DOCSLIB.ORG

Coronary Effect of Fibrates on Proteins and Enzymes Which Hydrolyze Triacylglycerols

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Coronary Effect of Fibrates on Proteins and Enzymes Which Hydrolyze Triacylglycerols Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 3 pp. 579ñ588, 2016 ISSN 0001-6837 Polish Pharmaceutical Society CORONARY EFFECT OF FIBRATES ON PROTEINS AND ENZYMES WHICH HYDROLYZE TRIACYLGLYCEROLS RENATA FRANCIK 1,2*, JADWIGA KRYCZYK 3 and S£AWOMIR FRANCIK 4 1 Department of Bioorganic Chemistry, 2 Department of Food Chemistry and Nutrition, Jagiellonian University, Medical College, Faculty of Pharmacy, 9 Medyczna St., 30-688 KrakÛw, Poland 2 Institute of Health, State Higher Vocational School, 1 Staszica St., 33-300 Nowy Sπcz, Poland 3 Jagiellonian University Medical College, Department of Food Chemistry and Nutrition, 9 Medyczna St., 30-688 KrakÛw, Poland 4 Department of Mechanical Engineering and Agrophysics, University of Agriculture in Krakow, Faculty of Production Engineering and Energetics, 116 B Balicka St., 30-149, KrakÛw, Poland Abstract: Clofibric acid derivatives called fibrates, are quite commonly used lipid-lowering drugs, so it is nec- essary to know beneficial and adverse effects of these compounds on the body. The European Medicines Agencyís Committee for Medicinal Products for Human Use (CHMP) has concluded that benefits of four fibrates such as: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil continue outweigh their risk in treatment of people with blood lipid disorders. According to recommendations of the CHMP fibrates should not be used as first-line drugs, except in patients with severe hypertriglyceridemia and patients who cannot use statins. In this paper, we focused on effect of clofibric acid derivatives on lipid metabolism, in particular on apo proteins and regulatory enzymes. Keywords: clofibric acid derivatives, apo proteins, regulatory enzymes, lipid metabolism Abbreviations: BF ñ bezafibrate, CE ñ cholesterol esters, CF ñ ciprofibrate, FC ñ free cholesterol, FF ñ fenofi- brate, GF ñ gemfibrozil, HDL ñ high density lipoproteins, HL ñ hepatic lipase (EC 3.1.1.3), IDL ñ intermedi- ate density lipoproteins, KF ñ clofibrate, LCAT ñ lecithin-cholesterol acyltransferase (EC2.3.1.43), LDL ñ low density lipoproteins, LDLR ñ low-density lipoprotein receptor, LPL ñ lipoprotein lipase (EC3.1.1.34), LRP ñ LDL receptor-related protein, PL ñ phospholipids, PPAR ñ peroxisome proliferator activated receptor, RAP ñ receptor-associated protein, SR-B1 ñ scavenger receptor class B, SREBP 1c ñ sterol regulatory element bind- ing protein 1c, VLDL ñ very low density lipoproteins Among many compounds that affect change in fatty acids taken with food. TG constitute lipid concentration of TG (triglycerides) in plasma are material in white adipose tissue (90% of lipid con- selected clofibric acid derivatives. These com- tent) as well as reserve and energy materials. pounds modify concentration of structural and enzy- In humans, there are lipoprotein fractions such matic proteins both in plasma, cytoplasm, and other as chylomicrons, very low density lipoprotein organelles, such as mitochondria or peroxisomes. (VLDL), low density lipoprotein (LDL) and high- Elevated concentrations of TG in plasma entails density lipoprotein (HDL). TG- rich are VLDL and serious health consequences as a development of chylomicrons. TG hydrolysis occurs with simultane- atherosclerosis, and therefore coronary heart disease ous degradation of these fractions and is prerequisite and ischemic heart disease. In contrast, clofibric for proper lipid metabolism because it provides fatty acid derivatives are among very few therapeutic acids to all tissues and organs. This process depends agents lowering TG levels by affecting structural on activities of many proteins including apolipopro- and regulatory proteins of lipoprotein fraction as teins (apo). In conditions when amount of TG frac- well as enzymatic and receptor proteins. tions in plasma is increased, are used lipid-lowering TG are esters of glycerol and higher fatty acids. drugs. In the body, TG are formed in liver, intestine and in adipose tissue. Then, triglycerides are bound in Fibrates as clofibric acid derivatives lipoprotein fractions, which move to plasma. In the Clofibric acid derivatives called fibrates, are body, as a TG are transported most of the long chain quite commonly used lipid-lowering drugs, so it is * Corresponding author: e-mail: [email protected]; phone: +48126205507, fax: +48126205405 579 580 RENATA FRANCIK et al. necessary to know adverse