Cross-Reactive Mechanism for the False Elevation of Free Triiodothyronine in the Patients Treated with Diclofenac

Total Page:16

File Type:pdf, Size:1020Kb

Cross-Reactive Mechanism for the False Elevation of Free Triiodothyronine in the Patients Treated with Diclofenac Endocrine Journal 2001, 48 (6), 717-722 NOTE Cross-Reactive Mechanism for the False Elevation of Free Triiodothyronine in the Patients Treated with Diclofenac KEIZO KASONO, HAJIME HIKINO*, SHINJI FUJINO**, NoBUYUKI TAKEMOTO*, TosHIHIRO KAI*, KIYosHI YAMAGUCHI***, FUMio KONISHI* AND MASANOBU KAWAKAMI Department of Endocrinology and Metabolism, Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan *Department of Surgery , Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan **Department of Pathology , Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan ***Department of Neurology , Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan Abstract. We report three cases of patients exhibiting a false elevation of serum free triiodothyronine (FT3) as a result of a cross-reaction with diclofenac. The first case is a 66-yr-old woman with a long history of rheumatoid arthritis (RA). The patient was receiving diclofenac for the treatment of her RA. The patient was subsequently diagnosed as having thyroid papillary adenocarcinoma and received a subtotal thyroidectomy. After the operation, the patient exhibited postoperative hypothyroidism except for a gradual elevation of FT3. The other two patients also exhibited an elevated serum FT3 level after the administration of diclofenac. Serum FT3 levels in these pa- tients decreased to normal or below normal after diclofenac administration was discontinued. In the first case, the elimination of immunoglobulin from the sera using polyethylene glycol precipitation did not reduce the FT3 level. In our hospital, Vitros ECi (enhanced chemiluminescence enzyme immunoassay) system and Vitros FT3 kit were used for FT3 assay. The patient's FT3 levels were normal or below normal when they were measured using other FT3 kits. FT3 was also detected when diclofenac was dissolved in a phosphate buffered saline. Therefore, we concluded that a cross-reaction between FT3 and diclofenac was the mechanism causing the false elevation of FT3 in these pa- tients. Key Words: Triiodothyronine, Thyroid, False elevation, Cross-reaction, Diclofenac (Endocrine Journal 48: 717-722, 2001) CLINICAL tests for evaluating thyroid function in- tion tests [2-6]. Diclofenac is a commonly used clude the measurement of TSH, FT4, FT3, T4 and NSAID that binds to thyroid hormone binding pro- T3. Circulating thyroid hormones are tightly bound teins, leading to the release of FT3 or FT4. There- to several serum proteins, including thyroxine bind- fore, the drug slightly raises free thyroid hormone ing globulin (TBG), thyroxine binding prealbumin levels and reduces total T4 and T3 concentrations [7, (TBPA), and albumin [1]. Nonsteroidal anti- 8]. Autoantibodies against hormones being assayed, inflammatory drugs (NSAIDs) as well as various heterophilic antibodies to immunoglobulins used in other medications, are known to affect thyroid func- the assay kits and rheumatoid factors (RF) may also interfere with the accurate measurement of hormone levels [9-12]. Cross-reactions with administered Received: May 11, 2001 drugs [13] or serum proteins [14J are a common cause Accepted: August 15, 2001 of falsely elevated hormone concentrations. In this Correspondence to: Dr. Keizo KASONO, Department of report, we describe the false elevation of serum FT3 Endocrinology and Metabolism, Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, levels assayed by Vitros FT3 kit in three patients. Japan We concluded that a cross-reaction with diclofenac 718 KASONO et al. was the mechanism for the false