DOCSLIB.ORG

Nitrosamines, Many of Which Are Car Cinogens,Are Now Known Not To

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nitrosamines, Many of Which Are Car Cinogens,Are Now Known Not To [Gann, 75, 245-252; March, 1984] FORMATION OF VOLATILE NITROSAMINES BY DRUG-NITRITE INTERACTIONS UNDER PHYSIOLOGICAL CONDITIONS Ayako SAKAI, Takiko INOUE and Akio TANIMURA Division of Food Additives, National Institute of Hygienic Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158 Twenty-eight drugs, most of which are tertiary amines, were tested for the forma tionof volatile nitrosamines by reaction with nitrite under physiological conditions; the drugs (10m•ôNH•ôM•ôNS•ô)were incubated with nitrite (40m•ôNH•ôM•ôNS•ô)at pH 3.0, 37•‹ for 1 and 4hr. The volatile nitrosamines formed were determined by gas chromatography-thermal energy analysis. Of the 28 drugs, 24 formed measurable amounts of volatile nitrosa minesthat are known carcinogens. The yields of nitrosodimethylamine (NDMA) from aminopyrine (55-65%) and minocycline (11%) were higher than that from dimethylamine under the same conditions. This result suggests that there may be a pathway not involving the secondary amine (dimethylamine) as an intermediate in the formation of NDMA from minocycline as well as from aminopyrine, Tolaza midegave rise to nitrosopiperidine (NPIP) in addition to nitrosohexamethylenei mine(NHXI), formation of which was expected from the chemical structure of tol azamide,and the yield of NPIP (2-7%) was higher than that of NHXI (0.2-1.2%). Ascor bicacid (40m•ôNH•ôM•ôNS•ô)was effective in decreasing the formation of nitrosamines from drugs by reaction with nitrite, although the blocking effects varied between 88 and 100% depending on the drugs tested or on the nitrosamines formed. Key words: Formation of nitrosamines-Drug-nitrite interactions-Ascorbic acid-Nitrosopiperidine from tolazamide-Gas chromatography-thermal energy analysis Nitrosamines, many of which are car tainedin many foods,2) as well as being used cinogens,are now known not to occur fre as a food additive. Not only secondary amines quentlyin the environment in significant but also many tertiary amines are potential quantities, contrary to initial expectations.2, precursors of nitrosamines,10,20) and such 3,15) Nevertheless , there are risks that man compounds are widely distributed in the may be exposed to nitrosamines, since in environment. gestedamines can interact with nitrite in Drugs have also been discussed as possible vivo to form nitrosamines.14,19) Nitrite is a precursors of nitrosamines,16,18) and some usual constituent of saliva,6,12) and is con drugs containing tertiary amino groups were found to give rise to carcinogenic volatile * Abbreviations used: NDMA nitrosamines by reaction with nitrite under , nitrosodimethyl amine;NDEA, nitrosodiethylamine; NDPA, ni the mildly acid conditions of the mamma trosodipropylamine;NHPI, nitrosoheptamethyl lianstomach.8,9) However, ease of forma eneimine;NHXI, nitrosohexamethyleneimine; tionof nitrosamines from such drugs varies NMP, N-nitroso-N'-methylpiperazine; NPIP, ni trosopiperidine;NPYR, nitrosopyrrolidine; GC quite widely. Aminopyrine reacts with nitrite very easily to form NDMA* in high yield, - TEA, gas chromatography-thermal energy anal ysis;GC-MS, gas chromatography-mass spec but chlorpromazine gives only a very low trometry. yield of NDMA.8) 75(3) 1984 245 A. SAKAI, ET AL. Fig. 1. Structures of the drugs used 246 Gann NITROSAMINES FROM DRUGS AND NITRITE In the present study, volatile nitrosamines Pure drugs were gifts from the manufacturers formed from the reaction of nitrite with 28 and were of the same grades as used for