effects of these com- in patients with severe hypertriglyceridemia and pounds on the body. The European Medicines patients who cannot use statins. Agencyís Committee for Medicinal Products for Clofibric acid derivatives impact on hepato- Human Use (CHMP) has concluded that benefits of cytes in different organelles, especially in nucleus, four fibrates such as: bezafibrate, ciprofibrate, mitochondrions and peroxisomes (Fig. 1). Most fenofibrate and gemfibrozil continue outweigh their studies relating to the effect of clofibric acid deriva- risk in treatment of people with blood lipid disor- tives were performed in order to determine their ders. According to recommendations of the CHMP, impact on the activity of peroxisomal enzymes (1- fibrates should not be used as first-line drugs, except 3). For example, in studies conducted on rats it was Figure 1. Half structural formulas of clofibric acid, clofibrate, and fenofibrate, bezafibrate, ciprofibrate, simfibrate and gemfibrozil (accord- ing to the IUPAC systematic name). Coronary effect of fibrates on proteins and enzymes which hydrolyze triacylglycerols 581 Table 1. Pharmacokinetics and metabolism of selected clofibric acid derivatives. Degree of Half-life Fibrates Excretion protein binding [%] [h] Fenofibrate > 99 19ñ27* 100% renal as glucuronides form Clofibrate 96 18ñ22** 100% renal as metabolized form Bezafibrate 95 1.5ñ3.0*** 100% renal as unchanged form Gemfibrozil 98 1.1ñ3,7**** 100% renal as metabolized and glucuronides form Ciprofibrate 99 70ñ81***** 100% renal as glucuronides form * The values are based on the publications: *(11, 13), **(12, 13), ***(13), ****(13, 58, 59), *****(60). demonstrated that clofibric acid derivatives cause results in improved absorption compared to a stan- significant hypertrophy of peroxisome in liver tissue dard substance. It increases about 30% bioavailabili- (4, 5). In turn, in humans, it is assumed that peroxi- ty of drug. Fibrates are very well absorbed into blood some hypertrophy under the influence of clofibrate from gastrointestinal tract. In blood, about 95% of occurs only to a limited extent (6). Clofibrate in fibrates are bound to plasma albumin. BF, CF and patients increases amount of liver mitochondrions GF reach maximum concentration after 2 h while FF (7). In consequence, it leads to increase of acetyl- after 4-6 h. The metabolism of these compounds CoA which is involved in Krebs cycle. takes place in the liver whereas they are excreted in 60-90% by kidney. Biological half-life of FF is equal Structure and mechanism of effects of clofibric to 22 h; BF - 2 h; CF - 18 h and GF - 1.1 h (Table 1). acid derivatives Fenofibrate is well absorbed after oral admin- Clofibrate (KF) was the first one to be used in istration, with peak plasma levels attained in 6 to 8 the early sixties (1967, in the U.S.) but then, due to hours. It is insoluble in aqueous media suitable for numerous side effects, it was withdrawn from use injection. It creates a metabolite - fenofibric acid, (8). Successively, fenofibrate (FF), bezafibrate (BF), which has a half life of about 20 hours (11). ciprofibrate (CF) and gemfibrozil (GF) were put on Bezafibrate in serum half life of a single 20 mg/kg the market in the seventies. Fibrates are halogen oral dose in monkeys was 2-3 hours. This is compa- derivatives and contain chlorine atom (excluding rable to t1/2 in man. Tissue distribution studies in ani- gemfibrozil). Their chemical structure refers to short mals found the highest bezafibrate concentration in chain fatty acids. In molecules of KF, FF and BF the liver and intestine 8 hours after oral dosing. one of substituents is chlorine connected by covalent Serum protein binding ranges from 88.4 to 93.5% bond to aromatic ring. It affects biological function after 0.5 to 8 hours, respectively. Male and female of clofibric acid derivatives. Replacement of chlo- beagle dogs receiving oral bezafibrate at 30 mg/kg rine atom in the molecule of clofibirc acid with had t1/2 = 3 and 2.7 hours (12, 13). extensive substituent such as 4-chlorobenzoyl in Half-life CF in normal volunteers averages case of FF, or 2-(4-chlorobenzamide)-ethyl in case 18 to 22 hours (range 14 to 35 hours) but can vary of BF increased lipophilicity of these compounds (9, by up to 7 hours in the same subject at different 10). times (13). Drugs with pharmacological properties similar Fibrates have been used in treatment of to FF and BF are: CF - (2-[4-(2,2-dichlorocyclo- endogenous hypertriglyceridemia, mixed hyperlipi- propyl)-phenoxy]-2-methylpropanoic acid) and sim- demia, chylomicronemia syndrome, hypercholes- fibrate - (2-(4-chlorophenoxy)-2-methylpropanoic terolemia or polymetabolic syndrome which acid 1,3-propanediyl ester). Gemfibrozil - 5-(2,5- includes hyperinsulinemia, diabetes type II, hyper- dimethylphenoxy)-2,2-dimethyl-pentanoic acid) is tension and obesity. These disorders occur with another drug belonging to clofibric acid derivatives. coronary heart disease, ischemic heart disease, or This compound is ω-hydroxyvaleric acid derivative diabetes type II (11, 12). Clofibric acid derivatives connected by ester bond with dimethylphenyl group are well tolerated drugs