elevation of FT3. In thyroglobulin antibodies and anti-microsomal anti- the first case, the false elevation of FT3 concentra- bodies were negative, TSH receptor antibody was tions in the patient's sera was affected by the pa- 1.2% (normal 0-15%), thyroglobulin was 6.6 pg/L tient's thyroid function. In severe hypothyroid (normal 0-30 ag/L), RF was 944 IU/ml, T-Chol was state, the elevation of FT3 was even more remarka- 4.09 mmol/L and ALP was 161 U/L. On the basis ble. An inverse relationship between FT3 level and of this data, we eliminated the diagnosis of autoim- thyroid function was thus observed in the first pa- mune thyroiditis and diagnosed her as postoperative tient. hypothyroidism with falsely evaluated FT3 concen- tration. Since the patient complained of slight general fatigue, we started to prescribe T4 (50 Case Report pg/day) for hypothyroidism, beginning on April 21, 1999. After starting medication, thyroid function Case 1 gradually returned to normal and the general fatigue A 66-year-old woman with a 30-year history of RA disappeared. On January 17, 2000, serum FT4 was was diagnosed as having thyroid papillary adenocar- 22.7 pmol/L, FT3 was 9.39 pmol/L and TSH was cinoma. A subtotal thyroidectomy was performed 4.02 mU/L. on January 27, 1999. Before operation, serum FT4 was 17.6 pmol/L (normal, 10.4-20.3 pmol/L), FT3 Interpretation of the mechanism for the false ele- was 8.45 pmol/L (normal, 4.27-8.12 pmol/L), and vation of FT3 in case 1 TSH was 1.48 mU/L (normal, 0.47-4.71 mU/L). RF was 608 IU/ml (normal, 0-15 IU/ml), total cho- To elucidate the mechanism of the false elevation lesterol (T-chol) was 3.44 mmol/L (normal, 3.29- in serum FT3, we performed several examinations. 5.96 mmol/L) and alkaline phosphatase (ALP) was The patient agreed orally to an additional blood 162 U/L (normal, 89-285 U/L). Although the FT3 sampling for the purpose of this study. level was slightly higher than normal, the TSH was In our hospital, thyroid function including FT3, not suppressed, and she had no signs of thyrotoxi- FT4, T3, T4 and TSH was routinely assayed using cosis. She had previously undergone an operation Vitros Eci (enhanced chemiluminescence enzyme im- for a carcinoma in her left breast in 1997. At the munoassay) system. These kits were purchased from time of thyroidectomy, she was taking the following Ortho-Clinical Diagnostics Inc. (Cardiff, UK). The medications: long-acting diclofenac (75 mg/day), principle of FT3 measurement in Vitros FT3 kit is tamoxifen (20 mg/day), retinol palmitate (30,000 competitive immune reaction using peroxidase- U/day), methotrexate (7.5 mg/week), active form of labelled sheep anti-FT3 polyclonal antibodies. When vitamin D (0.75 pg/day), Vitamin C (600 mg/day), the patient's stocked sera was assayed using the and tocopherol nicotinate (300 mg/day). After sub- Amerlex FT3 RIA kit from the same company or total thyroidectomy, serum FT4 concentration grad- using kits purchased from other companies, the FT3 ually decreased and TSH level increased remarkably concentrations were lower than normal (data not (Table 1). On April 20, 1999, FT4 was 9.27 pmol/L, shown). These results confirmed the diagnosis of FT3 was 12.1 pmol/L, TSH was 75.9 mU/L, anti- postoperative hypothyroidism in the patient. Table 1. Thyroid function of case 1 FALSE ELEVATION OF FREE TRIIODOTHYRONINE 719 Polyethylene glycol (PEG) precipitation was em- new Vitros FT3 kit may solve the disturbance with ployed to remove the immunoglobulin fraction from diclofenac in the assay. The T3 and FT4 concentra- the patient's serum. We used stocked samples col- tions assayed by the Vitros kits were also slightly lected on three different days: January 22, March 19 elevated after the administration of diclofenac. As and April 20, 1999. The FT3 