commercial drugs (Fig. 1), mainly tertiary amines, were drug formulations. NMP and NHXI were synthesized from N- determined by using a gas chromatograph methylpiperazine and hexamethyleneimine, re equipped with a thermal energy analyzer, spectively,according to the procedure of Lijinsky which is a sensitive and specific detector of and Reuber.11) The other nitrosamines used were nitrosamines.5) The drugs examined were purchased from Wako Pure Chemical Ind., Ltd., selected because they are commonly admin Osaka (NDMA, NDEA), Tokyo Chemical Ind. Co., Ltd., Tokyo (NDPA, NHPI), Aldrich Chem isteredby the oral route and represent a wide icalCo., Inc., Milwaukee (NPYR) and Sigma variety of chemical structures. Aminopyrine Chemical Co., St. Louis (NPIP). was selected as a reference compound known Reaction of Drugs with Nitrite Reactions of to form a volatile nitrosamine by reaction drugs with nitrite in vitro were carried out under the conditions recommended by the WHO Study with nitrite (its oral administration has been Group on the Potential Carcinogenicity of Nitro prohibited).8,12) satableDrugs (12-16 June 1978, in Geneva)22): Nitrosation of amines can be inhibited NaNO2 dissolved in 0.5M CH3COONa-HCl buffer solution (pH3.0) was added to a solution by ascorbate, which competes with amines or suspension (pH3.0) of a pure drug or formula for nitrite,1) and Mirvish et al.12,13)have re tion,and the mixture was immediately readjusted commendedsimultaneous administration of to pH3.0 with diluted HCl, if necessary. The final ascorbate with nitrosatable drugs. Thus, the concentrations of NaNO2 and drugs were 40mM and 10mM, respectively. The reaction mixture inhibitory effect of ascorbic acid was exam was incubated at 37•‹ for 1 and 4hr. inedon the formation of nitrosamines from The effect of ascorbic acid was examined by the test drugs. adding ascorbic acid to the solution or suspension of a pure drug before the addition of NaNO2. MATERIALSAND METHODS The final concentration of ascorbic acid was 40mM, and the incubation time was 4hr. Chemicals Formulations of the drugs tested Commercial formulations (tablets, dragees, werepurchased at retail outlets in the Tokyo area. capsules or powder) were used for nitrosation re Each formulation contained only the intended actionsafter being ground in a mortar without drug and additivesand did not contain other me removing any additives, and the drug contents dicinallyactive components. The contents of claimed by the manufacturers were adopted in drugsin the formulations, according to the manu the preparation of reaction solutions. facturers,are as follows (the weight of one tablet, Determination of Volatile Nitrosamines At dragee or capsule is given in parentheses): chlor the end of the allotted time the reaction was ter promazinehydrochloride, 25mg/dragee (222 minatedby the addition of a large excess of am mg); oxytetracycline hydrochloride, 250mg/ moniumsulfamate to remove nitrite, and the re capsule (526mg); diphenyldimethylaminoethane actionmixture was extracted 3 times with an hydrochloride,25mg/dragee (490mg); erythro equal volume of CH2Cl2. When the extraction of mycin,200mg/dragee(708mg); acetylspiramycin, NMP was intended, the reaction mixture was 200mg/dragee (463mg); metformin hydrochlo neutralized with NaHCO3 prior to the extraction ride,250mg/tablet (352mg); thioproperazine procedure. The CH2Cl2 extract was rinsed with dimethanesulfonate,7.15mg/dragee (120mg); a small volume of 1% NaHCO3 solution, dried etamsylate,500mg/1g of powder; procainamide over anhydrous Na2SO4, and concentrated to 10 hydrochloride, 125mg/tablet (203mg); proglu ml in a rotary evaporator under reduced pres mide,200mg/tablet (250mg); probenecid, 250 sure.Nitrosamines in the concentrates were deter mg/tablet (388mg); clemizole hydrochloride, minedby GC-TEA. Identification of the nitrosa 20mg/dragee (188mg); glyclopyramide, 250 mineformed was based on the retention time in a mg/tablet (329mg); triprolidine hydrochloride, GC-TEA chromatogram. Recoveries of nitrosa 10mg/1g of powder; piromidic acid, 250mg/ mineswere 83 to 90%. The values presented in tablet (300mg); dipyridamole, 25mg/dragee (120 tables are not corrected for the recoveries. mg); thiethylperazinedimaleate, 10.276mg/dragee Chromatography (179mg); perlapine, 25mg/tablet (132mg); a) GC-TEA: Gas chromatograph; Shimadzu tolazamide,250mg/tablet (369mg); guanethidine GC-6AM. Column; 1.5m•~3mm glass, 10% sulfate,100mg/1g of powder. Carbowax 20M on 60/80 mesh Gaschrom P. 75(3) 1984 247 A. SAKAI, ET AL. Column temperature; 110•‹ for NDMA and NDEA, or 170•‹ for other nitrosamines. Injection port tem RESULTS perature;160 or 190•‹. Carrier gas; argon, 60 The yields of volatile nitrosamines ob ml/min. Thermal energy analyzer; Thermo Elec tronCorp., TEA-502. Furnace temperature; 400•‹. tainedby the reaction of drugs with nitrite Cold trap; liquid N2-CH2Cl2. Reaction chamber are shown in Table I. The yields were based pressure; 1mmHg. on the concentration of drugs. b) GC-MS: Gas chromatograph; Hewlett- Volatile nitrosamines were formed from Packard 5710A. Column; 25m•~0.3mm capil larycolumn, SE-54, 0.17ƒÊm film. Column tem all of the drugs incubated with nitrite except perature;programmed at the rate of 30•‹/min from diphenhydramine, procainamide, probenecid 70 to 170•‹. Injection port temperature; 200•‹. and piromidic acid. The yields of NDMA Carrier gas; helium, 25cm/sec. Mass spectrome from aminopyrine (55-65%), NDMA from ter;Hewlett-Packard 5985B. Ionization source; minocycline (11%) and NPIP from tolaza electron impact. Source temperature; 200•‹. Elec tronvoltage; 70 eV. mide(2-7%) by reaction with nitrite were Table I. Yields of Volatile Nitrosamines from Drugs and Nitritea) a) The concentrations of drugs and nitrite were 10 and 40mM, respectively. Reaction mixtures were incubated at 37•‹, pH3.0 for 1 and 4hr. b) Percentage with respect to the concentration of drugs (10mM) c) Not detected, <0.001%. 248 Gann NITROSAMINES FROM DRUGS AND NITRITE high under the mild conditions used for the NDMA or other nitroso compounds as con present experiment,
Load more

Recommended publications
  • (Trulicity) Pen and the Semaglutide (Ozempic) Pen
    Protocol H9X-MC-B021(b) Crossover Study Comparing Dulaglutide (Trulicity) Pen and the Semaglutide (Ozempic) Pen NCT03724981 Approval Date: 30-Nov-2018 H9X-MC-B021(b) Clinical Protocol Page 1 Protocol H9X-MC-B021(b): Crossover Study Comparing the Dulaglutide (Trulicity) Pen and the Semaglutide (Ozempic) Pen Confidential Information The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical investigation of dulaglutide (LY2189265), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries. Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. Dulaglutide (LY2189265) Eli Lilly and Company Indianapolis, Indiana USA 46285 Protocol Electronically Signed and Approved by Lilly on 07 Aug 2018 Amendment (a) Electronically Signed and Approved by Lilly on 11 Sep 2018 Amendment (b) Electronically Signed and Approved by Lilly on date below Approval Date: 30-Nov-2018 GMT LY2189265 H9X-MC-B021(b) Clinical Protocol Page 2 Table of Contents Section Page Protocol H9X-MC-B021(b): Crossover Study Comparing the Dulaglutide (Trulicity) Pen and the Semaglutide (Ozempic) Pen ............................................................1 Table of Contents........................................................................................................................2 1.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 De Juan Et Al