Load more

Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn Et Al
    US 2004O224012A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn et al. (43) Pub. Date: Nov. 11, 2004 (54) TOPICAL APPLICATION AND METHODS Related U.S. Application Data FOR ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME MACRO-BEADS (63) Continuation-in-part of application No. 10/264,205, filed on Oct. 3, 2002. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); (60) Provisional application No. 60/327,643, filed on Oct. Tanusin Ploysangam, Bangkok (TH); 5, 2001. Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok Publication Classification (TH); Nardo Zaias, Miami Beach, FL (US) (51) Int. CI.7. A61K 9/127; A61K 9/14 (52) U.S. Cl. ............................................ 424/450; 424/489 Correspondence Address: (57) ABSTRACT Eric G. Masamori 6520 Ridgewood Drive A topical application and methods for administration of Castro Valley, CA 94.552 (US) active agents encapsulated within non-permeable macro beads to enable a wider range of delivery vehicles, to provide longer product shelf-life, to allow multiple active (21) Appl. No.: 10/864,149 agents within the composition, to allow the controlled use of the active agents, to provide protected and designable release features and to provide visual inspection for damage (22) Filed: Jun. 9, 2004 and inconsistency. US 2004/0224012 A1 Nov. 11, 2004 TOPCAL APPLICATION AND METHODS FOR 0006 Various limitations on the shelf-life and use of ADMINISTRATION OF ACTIVE AGENTS USING liposome compounds exist due to the relatively fragile LPOSOME MACRO-BEADS nature of liposomes. Major problems encountered during liposome drug Storage in vesicular Suspension are the chemi CROSS REFERENCE TO OTHER cal alterations of the lipoSome compounds, Such as phos APPLICATIONS pholipids, cholesterols, ceramides, leading to potentially toxic degradation of the products, leakage of the drug from 0001) This application claims the benefit of U.S.
    [Show full text]
  • Title Page Alcohol Use, Vascular Disease and Lipid-Lowering Drugs
    JPET Fast Forward. Published on April 20, 2006 as DOI: 10.1124/jpet.106.102269 JPET ThisFast article Forward. has not been Published copyedited andon formatted.April 20, The 2006 final versionas DOI:10.1124/jpet.106.102269 may differ from this version. JPET #102269 PiP Title page Alcohol use, Vascular Disease and Lipid-Lowering Drugs Genovefa D. Kolovou Klelia D. Salpea Downloaded from Katherine K. Anagnostopoulou Dimitri P. Mikhailidis jpet.aspetjournals.org (G.D.K., K.D.S., K.K.A.): 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, at ASPET Journals on September 24, 2021 Greece (D.P.M.): Department of Clinical Biochemistry, Vascular Disease Prevention Clinics, Royal Free Hospital, Royal Free and University College Medical School, London, UK 1 Copyright 2006 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on April 20, 2006 as DOI: 10.1124/jpet.106.102269 This article has not been copyedited and formatted. The final version may differ from this version. JPET #102269 PiP Running title page Alcohol and Lipid-Lowering Drugs Corresponding author: Genovefa D. Kolovou, MD, PhD, FESC, SFASA 1st Cardiology Department, Onassis Cardiac Surgery Center 356 Sygrou Ave, 176 74 Athens, Greece Tel: +30 210 9493520, Fax: +30 210 9493336 Downloaded from E-mail: [email protected] Document statistics: Number of text pages: 13 double spaced pages jpet.aspetjournals.org Tables: 0 Figures: 2 References: 67 at ASPET Journals on September 24, 2021 Number of words in the abstract: 136 words Number of words in the introduction: 217 words Number of words in the body article (excluding introduction): 3725 words Abbreviations: Alc: alcohol, CHD: coronary heart disease, HDL: high density lipoprotein, LDL: low density lipoprotein, VLDL: very low density lipoprotein, TG: triglyceride, AST: aspartate aminotransferase, ALT: alanine aminotransferase, NAD: nicotinamide adenine dinucleotide, NADP: nicotinamide adenine dinucleotide phosphate, NA: nicotinic acid.
