Glucuronidation of Nicotine and Cotinine by UGT2B10: Loss of Function by the UGT2B10 Codon 67 (Asp>Tyr) Polymorphism
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CASODEX (Bicalutamide)
HIGHLIGHTS OF PRESCRIBING INFORMATION • Gynecomastia and breast pain have been reported during treatment with These highlights do not include all the information needed to use CASODEX 150 mg when used as a single agent. (5.3) CASODEX® safely and effectively. See full prescribing information for • CASODEX is used in combination with an LHRH agonist. LHRH CASODEX. agonists have been shown to cause a reduction in glucose tolerance in CASODEX® (bicalutamide) tablet, for oral use males. Consideration should be given to monitoring blood glucose in Initial U.S. Approval: 1995 patients receiving CASODEX in combination with LHRH agonists. (5.4) -------------------------- RECENT MAJOR CHANGES -------------------------- • Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate Warnings and Precautions (5.2) 10/2017 for clinical progression if PSA increases. (5.5) --------------------------- INDICATIONS AND USAGE -------------------------- ------------------------------ ADVERSE REACTIONS ----------------------------- • CASODEX 50 mg is an androgen receptor inhibitor indicated for use in Adverse reactions that occurred in more than 10% of patients receiving combination therapy with a luteinizing hormone-releasing hormone CASODEX plus an LHRH-A were: hot flashes, pain (including general, back, (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral the prostate. (1) edema, dyspnea, diarrhea, hematuria, nocturia, and anemia. (6.1) • CASODEX 150 mg daily is not approved for use alone or with other treatments. (1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca Pharmaceuticals LP at 1-800-236-9933 or FDA at 1-800-FDA-1088 or ---------------------- DOSAGE AND ADMINISTRATION ---------------------- www.fda.gov/medwatch The recommended dose for CASODEX therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening). -
An Unexpected Target for Androgen Deprivation Therapy with Prognosis and Diagnostic Implications
Author Manuscript Published OnlineFirst on October 11, 2013; DOI: 10.1158/0008-5472.CAN-13-1462 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Androgen glucuronidation: an unexpected target for androgen deprivation therapy with prognosis and diagnostic implications. Laurent Grosse1, Sophie Pâquet1, Patrick Caron1, Ladan Fazli2, Paul S. Rennie2, Alain Bélanger3 and Olivier Barbier1 1Laboratory of Molecular Pharmacology, CHU-Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, Canada 2 Vancouver Prostate Centre at VGH, University of British Columbia, Vancouver, British Columbia, Canada. 3CHU-Québec Research Centre and Faculty of Medicine, Laval University, Québec, Canada Running title: Ablation therapy improves androgen glucuronidation in PCa Keywords: Prostate cancer, androgen ablation therapy, glucuronidation, biomarker, drug target. Financial support: This study was supported by grants from the Canadian Institutes of Health Research (CIHR), the Terry Fox foundation and the Canadian Foundation for Innovation. S. Pâquet is holder of scholarships from CIHR and the Fonds pour la Recherche en Santé du Québec (FRSQ). L. Grosse is supported by a scholarship from the Fonds pour l’Enseignement et la Recherche (FER) from the Faculty of Pharmacy, Laval University (Québec). O. Barbier is holder of salary grants from the CIHR (New Investigator Award #MSH95330) and FRSQ (Junior 2 Scholarship). Address correspondence to: Olivier Barbier, Ph.D. Laboratory of Molecular Pharmacology CHU-Québec Research Centre 2705, boulevard Laurier Québec (QC) G1V 4G2, Canada Phone: 418 654 2296 Fax: 418 654 2769 Email: [email protected] Conflict of interests: Authors have nothing to disclose. Downloaded from cancerres.aacrjournals.org on September 26, 2021. -
140503 IPF Signatures Supplement Withfigs Thorax
Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network. -
Conjugated Estrogens Sustained Release Tablets) 0.3 Mg, 0.625 Mg, and 1.25 Mg