    US 200601 10428A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 de Juan et al. (43) Pub. Date: May 25, 2006 (54) METHODS AND DEVICES FOR THE Publication Classification TREATMENT OF OCULAR CONDITIONS (51) Int. Cl. (76) Inventors: Eugene de Juan, LaCanada, CA (US); A6F 2/00 (2006.01) Signe E. Varner, Los Angeles, CA (52) U.S. Cl. .............................................................. 424/427 (US); Laurie R. Lawin, New Brighton, MN (US) (57) ABSTRACT Correspondence Address: Featured is a method for instilling one or more bioactive SCOTT PRIBNOW agents into ocular tissue within an eye of a patient for the Kagan Binder, PLLC treatment of an ocular condition, the method comprising Suite 200 concurrently using at least two of the following bioactive 221 Main Street North agent delivery methods (A)-(C): Stillwater, MN 55082 (US) (A) implanting a Sustained release delivery device com (21) Appl. No.: 11/175,850 prising one or more bioactive agents in a posterior region of the eye so that it delivers the one or more (22) Filed: Jul. 5, 2005 bioactive agents into the vitreous humor of the eye; (B) instilling (e.g., injecting or implanting) one or more Related U.S. Application Data bioactive agents Subretinally; and (60) Provisional application No. 60/585,236, filed on Jul. (C) instilling (e.g., injecting or delivering by ocular ion 2, 2004. Provisional application No. 60/669,701, filed tophoresis) one or more bioactive agents into the Vit on Apr. 8, 2005. reous humor of the eye. Patent Application Publication May 25, 2006 Sheet 1 of 22 US 2006/0110428A1 R 2 2 C.6 Fig.
    [Show full text]
  • Sulfonylurea Review
    Human Journals Review Article February 2018 Vol.:11, Issue:3 © All rights are reserved by Farah Yousef et al. Sulfonylurea Review Keywords: Type II diabetes, Sulfonylurea, Glimipiride, Glybu- ride, Structure Activity Relationship. ABSTRACT Farah Yousef*1, Oussama Mansour2, Jehad Herbali3 Diabetes Mellitus is a chronic disease represented with high 1 Ph.D. candidate in pharmaceutical sciences, Damas- glucose blood levels. Although sulfonylurea compounds are the cus University, Damascus, Syria. second preferred drug to treat Type II Diabetes (TYIID), they are still the most used agents due to their lower cost and as a 2 Assistant Professor in pharmaceutical chimestry, Ti- mono-dosing. Literature divides these compounds according to st nd rd shreen University, Lattakia, Syria their discovery into 1 , 2 , 3 generations. However, only six sulfonylurea compounds are now available for use in the United 3 Assistant Professor in pharmaceutical chimestry, Da- States: Chlorpropamide, Glimepiride, Glipizide, Glyburide, mascus University, Damascus, Syria. Tolazamide, and Tolbutamide. They function by increasing Submission: 24 January 2018 insulin secretion from pancreatic beta cells. Their main active site is ATP sensitive potassium ion channels; Kir 6.2\SUR1; Accepted: 29 January 2018 Published: 28 February 2018 Potassium Inward Rectifier ion channel 6.2\ Sulfonylurea re- ceptor 1. They are sulfonamide derivatives. However, research- ers have declared that sulfonylurea moiety is not the only one responsible for this group efficacy. It has been known that sud- den and acute hypoglycemia incidences and weight gain are the www.ijppr.humanjournals.com two most common adverse effects TYIID the patient might face during treatment with sulfonylurea agents. This review indi- cates the historical development of sulfonylurea and the differ- ences among this group members.