    [Show full text]
  • Clofibrate Causes an Upregulation of PPAR- Target Genes but Does Not
    tapraid4/zh6-areg/zh6-areg/zh600707/zh65828d07a xppws S� 1 4/20/07 9: 48 MS: R-00603-2006 Ini: 07/rgh/dh A " #h!si$l %egul Integr &$ ' #h!si$l 2%&' R000 (R000) 200!$ 3. Originalarbeiten *irst publis#ed "arc# + 5) 200! doi' + 0$ + + 52,a-pregu$ 0060&$ 2006$ Clofibrate causes an upregulation of PPAR-� target genes but does not alter AQ: 1 expression of SREBP target genes in liver and adipose tissue of pigs Sebastian Luci, Beatrice Giemsa, Holger Kluge, and Klaus Eder Institut fu¨r Agrar- und Erna¨hrungswissenschaften, Martin-Luther-Universita¨t Halle-Wittenberg, Halle (Saale), Ger an! Submitted 25 August 2006 accepted in final form ! "arc# 200! AQ: 2 Luci S, Giemsa B, Kluge H, Eder K. Clofibrate causes an usuall0 increased 3#en baseline concentrations are lo3 1?62$ upregulation of PPAR-� target genes but does not alter expression of Effects of PPAR-� activation #ave been mostl0 studied in SREBP target genes in liver and adipose tissue of pigs$ A " #h!si$l rodents) 3#ic# ex#ibit a strong expression of PPAR-� in liver %egul Integr &$ ' #h!si$l 2%&' R000 (R000) 200!$ *irst publis#ed and s#o3 peroxisome proliferation in t#e liver in response to "arc# + 5) 200! doi' + 0$ + + 52,a-pregu$ 0060&$ 2006$ ./#is stud0 inves- PPAR-� activation 1&62$ Expression of PPAR-� and sensitivit0 tigated t#e effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor 1PPAR2-� and various to peroxisomal induction b0 PPAR-� agonists) #o3ever) var0 genes of t#e lipid metabolism in liver and adipose tissue of pigs$ An greatl0
    [Show full text]
  • Regulation of Pharmaceutical Prices: Evidence from a Reference Price Reform in Denmark
    A Service of Leibniz-Informationszentrum econstor Wirtschaft Leibniz Information Centre Make Your Publications Visible. zbw for Economics Kaiser, Ulrich; Mendez, Susan J.; Rønde, Thomas Working Paper Regulation of pharmaceutical prices: Evidence from a reference price reform in Denmark ZEW Discussion Papers, No. 10-062 Provided in Cooperation with: ZEW - Leibniz Centre for European Economic Research Suggested Citation: Kaiser, Ulrich; Mendez, Susan J.; Rønde, Thomas (2010) : Regulation of pharmaceutical prices: Evidence from a reference price reform in Denmark, ZEW Discussion Papers, No. 10-062, Zentrum für Europäische Wirtschaftsforschung (ZEW), Mannheim This Version is available at: http://hdl.handle.net/10419/41440 Standard-Nutzungsbedingungen: Terms of use: Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Documents in EconStor may be saved and copied for your Zwecken und zum Privatgebrauch gespeichert und kopiert werden. personal and scholarly purposes. Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle You are not to copy documents for public or commercial Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich purposes, to exhibit the documents publicly, to make them machen, vertreiben oder anderweitig nutzen. publicly available on the internet, or to distribute or otherwise use the documents in public. Sofern die Verfasser die Dokumente unter Open-Content-Lizenzen (insbesondere CC-Lizenzen) zur Verfügung gestellt haben sollten, If the documents have been made available under an Open gelten abweichend von diesen Nutzungsbedingungen die in der dort Content Licence (especially Creative Commons Licences), you genannten Lizenz gewährten Nutzungsrechte. may exercise further usage rights as specified in the indicated licence. www.econstor.eu Dis cus si on Paper No. 10-062 Regulation of Pharmaceutical Prices: Evidence from a Reference Price Reform in Denmark Ulrich Kaiser, Susan J.