PRODUCT MONOGRAPH PrPREMARIN® (conjugated estrogens sustained release tablets) 0.3 mg, 0.625 mg, and 1.25 mg ESTROGENIC HORMONES ® Wyeth Canada Date of Revision: Pfizer Canada Inc., Licensee December 1, 2014 17,300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Submission Control No: 177429 PREMARIN (conjugated estrogens sustained release tablets) Page 1 of 46 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ...........................................................................3 INDICATIONS AND CLINICAL USE ................................................................................3 CONTRAINDICATIONS ......................................................................................................4 WARNINGS AND PRECAUTIONS ....................................................................................4 ADVERSE REACTIONS ....................................................................................................14 DRUG INTERACTIONS ....................................................................................................20 DOSAGE AND ADMINISTRATION ................................................................................23 OVERDOSAGE ...................................................................................................................25 ACTION AND CLINICAL PHARMACOLOGY ...............................................................25 STORAGE AND STABILITY ............................................................................................28 -
Molecular Mechanisms Regulating Copper Balance in Human Cells
MOLECULAR MECHANISMS REGULATING COPPER BALANCE IN HUMAN CELLS by Nesrin M. Hasan A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland August 2014 ©2014 Nesrin M. Hasan All Rights Reserved Intended to be blank ii ABSTRACT Precise copper balance is essential for normal growth, differentiation, and function of human cells. Loss of copper homeostasis is associated with heart hypertrophy, liver failure, neuronal de-myelination and other pathologies. The copper-transporting ATPases ATP7A and ATP7B maintain cellular copper homeostasis. In response to copper elevation, they traffic from the trans-Golgi network (TGN) to vesicles where they sequester excess copper for further export. The mechanisms regulating activity and trafficking of ATP7A/7B are not well understood. Our studies focused on determining the role of kinase-mediated phosphorylation in copper induced trafficking of ATP7B, and identifying and characterizing novel regulators of ATP7A. We have shown that Ser- 340/341 region of ATP7B plays an important role in interactions between the N-terminus and the nucleotide-binding domain and that mutations in these residues result in vesicular localization of the protein independent of the intracellular copper levels. We have determined that structural changes that alter the inter-domain interactions initiate exit of ATP7B from the TGN and that the role of copper-induced kinase-mediated hyperphosphorylation might be to maintain an open interface between the domains of ATP7B. In a separate study, seven proteins were identified, which upon knockdown result in increased intracellular copper levels. We performed an initial characterization of the knock-downs and obtained intriguing results indicating that these proteins regulate ATP7A protein levels, post-translational modifications, and copper-dependent trafficking. -
(12) Patent Application Publication (10) Pub. No.: US 2003/0082511 A1 Brown Et Al
US 20030082511A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0082511 A1 Brown et al. (43) Pub. Date: May 1, 2003 (54) IDENTIFICATION OF MODULATORY Publication Classification MOLECULES USING INDUCIBLE PROMOTERS (51) Int. Cl." ............................... C12O 1/00; C12O 1/68 (52) U.S. Cl. ..................................................... 435/4; 435/6 (76) Inventors: Steven J. Brown, San Diego, CA (US); Damien J. Dunnington, San Diego, CA (US); Imran Clark, San Diego, CA (57) ABSTRACT (US) Correspondence Address: Methods for identifying an ion channel modulator, a target David B. Waller & Associates membrane receptor modulator molecule, and other modula 5677 Oberlin Drive tory molecules are disclosed, as well as cells and vectors for Suit 214 use in those methods. A polynucleotide encoding target is San Diego, CA 92121 (US) provided in a cell under control of an inducible promoter, and candidate modulatory molecules are contacted with the (21) Appl. No.: 09/965,201 cell after induction of the promoter to ascertain whether a change in a measurable physiological parameter occurs as a (22) Filed: Sep. 25, 2001 result of the candidate modulatory molecule. Patent Application Publication May 1, 2003 Sheet 1 of 8 US 2003/0082511 A1 KCNC1 cDNA F.G. 1 Patent Application Publication May 1, 2003 Sheet 2 of 8 US 2003/0082511 A1 49 - -9 G C EH H EH N t R M h so as se W M M MP N FIG.2 Patent Application Publication May 1, 2003 Sheet 3 of 8 US 2003/0082511 A1 FG. 3 Patent Application Publication May 1, 2003 Sheet 4 of 8 US 2003/0082511 A1 KCNC1 ITREXCHO KC 150 mM KC 2000000 so 100 mM induced Uninduced Steady state O 100 200 300 400 500 600 700 Time (seconds) FIG. -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in -