    [Show full text]
  • Us 2017 / 0239276 A1
    US 20170239276A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0239276 A1 MUTLU et al. ( 43 ) Pub . Date: Aug . 24 , 2017 ( 54 ) PHARMACEUTICAL COMBINATIONS OF ( 30 ) Foreign Application Priority Data SITAGLIPTIN Sep. 5 , 2014 ( TR ) .. .. .. .. .. 2014 / 10448 (71 ) Applicant : SANOVEL ILAC SANAYI VE TICARET ANONIM SIRKETI, Publication Classification ISTANBUL ( TR ) (51 ) Int. Cl. ( 72 ) Inventors : ONUR MUTLU , ISTANBUL ( TR ) ; A61K 31/ 64 (2006 .01 ) ALI TÜRKYILMAZ , ISTANBUL A61K 9 / 20 ( 2006 . 01 ) ( TR ) ; GÜLAY YELKEN , ISTANBUL A61K 9 / 28 ( 2006 . 01 ) ( TR ); MEHTAP SAYDAM , A61K 31/ 4985 ( 2006 . 01 ) ISTANBUL ( TR ) (52 ) U . S . CI. CPC .. .. .. A61K 31 /64 ( 2013 .01 ) ; A61K 31 /4985 ( 21 ) Appl. No. : (2013 .01 ) ; A61K 9 / 2027 ( 2013 .01 ) ; A61K 15 / 507, 946 9 /2054 ( 2013 .01 ) ; A61K 9 / 28 (2013 .01 ) ( 22 ) PCT Filed : Sep . 4 , 2015 (57 ) ABSTRACT (86 ) PCT NONo . : PCT /EP2015 /070251 A pharmaceutical combination comprising sitagliptin or a $ 371 ( c ) ( 1 ) , pharmaceutically acceptable salt thereof in combination ( 2 ) Date : Mar. 1 , 2017 with a sulfonylurea . US 2017 /0239276 A1 Aug . 24 , 2017 PHARMACEUTICAL COMBINATIONS OF 4 - ( 2 , 4 , 5 - trifluorophenyl) butan - 1 - one or (2R ) - 4 - oxo - 4 - [ 3 SITAGLIPTIN ( trifluoromethyl) - 5 ,6 - dihydro [ 1, 2 , 4 ] triazolo [ 4 , 3 - a ]pyrazin FIELD OF INVENTION 7 (8H )- yl )- 1 - ( 2 ,4 ,5 -trifluorophenyl ) butan - 2 - amine) and its [0001 ] The present invention relates to a pharmaceutical chemical structure is shown in the Formula I . combination comprising sitagliptin or a pharmaceutically [0004 ] Sitagliptin is licensed in the US and EU under the acceptable salt thereof in combination with a sulfonylurea name of JANUVIA in the strength of 100 mg, 50 mg, and 25 and at least one pharmaceutically acceptable excipient.
    [Show full text]
  • Multidrug Treatment with Nelfinavir and Cepharanthine Against COVID-19
    Supplemental Information Multidrug treatment with nelfinavir and cepharanthine against COVID-19 Hirofumi Ohashi1,2,¶, Koichi Watashi1,2,3,4*, Wakana Saso1,5.6,¶, Kaho Shionoya1,2, Shoya Iwanami7, Takatsugu Hirokawa8,9,10, Tsuyoshi Shirai11, Shigehiko Kanaya12, Yusuke Ito7, Kwang Su Kim7, Kazane Nishioka1,2, Shuji Ando13, Keisuke Ejima14, Yoshiki Koizumi15, Tomohiro Tanaka16, Shin Aoki16,17, Kouji Kuramochi2, Tadaki Suzuki18, Katsumi Maenaka19, Tetsuro Matano5,6, Masamichi Muramatsu1, Masayuki Saijo13, Kazuyuki Aihara20, Shingo Iwami4,7,21,22,23, Makoto Takeda24, Jane A. McKeating25, Takaji Wakita1 1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan, 2Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan, 3Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan, 4MIRAI, JST, Saitama 332-0012, Japan, 5The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, 6AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan, 7Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan, 8Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan, 9Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan, 10Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan, 11Faculty of Bioscience, Nagahama Institute
    [Show full text]
  • The Use of Sequential Pattern Mining to Predict Next Prescribed Medications ⇑ Aileen P
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Journal of Biomedical Informatics 53 (2015) 73–80 Contents lists available at ScienceDirect Journal of Biomedical Informatics journal homepage: www.elsevier.com/locate/yjbin The use of sequential pattern mining to predict next prescribed medications ⇑ Aileen P. Wright a, , Adam T. Wright b, Allison B. McCoy c, Dean F. Sittig d a Yale School of Medicine, New Haven, CT, United States b Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States c Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States d The University of Texas School of Biomedical Informatics at Houston and the UT-Memorial Hermann Center for Healthcare Quality & Safety, Houston, TX, United States article info abstract Article history: Background: Therapy for certain medical conditions occurs in a stepwise fashion, where one medication Received 13 March 2014 is recommended as initial therapy and other medications follow. Sequential pattern mining is a data Accepted 8 September 2014 mining technique used to identify patterns of ordered events. Available online 16 September 2014 Objective: To determine whether sequential pattern mining is effective for identifying temporal relation- ships between medications and accurately predicting the next medication likely to be prescribed for a Keywords: patient. Sequential pattern mining Design: We obtained claims data from Blue Cross Blue Shield of Texas for patients prescribed at least one Data mining diabetes medication between 2008 and 2011, and divided these into a training set (90% of patients) and Knowledge base Clinical decision support test set (10% of patients).