    [Show full text]
  • Chemoprevention for Hepatocellular Carcinoma: the Role of Statins
    Editorial Chemoprevention for hepatocellular carcinoma: the role of statins Giuseppe Cabibbo, Salvatore Petta, Calogero Cammà Section of Gastroenterology, DIBIMIS, University of Palermo, 90127 Palermo, Italy Corresponding to: Giuseppe Cabibbo, MD, PhD. Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy. Email: [email protected]. Submitted Aug 25 2012. Accepted for publication Sep 27, 2012. doi: 10.3978/j.issn.2304-3881.2012.09.01 Scan to your mobile device or view this article at: http://www.thehbsn.org/article/view/1272 In oncology, cancer prevention may be categorized as a challenging malignancy of global importance. It is the primary, secondary and tertiary. Primary prevention refers sixth most common cancer, and the third cause of cancer- to the identification of genetic, biologic, and environmental related death worldwide. Cirrhosis is the strongest and factors that play an etiologic or pathogenetic role, in order the most common known risk factor for HCC, usually to impair their effects on tumor development and halt due to hepatitis C virus (HCV) and hepatitis B virus progression of cancer and ultimately death. The objective of (HBV) infections. However, different lines of evidence primary prevention is to prohibit or to halt effective contact identify in non-alcoholic fatty liver disease (NAFLD) a of a carcinogenic agent with a susceptible target in the possible relevant risk factor for occurrence of HCC. The human body. Secondary prevention refers to identification of geographic distribution of HCC is highly uneven: three existing pre-neoplastic and early neoplastic lesions in order areas with different incidence rates (low, intermediate, and to treat them thoroughly and expeditiously.
    [Show full text]
  • 2 12/ 35 74Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE).
    [Show full text]
  • Anatomical Classification Guidelines V2020 EPHMRA ANATOMICAL
    EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2020 Anatomical Classification Guidelines V2020 "The Anatomical Classification of Pharmaceutical Products has been developed and maintained by the European Pharmaceutical Marketing Research Association (EphMRA) and is therefore the intellectual property of this Association. EphMRA's Classification Committee prepares the guidelines for this classification system and takes care for new entries, changes and improvements in consultation with the product's manufacturer. The contents of the Anatomical Classification of Pharmaceutical Products remain the copyright to EphMRA. Permission for use need not be sought and no fee is required. We would appreciate, however, the acknowledgement of EphMRA Copyright in publications etc. Users of this classification system should keep in mind that Pharmaceutical markets can be segmented according to numerous criteria." © EphMRA 2020 Anatomical Classification Guidelines V2020 CONTENTS PAGE INTRODUCTION A ALIMENTARY TRACT AND METABOLISM 1 B BLOOD AND BLOOD FORMING ORGANS 28 C CARDIOVASCULAR SYSTEM 35 D DERMATOLOGICALS 50 G GENITO-URINARY SYSTEM AND SEX HORMONES 57 H SYSTEMIC HORMONAL PREPARATIONS (EXCLUDING SEX HORMONES) 65 J GENERAL ANTI-INFECTIVES SYSTEMIC 69 K HOSPITAL SOLUTIONS 84 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 92 M MUSCULO-SKELETAL SYSTEM 102 N NERVOUS SYSTEM 107 P PARASITOLOGY 118 R RESPIRATORY SYSTEM 120 S SENSORY ORGANS 132 T DIAGNOSTIC AGENTS 139 V VARIOUS 141 Anatomical Classification Guidelines V2020 INTRODUCTION The Anatomical Classification was initiated in 1971 by EphMRA. It has been developed jointly by Intellus/PBIRG and EphMRA. It is a subjective method of grouping certain pharmaceutical products and does not represent any particular market, as would be the case with any other classification system.