Receptor Af®Nity and Potency of Non-Steroidal Antiandrogens: Translation of Preclinical ®Ndings Into Clinical Activity
Prostate Cancer and Prostatic Diseases (1998) 1, 307±314 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 http://www.stockton-press.co.uk/pcan Review Receptor af®nity and potency of non-steroidal antiandrogens: translation of preclinical ®ndings into clinical activity GJCM Kolvenbag1, BJA Furr2 & GRP Blackledge3 1Medical Affairs, Zeneca Pharmaceuticals, Wilmington, DE, USA; 2Therapeutic Research Department, and 3Medical Research Department, Zeneca Pharmaceuticals, Alderley Park, Maccles®eld, Cheshire, UK The non-steroidal antiandrogens ¯utamide (Eulexin1), nilutamide (Anandron1) and bicalutamide (Casodex1) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5a-DHT has higher binding af®nity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an af®nity two to four times higher than 2-hydroxy¯utamide, the active metabolite of ¯utamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhi- bits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than ¯utamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival bene®ts of ¯utamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival bene®ts, including those comparing ¯utamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone. -
Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation
1521-009X/46/2/100–108$25.00 https://doi.org/10.1124/dmd.117.076745 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:100–108, February 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation Michael Z. Liao, Chunying Gao, Brian R. Phillips, Naveen K. Neradugomma, Lyrialle W. Han, Deepak Kumar Bhatt, Bhagwat Prasad, Danny D. Shen, and Qingcheng Mao Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington Received May 5, 2017; accepted November 17, 2017 ABSTRACT Norbuprenorphine (NBUP) is the major active metabolite of bupre- proteomics quantification revealed that hepatic Ugt1a1 and norphine (BUP) that is commonly used to treat opiate addiction Ugt2b1 protein levels in the same amount of total liver membrane ’ ∼ during pregnancy; it possesses 25% of BUP s analgesic activity proteins were significantly increased by 50% in pregnant mice Downloaded from and 10 times BUP’s respiratory depression effect. To optimize versus nonpregnant mice. After scaling to the whole liver with BUP’s dosing regimen during pregnancy with better efficacy and consideration of the increase in liver protein content and liver safety, it is important to understand how pregnancy affects NBUP weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, disposition. In this study, we examined the pharmacokinetics of and Ugt2b35 protein in the whole liver of pregnant mice were NBUP in pregnant and nonpregnant mice by administering the significantly increased ∼2-fold compared with nonpregnant mice. same amount of NBUP through retro-orbital injection. We demon- These data suggest that the increased systemic CL of NBUP in dmd.aspetjournals.org strated that the systemic clearance (CL) of NBUP in pregnant mice pregnant mice is likely caused by an induction of hepatic Ugt increased ∼2.5-fold compared with nonpregnant mice. -
Strand Breaks for P53 Exon 6 and 8 Among Different Time Course of Folate Depletion Or Repletion in the Rectosigmoid Mucosa
SUPPLEMENTAL FIGURE COLON p53 EXONIC STRAND BREAKS DURING FOLATE DEPLETION-REPLETION INTERVENTION Supplemental Figure Legend Strand breaks for p53 exon 6 and 8 among different time course of folate depletion or repletion in the rectosigmoid mucosa. The input of DNA was controlled by GAPDH. The data is shown as ΔCt after normalized to GAPDH. The higher ΔCt the more strand breaks. The P value is shown in the figure. SUPPLEMENT S1 Genes that were significantly UPREGULATED after folate intervention (by unadjusted paired t-test), list is sorted by P value Gene Symbol Nucleotide P VALUE Description OLFM4 NM_006418 0.0000 Homo sapiens differentially expressed in hematopoietic lineages (GW112) mRNA. FMR1NB NM_152578 0.0000 Homo sapiens hypothetical protein FLJ25736 (FLJ25736) mRNA. IFI6 NM_002038 0.0001 Homo sapiens interferon alpha-inducible protein (clone IFI-6-16) (G1P3) transcript variant 1 mRNA. Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 15 GALNTL5 NM_145292 0.0001 (GALNT15) mRNA. STIM2 NM_020860 0.0001 Homo sapiens stromal interaction molecule 2 (STIM2) mRNA. ZNF645 NM_152577 0.0002 Homo sapiens hypothetical protein FLJ25735 (FLJ25735) mRNA. ATP12A NM_001676 0.0002 Homo sapiens ATPase H+/K+ transporting nongastric alpha polypeptide (ATP12A) mRNA. U1SNRNPBP NM_007020 0.0003 Homo sapiens U1-snRNP binding protein homolog (U1SNRNPBP) transcript variant 1 mRNA. RNF125 NM_017831 0.0004 Homo sapiens ring finger protein 125 (RNF125) mRNA. FMNL1 NM_005892 0.0004 Homo sapiens formin-like (FMNL) mRNA. ISG15 NM_005101 0.0005 Homo sapiens interferon alpha-inducible protein (clone IFI-15K) (G1P2) mRNA. SLC6A14 NM_007231 0.0005 Homo sapiens solute carrier family 6 (neurotransmitter transporter) member 14 (SLC6A14) mRNA. -
PHASE II DRUG METABOLIZING ENZYMES Petra Jancovaa*, Pavel Anzenbacherb,Eva Anzenbacherova
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Jun; 154(2):103–116. 103 © P. Jancova, P. Anzenbacher, E. Anzenbacherova PHASE II DRUG METABOLIZING ENZYMES Petra Jancovaa*, Pavel Anzenbacherb, Eva Anzenbacherovaa a Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic b Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc E-mail: [email protected] Received: March 29, 2010; Accepted: April 20, 2010 Key words: Phase II biotransformation/UDP-glucuronosyltransferases/Sulfotransferases, N-acetyltransferases/Glutathione S-transferases/Thiopurine S-methyl transferase/Catechol O-methyl transferase Background. Phase II biotransformation reactions (also ‘conjugation reactions’) generally serve as a detoxifying step in drug metabolism. Phase II drug metabolising enzymes are mainly transferases. This review covers the major phase II enzymes: UDP-glucuronosyltransferases, sulfotransferases, N-acetyltransferases, glutathione S-transferases and methyltransferases (mainly thiopurine S-methyl transferase and catechol O-methyl transferase). The focus is on the presence of various forms, on tissue and cellular distribution, on the respective substrates, on genetic polymorphism and finally on the interspecies differences in these enzymes. Methods and Results. A literature search using the following databases PubMed, Science Direct and EBSCO for the years, 1969–2010. Conclusions. Phase II drug metabolizing enzymes play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologi- cally active compounds. Reduced metabolising capacity of Phase II enzymes can lead to toxic effects of clinically used drugs. Gene polymorphism/ lack of these enzymes may often play a role in several forms of cancer. -
Drug Metabolism and Pharmacokinetics (DMPK)
Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE Received; February 25, 2012 Published online; April 27, 2012 Accepted; April 19, 2012 doi; 10.2133/dmpk.DMPK-12-RG-023 Identification and Characterization of Human UDP-Glucuronosyltransferases Responsible for the In Vitro Glucuronidation of Salvianolic acid A De-en Hana,b, Yi Zhengb, Xijing Chenb, Jiake Heb, Di Zhaob, Shuoye Yangb, Chunfeng Zhanga*,Zhonglin Yanga,* aState Key laboratory of Natural Products and Functions, China Pharmaceutical University, Ministry of Education, Nanjing, P. R. China. bCenter of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. 1 Copyright C 2012 by the Japanese Society for the Study of Xenobiotics (JSSX) Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE Running title:Glucuronidation of salvianolic acid A in Vitro Corresponding Author: Chunfeng Zhang, PhD State Key laboratory of Natural Products and Functions, China Pharmaceutical University 24# Tong Jia Xiang, Nanjing 210009, PR China. E-mail: [email protected] Phone: +86 25 8337 1694 Zhonglin Yang, PhD State Key laboratory of Natural Products and Functions, China Pharmaceutical University 24# Tong Jia Xiang, Nanjing 210009, PR China. E-mail: [email protected] Phone: +86 25 8337 1694 Fax: +86 25 8337 1694 Number of text pages: 23 Number of tables: 2 Number of figures: 6 2 Drug Metabolism and Pharmacokinetics (DMPK) Advance Publication by J-STAGE ABSTRACT: Glucuronidation is an important pathway in the elimination of salvianolic acid A (Sal A), however the mechanism of UDP-glucuronosyltransferases (UGTs) in this process remains to be investigated. In this study, the kinetics s of salvianolic acid A glucuronidation by pooled human liver microsomes (HLMs), pooled human intestinal microsomes (HIMs) and 12 recombinant UGTs isozymes were investigated.