concentrations were previously reported, serum TSH was weakly sup- reassayed using the Vitros FT3 kit before the PEG pressed after diclofenac administration [8, 16]. precipitation and values of 5.84, 6.67 and 7.68 These results suggested that a cross-reaction be- pmol/L were obtained, respectively. A slight reduc- tween FT3 and diclofenac or its metabolites might tion in FT3 levels occurred in the samples that had have caused a false elevation of FT3 level. To been stocked for a long period of time. After the confirm this mechanism, cyclooxigenase-2 (Cox-2), a PEG precipitation, the FT3 values for these three target enzyme of diclofenac, was used to neutralize samples were 5.59, 6.93 and 8.45 pmol/L, respec- the drug. First, two normal volunteers were ad- tively. The levels before and after PEG precipitation ministered by diclofenac (75 mg/day) for 3 days. showed no significant difference. This showed that One-hundred microliters of their sera were added to RF and other immunoglobulins were not involved in frozen tubes containing 10 it of a Cox-2 reaction the mechanism that produced the false elevation of solution containing 300 iM of diethyldithiocarba- FT3 level. mate (Wako, Osaka, Japan), 1.0% trehalose (Wako) To evaluate the effect of diclofenac on thyroid and 1 U of Cox-2 (Alexis Biochemicals, San Diego, function in the patient, the drug was removed from CA). The mixture of serum and Cox-2 was im- the patient's prescription. Diclofenac was replaced mediately used for FT3 assay using the Vitros FT3 with loxioprofen for seven days. The patient was kit. Before Cox-2 treatment, their FT3 concentra- then given one capsule of long-acting diclofenac (37.5 tions assayed by Vitros FT3 kit were 16.2 and 11.4 mg/C) in the morning, and serum samples were taken pmol/L, respectively. After the addition of Cox-2 to before and 1 to 8 hours after the administration. their sera, the FT3 values decreased to 6.98 and 6.34 Table 2 shows the high concentration of FT3 that was pmol/L, respectively. detected by the Vitros FT3 kit after the admin- Finally, we measured the FT3 level in a diclofenac istration of the long-acting diclofenac.
Recommended publications
  • Fatal Hepatitis Associated with Diclofenac
    Gut: first published as 10.1136/gut.27.11.1390 on 1 November 1986. Downloaded from Gut, 1986, 27, 1390-1393 Case reports Fatal hepatitis associated with diclofenac E G BREEN, J McNICHOLL, E COSGROVE, J MCCABE, AND F M STEVENS From the Department of Medicine, Regional Hospital, Galway, Eire SUMMARY Non-steroidal anti-inflammatory agents (NSAIDS) are a well recognised cause of hepatotoxicity. Diclofenac, a relatively new NSAID, was first introduced into the UK in 1979. Five cases of hepatitis have recently been reported, principally in the French literature. -5 We report the first fulminant case of hepatitis in the English literature in a patient taking diclofenac and indomethacin. Diclofenac is a member of the arylalkanoic group of 100 mg per day for five weeks. Ferrous sulphate one NSAIDS (Fig. 1). Three other agents in this group tablet daily was added on 16 May. The patient was have been shown to be significantly hepatotoxic. admitted to hospital on 26 June. A week before this Ibufenac was withdrawn from circulation because of he had felt unwell with anorexia, nausea, abdominal the frequent rise in transaminases,6 7 the use of discomfort, and dark urine. On admission he was benoxaprofen was stopped in Britain after 10 icteric, the liver edge was palpable 4 cm below the patients died with hepatitis8 9 and more recently a costal margin and there were no signs of chronic fatal case of hepatitis due to pirprofen has been liver disease. Ultrasound showed early ascites with reported."' Early reports about diclofenac showed no obstruction of the biliary tract.