    [Show full text]
  • Toxicity Review for Di(2-Ethylhexyl) Phthalate (DEHP)
    (including carcinogenicity, neurotoxicity, and reproductive and developmental toxicity) are assessed by the CPSC staff using guidelines issued by the Commission (CPSC, 1992). If it is concluded that a substance is “toxic” due to chronic toxicity, then a quantitative assessment of exposure and risk is performed to evaluate whether the chemical may be considered a “hazardous substance”. This memo represents the first step in the risk assessment process; that is, the hazard identification step. * These comments are those of the CPSC staff, have not been reviewed or approved by, and may not necessarily represent the views of, the Commission. Page 2 of 2 KRC Table of Contents Tables ...................................................................................................................................v Figures............................................................................................................................... vii Appendices ........................................................................................................................ vii Abbreviations ................................................................................................................... viii Executive Summary .............................................................................................................x 1. Introduction ....................................................................................................................1 2. Physico-chemical Characteristics ..................................................................................1
    [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]
  • Association of Cardiovascular Risk with Inhaled Long-Acting Bronchodilators in Patients with Chronic Obstructive Pulmonary Disease: a Nested Case-Control Study
    Supplementary Online Content Wang M-T, Liou J-T, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study. JAMA Intern Med. Published online January 2, 2018. doi: 10.1001/jamainternmed.2017.7720 eMethods 1. Development of a disease risk score-matched nested case-control study eMethods 2. Modeling a nonlinear duration-response association using a restricted cubic splines function model. eMethods 3. A case-crossover study for assessing the association between the CVD risk and use of LABAs and LAMAs eTable 1. Diagnosis codes used to define the comorbidities and individual drugs of comedications eTable 2. Comparison of CVD risk between new LAMA use and new LABA use eTable 3. Risk of each primary cardiovascular outcome with new LABA and LAMA use eTable 4. Case-crossover analysis for the risk of CVDs with use of LABA and LAMA within 30 days eTable 5. Clinical characteristics of CVD patients during the case and control periods in an alternative case-crossover study eTable 6. Numbers needed to harm for patients who had an increased CVD risk from using LABAs and LAMAs in our primary and secondary analyses eFigure 1. Overview for the adopted nested case-control study design. CVD, cardiovascular disease; COPD, chronic obstructive pulmonary disease; ER, emergency room; NHI represents National Health Insurance eFigure 2. Specification of case and control periods in an alternative case-crossover study eFigure 3. The impact of unmeasured confounders assessed by the rule-out method eFigure 4. Study flow diagram outlining the selection of study cohort © 2018 American Medical Association.
    [Show full text]
  • Section B Changed Classes/Guidelines Final Version Date of Issue
    EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2021 Section B Changed Classes/Guidelines Final Version Date of issue: 19th December 2020 1 A2B ANTIULCERANTS r2020 Combinations of specific antiulcerants with other substances, such as anti- infectives against Helicobacter pylori, antispasmodics, gastroprokinetics, that are for ulcers, gastro-oesophageal reflux disease or similar conditions are classified according to the antiulcerant substance. For example, proton pump inhibitors in combination with these anti-infectives are classified in A2B2. Combinations of antiulcerants with non-steroidal anti-inflammatories where the antiulcerant is present for gastric protection are classified in M1A1. A2B1 H2 antagonists R2002 Includes, for example, cimetidine, famotidine, nizatidine, ranitidine, roxatidine. Combinations of low dose H2 antagonists with antacids are classified with antacids in A2A6. A2B2 Proton pump inhibitors r2021 Includes esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. Combinations of proton pump inhibitors with gastroprokinetics for ulcers, gastro- oesophageal disease or similar conditions are classified here. Includes potassium- competitive acid blockers (P-CABs) such as revaprazan, tegoprazan, vonoprazan, etc. A2B3 Prostaglandin antiulcerants Includes misoprostol, enprostil. A2B4 Bismuth antiulcerants Includes combinations with antacids. A2B9 All other antiulcerants r2020 Includes all other products containing substances with antiulcerant action where the type of substance is not specified in classes A2B1 to
    [Show full text]
  • BMC Pharmacology Biomed Central
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central BMC Pharmacology BioMed Central Research article Open Access Clofibrate treatment in pigs: Effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents Sebastian Luci1, Beatrice Giemsa1, Gerd Hause2, Holger Kluge1 and Klaus Eder*1 Address: 1Institut für Agrar- und Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle (Saale), Germany and 2Biozentrum, Martin-Luther-Universität Halle-Wittenberg, Weinbergweg 22, 06120 Halle (Saale), Germany Email: Sebastian Luci - [email protected]; Beatrice Giemsa - [email protected]; Gerd Hause - [email protected]; Holger Kluge - [email protected]; Klaus Eder* - [email protected] halle.de * Corresponding author Published: 16 April 2007 Received: 10 January 2007 Accepted: 16 April 2007 BMC Pharmacology 2007, 7:6 doi:10.1186/1471-2210-7-6 This article is available from: http://www.biomedcentral.com/1471-2210/7/6 © 2007 Luci et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation.
    [Show full text]