    [Show full text]
  • Oral Anti-Diabetic Agents-Review and Updates
    British Journal of Medicine & Medical Research 5(2): 134-159, 2015, Article no.BJMMR.2015.016 ISSN: 2231-0614 SCIENCEDOMAIN international www.sciencedomain.org Oral Anti-Diabetic Agents-Review and Updates Patience O. Osadebe1, Estella U. Odoh2 and Philip F. Uzor1* 1Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria. 2Department of Pharmacognosy and Environmental Medicine, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria. Authors’ contributions Author POO designed the study, participated in the literature search. Author EUO participated in designing the work and in searching the literature. Author PFU participated in designing the work, searched the literature and wrote the first draft of the manuscript. All authors read and approved the final manuscript. Article Information DOI:10.9734/BJMMR/2015/8764 Editor(s): (1) Mohamed Essa, Department of Food Science and Nutrition, Sultan Qaboos University, Oman. (2) Franciszek Burdan, Experimental Teratology Unit, Human Anatomy Department, Medical University of Lublin, Poland and Radiology Department, St. John’s Cancer Center, Poland. Reviewers: (1) Anonymous, Bushehr University of Medical, Iran. (2) Anonymous, Tehran University of Medical Sciences, Iran. (3) Anonymous, King Fahad Armed Forces Hospital, Saudi Arabia. (4) Awadhesh Kumar Sharma, Mlb Medical College, Jhansi, UP, India. Peer review History: http://www.sciencedomain.org/review-history.php?iid=661&id=12&aid=5985 Received 30th December 2013 Review Article Accepted 13th March 2014 Published 8th September 2014 ABSTRACT Diabetes is a chronic metabolic disorder with high mortality rate and with defects in multiple biological systems. Two major types of diabetes are recognized, type 1 and 2 with type 2 diabetes (T2D) being by far the more prevalent type.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • Appendix 1. Websites for Patients the NHS Scotland Interactive Website
    Appendix 1. Websites for patients The NHS Scotland interactive website This well-constructed website has a wealth of resources for patients. For example, under their heading “My lifestyle”-there are three areas, where patients can read information, watch videos, or interact actively online. Go to this link: http://www.mydiabetesmyway.scot.nhs.uk/ The Diabetes UK site is also well-reviewed and has large sections on prediabetes and “know your risk “score tools. Go to this link: https://www.diabetes.org.uk/ 25 Published November 2016 Appendix 2a. Medications and their mechanism of action Metformin decreases hepatic glucose production and may improve peripheral glucose disposal while suppressing appetite and promoting weight reduction. Metformin should be taken with or immediately after a meal. It should be introduced in low dose, with gradual escalation (e.g. 500 mg once daily for one week, 500 mg twice daily in week two, 500 mg thrice daily in week three, and 1 g twice daily in week four). Some individuals may not tolerate higher doses, in which case dose reduction is appropriate. Nausea, diarrhoea, and abdominal pain are the most common adverse effects. People should be informed that these side effects often improve after a few days of continued therapy, or with a small dose reduction. A modified release preparation (metformin MR) is also available suitable for once daily dosing; some individuals otherwise intolerant of metformin may find this more acceptable, or may in some cases be able to take higher doses. Metformin should usually be discontinued during a severe illness (e.g. myocardial infarction, pneumonia, severe infection and/or dehydration) as it may aggravate tissue hypoxia and accumulate when renal function is impaired.