    [Show full text]
  • Søgeprotokol for Nationale Kliniske Retningslinjer
    Søgeprotokol for nationale kliniske retningslinjer Projekttitel/aspekt NKR behandling af patienter med lumbal spinalstenose – Søgning efter primærlitteratur Fagkonsulent /projektleder Rikke Rousing / Maria Herlev Ahrenfeldt Søgespecialist Kirsten Birkefoss Senest opdateret 23.12.2016 Fokuserede spørgsmål Bør patienter med lumbal spinalstenose have tilbudt aktiv PICO 1: behandling i form af superviseret træning fremfor vanlig behandling? PICO 2: Bør patienter med lumbal spinalstenose have tilbudt ledmobiliserende behandling frem for vanlig behandling? PICO 3: Bør patienter med lumbal spinalstenose have tilbudt paracetamol frem for ingen smertestillende behandling? PICO 4: Bør patienter med lumbal spinalstenose have tilbudt non steroid antiinflammatorisk medicin (NSAID) frem for ingen smertestillende behandling? PICO 5: Bør patienter med lumbal spinalstenose have tilbudt smertestillende medicin i form af opioider i tillæg til eventuel behandling med svage smertestillende? PICO 6: Bør patienter med lumbal spinalstenose have tilbudt muskelrelaxantia i tillæg til eventuel behandling med svage smertestillende? PICO 7: Bør patienter med lumbaspinalstenose have tilbudt medicin for neuropatiske smerter? PICO 8: Bør patienter med lumbal spinalstenose have tilbudt kirurgisk dekompression i tilfælde af manglende effekt af ikke kirurgisk behandling? PICO 9: Bør patienter med lumbal spinalstenose have tilbudt stivgørende operation med eller uden instrumentering i tillæg til dekompression? PICO 10: Bør patienter opereret for lumbal spinalstenose tilbydes
    [Show full text]
  • Variable in Their Efficacy? a Description of Ion Trapping
    Annals of the Rheumatic Diseases 1993; 52: 241-243 241 HYPOTHESIS Why are non-steroidal anti-inflammatory drugs so variable in their efficacy? A description of ion trapping G A Ellis, D R Blake Hypothesis Non-steroidal anti-inflammatory drugs vary in Our hypothesis is that acidic non-steroidal their aqueous solubility, but most are highly anti-inflammatory drugs (NSAIDs) undergo albumin bound and will be co-distributed with ion trapping in acidotic tissue and that this this protein. Diffusion of an NSAID into the affects not only their gastrotoxicity, which is cell follows Fick's law, as it is dependent on the well known, but also their selectivity for, and concentration gradient across the plasma their efficacy in, inflammatory joint disease. membrane and the lipid/water partition Tissue acidosis may not be a feature of all coefficient of the drug molecule. chronic inflammatory disease states, but it does For weak acids, such as most NSAIDs, the occur in inflammatory joint disease and is effective concentration gradient is that of the highly variable depending on the extent of the non-ionised form, as ionised molecules are not mismatch between synovial perfusion and lipid soluble metabolic demand. This mismatch is influ- HD D- + H+ enced not only by disease activity, but also by Non-ionised Ionised joint movement, which causes transient hypoxic episodes. Interventions, such as rest The position ofthe equilibrium depends on the and drug treatment, would serve to reduce ion intrinsic ionisation constant of the molecule trapping and, therefore, NSAID efficacy (pKa) and on the pH value of the aqueous through their effects on disease activity.
    [Show full text]
  • The Acceleration of Articular Cartilage Degeneration in Osteoarthritis by Nonsteroidal Anti-Inflammatory Drugs Ross A
    WONDER WHY? THE ACCELERATION OF ARTICULAR CARTILAGE DEGENERATION IN OSTEOARTHRITIS WONDER WHY? The Acceleration of Articular Cartilage Degeneration in Osteoarthritis by Nonsteroidal Anti-inflammatory Drugs Ross A. Hauser, MD A B STRA C T introduction over the past forty years is one of the main causes of the rapid rise in the need for hip and knee Nonsteroidal anti-inflammatory drugs (NSAIDs) are replacements, both now and in the future. among the most commonly used drugs in the world for the treatment of osteoarthritis (OA) symptoms, and are While it is admirable for the various consensus and taken by 20-30% of elderly people in developed countries. rheumatology organizations to educate doctors and Because of the potential for significant side effects of the lay public about the necessity to limit NSAID use in these medications on the liver, stomach, gastrointestinal OA, the author recommends that the following warning tract and heart, including death, treatment guidelines label be on each NSAID bottle: advise against their long term use to treat OA. One of the best documented but lesser known long-term side effects The use of this nonsteroidal anti-inflammatory of NSAIDs is their negative impact on articular cartilage. medication has been shown in scientific studies to accelerate the articular cartilage breakdown In the normal joint, there is a balance between the in osteoarthritis. Use of this product poses a continuous process of cartilage matrix degradation and significant risk in accelerating osteoarthritis joint repair. In OA, there is a disruption of the homeostatic breakdown. Anyone using this product for the pain state and the catabolic (breakdown) processes of of osteoarthritis should be under a doctor’s care and chondrocytes.
