Ocimum basilicum var. thyrsiflorum (L.) Benth., Received 12 February 2016 Lamiaceae, growing in KSA, exhibited a significant antioxidant activity compared to the ethyl acetate and Accepted 7 June 2016 butanol extracts, which was correlated to its higher phenolic and flavonoid contents. Chromatographic Available online 20 July 2016 separation of the 80% ethanol extract resulted in the isolation of ten known compounds; cinnamic acid, gallic acid, methylgallate, ellagic acid, methyl ellagic acid, apigenin, luteolin, vitexin, isovitexin, and 3 -O- Keywords: acetylvitexin. Compound 3 -O-acetylvitexin, a C-glycosylated derivative of apigenin, was isolated for the Ocimum basilicum first time from genus Ocimum. The 80% ethanolic extract and 3 -O-acetylvitexin showed significant cyto- HCT116 toxic activities against the HCT human colon cancer cell line [IC values 22.3 ± 1.1 and 16.8 ± 2.0 ␮g/ml Cytotoxic 116 50 ␮ Antioxidant (35.4 M), respectively].
    [Show full text]
  • Efficacy and Safety of Intestinal Secretagogues for Chronic Constipation: a Systematic Review and Meta-Analysis
    AG-2017-127 AHEADORIGINAL OF ARTICLEPRINT dx.doi.org/10.1590/S0004-2803.201800000-41 Efficacy and safety of intestinal secretagogues for chronic constipation: a systematic review and meta-analysis Juan Sebastian LASA, María Josefina ALTAMIRANO, Luis Florez BRACHO, Silvina PAZ and Ignacio ZUBIAURRE Received 23/12/2017 Accepted 19/2/2018 ABSTRACT – Background – Intestinal secretagogues have been tested for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome. The class-effect of these type of drugs has not been studied. Objective – To determine the efficacy and safety of intestinal secretagogues for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome. Methods – A computer-based search of papers from 1966 to September 2017 was performed. Search strategy consisted of the following MESH terms: intestinal secretagogues OR linaclotide OR lubiprostone OR plecanatide OR tenapanor OR chloride channel AND chronic constipation OR irritable bowel syndrome. Data were extracted as intention-to-treat analyses. A random-effects model was used to give a more conservative estimate of the effect of individual therapies, allowing for any heterogeneity among studies. Outcome measures were described as Relative Risk of achieving an improvement in the symptom under consideration. Results – Database Search yielded 520 bibliographic citations: 16 trials were included for analysis, which enrolled 7658 patients. Twelve trials assessed the efficacy of intestinal secretagogues for chronic constipation. These were better than placebo at achieving an increase in the number of complete spontaneous bowel movements per week [RR 1.87 (1.24-2.83)], at achieving three or more spontaneous bowel movements per week [RR 1.56 (1.31- 1.85)] and at inducing spontaneous bowel movement after medication intake [RR 1.49 (1.07-2.06)].
    [Show full text]
  • Influence of the Nuclear Hormone Receptor Axis in the Progression and Treatment of Hormone Dependent Cancers
    Influence of the nuclear hormone receptor axis in the progression and treatment of hormone dependent cancers A dissertation submitted to the Division of Research and Advanced Studies at the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctorate of Philosophy (Ph.D.) In the Department of Cell and Cancer Biology of the College of Medicine 2007 by Janet K. Hess-Wilson B.A., Wittenberg University, 2000 Committee Chair: Karen E. Knudsen, Ph.D. Abstract Due to its pivotal role in prostatic growth and survival, the androgen receptor (AR) is the primary target of disseminated prostate cancer (CaP), as achieved via androgen deprivation therapy (ADT). Unfortunately, ADT is circumvented by restoration of AR activity, resulting in ADT resistant tumors for which there is no alternate treatment option. Through multiple mechanisms, reactivation of the AR specifically underlies the progression to therapy resistant tumors. The environmentally prevalent endocrine disrupting compound (EDC), bisphenol A (BPA) is able to activate specific somatically mutated ARs commonly found in CaP, resulting in androgen-independent proliferation of CaP cells. To directly assess the effect of BPA on ADT, we used an in vivo xenograft model of CaP that expresses a BPA-sensitive mutant AR, and mimics standard human cytotoxic response to ADT, followed by subsequent tumor re-growth. When tumor- bearing animals were exposed to environmentally relevant levels of BPA during ADT, the tumors failed therapy more rapidly (compared to placebo controls), with AR re- activation and concomitant increased tumor cell proliferation. These data suggest that environmentally relevant exposure to EDCs may reduce the efficacy of mainline ADT for CaP.
    [Show full text]
  • The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins
    toxins Review Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins Chia-Ter Chao 1,2,3 and Shih-Hua Lin 4,* 1 Nephrology Division, Department of Medicine, National Taiwan University Hospital BeiHu Branch, Taipei 10845, Taiwan; [email protected] 2 Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 100233, Taiwan 3 Nephrology Division, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan 4 Department of Internal Medicine, Tri-Service General Hospital and National Defense Medical Center, Taipei 11490, Taiwan * Correspondence: [email protected] Received: 30 October 2020; Accepted: 11 December 2020; Published: 21 December 2020 Abstract: Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment
    [Show full text]
  • Ibsrela (Tenapanor)
    Federal Employee Program® 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.50.26 Section: Prescription Drugs Effective Date: July 1, 2020 Subsection: Gastrointestinal Agents Original Policy Date: October 11, 2019 Subject: Ibsrela Page: 1 of 5 Last Review Date: June 18, 2020 Ibsrela Description Ibsrela (tenapanor) Background Ibsrela (tenapanor) is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for the absorption of dietary sodium. By inhibiting NHE3 on the apical surface of the enterocytes, Ibsrela reduces absorption of sodium from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in softer stool consistency (1). Regulatory Status FDA-approved indication: Ibsrela is a sodium/hydrogen exchanger 3 (NHE3) inhibitor indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in adults (1). Ibsrela has a boxed warning regarding the risk of serious dehydration in pediatric patients. Ibsrela is contraindicated in patients less than 6 years of age. Use should be avoided in patients 6 years to less than 12 years of age. The safety and effectiveness of Ibsrela have not been established in pediatric patients less than 18 years of age (1). Ibsrela is also contraindicated in patients with known or suspected mechanical gastrointestinal obstruction (1). The safety and effectiveness
    [Show full text]