    [Show full text]
  • Pharmaceutical Compositions
    (19) TZZ Z_9A T (11) EP 2 601 949 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 12.06.2013 Bulletin 2013/24 A61K 31/382 (2006.01) A61K 31/155 (2006.01) A61K 31/4439 (2006.01) A61K 31/64 (2006.01) (2006.01) (2006.01) (21) Application number: 13157571.4 A61K 45/00 A61P 3/10 A61P 5/50 (2006.01) A61P 9/10 (2006.01) (2006.01) (2006.01) (22) Date of filing: 16.04.2010 A61P 9/14 A61P 13/12 A61P 25/00 (2006.01) A61P 27/02 (2006.01) A61P 43/00 (2006.01) C07D 335/02 (2006.01) (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Takahashi, Teisuke HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Tokyo, 170-8633 (JP) PT RO SE SI SK SM TR • Uchida, Saeko Designated Extension States: Tokyo, 170-8633 (JP) AL BA ME RS (74) Representative: HOFFMANN EITLE (30) Priority: 16.04.2009 JP 2009100210 Patent- und Rechtsanwälte Arabellastrasse 4 (62) Document number(s) of the earlier application(s) in 81925 München (DE) accordance with Art. 76 EPC: 10764570.7 / 2 419 097 Remarks: This application was filed on 04-03-2013 as a (71) Applicant: Taisho Pharmaceutical Co., Ltd. divisional application to the application mentioned Tokyo 170-8633 (JP) under INID code 62. (54) Pharmaceutical compositions (57) A pharmaceutical composition comprising a GLP-1 mimetics, has superior efficacy in preventing or combination of (A) (1S)-1,5-anhydro-1-[5-(4-ethoxyben- treating diabetes mellitus, diseases associated with dia- zyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol and betes mellitus, or complications of diabetes mellitus and (B) at least one member of the group consisting of insulin yet it causes no appreciable side effects.
    [Show full text]
  • Drug Formulations Using Water Soluble Antioxidants
    (19) TZZ __ _T (11) EP 2 611 442 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/403 (2006.01) A61K 31/155 (2006.01) 04.07.2018 Bulletin 2018/27 A61K 9/32 (2006.01) A61K 9/36 (2006.01) A61K 9/34 (2006.01) A61K 47/12 (2006.01) (2006.01) (2006.01) (21) Application number: 11758019.1 A61K 9/20 A61K 9/28 A61K 47/02 (2006.01) A61K 47/10 (2017.01) A61K 47/14 (2017.01) A61K 45/06 (2006.01) (22) Date of filing: 01.09.2011 A61K 9/24 (2006.01) A61K 31/4985 (2006.01) A61K 31/70 (2006.01) (86) International application number: PCT/US2011/050212 (87) International publication number: WO 2012/031124 (08.03.2012 Gazette 2012/10) (54) DRUG FORMULATIONS USING WATER SOLUBLE ANTIOXIDANTS WIRKSTOFFFORMULIERUNGEN MIT WASERLÖSLICHEN ANTIOXIDANZIEN FORMULATIONS DE MÉDICAMENT AU MOYEN D’ANTIOXYDANTS HYDROSOLUBLES (84) Designated Contracting States: • DESAI, Divyakant, S. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB New Brunswick, NJ 08903 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Reitstötter Kinzebach Patentanwälte (30) Priority: 03.09.2010 US 379970 P Sternwartstrasse 4 81679 München (DE) (43) Date of publication of application: 10.07.2013 Bulletin 2013/28 (56) References cited: WO-A1-02/102376 WO-A1-2009/099734 (73) Proprietors: WO-A1-2009/111200 US-A1- 2010 074 950 • Bristol-Myers Squibb Company Princeton, NJ 08543 (US) • MIKHAL’CHUK V.M., KRYUK T.V., PETRENKO • AstraZeneca UK Limited L.V., NELEPOVA O.A., NIKOLAEVSKII A.N.: London W1K 1LN (GB) "Antioxidative Stabilization of Polyethylene Glycol in Aqueous Solutions with Herb Phenols", (72) Inventors: RUSSIAN JOURNAL OF APPLIED CHEMISTRY, • NARANG, Ajit vol.
    [Show full text]