    [Show full text]
  • United States Patent (19) 11 Patent Number: 5,192,753 Mcgeer Et Al
    USOO5192753A United States Patent (19) 11 Patent Number: 5,192,753 McGeer et al. 45 Date of Patent: Mar. 9, 1993 54 ANTI-RHEUMATOID ARTHRITIC DRUGS mentia: Prevalance and Incidence', In: B. Reisberg (ed) N THE TREATMENT OF DEMENTIA Alzheimer's Disease, The Free Press, 1983, 141-148. 76 Inventors: Patrick L. McGeer, 4727 West 2nd R. Sulkava, J. Wikstrom, A. Aromaa et al., "Prevalence Ave., Vancouver, B. C., Canada, of Severe Dementia in Finland’, Neurology 1985; 35: V6T Cl; Joseph Rogers, 7646 W. 1025-1029. Julie Dr., Glendale, Ariz. 85308; S. Itagaki, P. L. McGeer, H. Akiyama, "Presence of John Sibley, 87 Leddy Crescent, T-cytotoxic Suppressor and Leucocyte Common Anti Saskatoon, Saskatchewan, Canada, gen Positive Cells in Alzheimer's Disease Brain Tissue", S7H 3Y9; Edith McGeer, 4727 West Neuroscience Letters 1988; 91: 259-264. 2nd Ave., Vancouver, B.C., Canada, J. Rogers, J. Luber-Narod, S. D. Styren, and W. H. V6T 1C Civin, "Expression of Immune System-Associated An tigens By Cells of the Human Central Nervous System: (21) Appl. No.: 689,499 Relationship to the Pathology of Alzheimer's Disease" (22 Filed: Apr. 23, 1991 Neurobiology of Aging, 1988, vol. 9. 339-349. 51 Int. Cl. ................... A61K 31/60; A61K 31/615; P. L. McGeer, H. Akiyama, S. Itagaki, and E. G. A61K 31/54; A61K 31/44; A61K 3/425; McGeer, "Immune System Response in Alzheimer's A61K 31/42; A61K 31/415, A61K 31/40; Disease', The Canadian Journal of Neurological Sci A61K 31/38; A61K 31/195; A61K 31/19 ences 1989; 16:56-527.
    [Show full text]
  • Inflammatory Drug
    Abbreviations used: AR(s), adverse hepatotoxicity, 17 reaction(s); ADR(s), adverse drug manufacturers, 9 reaction(s); NSAID(s), non-steroid anti­ amorfazone, trade mark names and inflammatory drug(s) manufacturers, 9 Amuno, generic name and manufacturer, 12 anaemia absorption interactions, drug, 180-1 aplastic, 83 acemetacin, trade mark names and report rate, 33 manufacturers, 8 haemolytic, 84-5 acetyl salicylic acid, see Aspirin in rheumatoid patients, inappropriate action, drug, ~ pharmacoactivity therapy, 250 activation (of drugs), 243-5, 246, 247 anaphylaxis/anaphylactoid reactions, 17, pathway, 244 81 Actol, generic name and manufacturer, 13 Anaprox, generic name and manufacturer, Actosal, generic name and manufacturer, 13 9 angioedema, 6 acyl-coenzyme A formation, 221-2 angiotensin-converting enzyme, 195, 196 adjuvant induced arthritis, ~ inhibitors arthritis function, 195 Af1oxan, generic name and manufacturer, NSAID interactions with, 195-200 14 animal(s) age see also elderly experimentation, ethics of, 267 gastrointestinal susceptibility re­ inter species differences in lated to, 164, 286-8 propionate chiral inversion, use of anti-arthritics correlated 222-3, 223 with, 152 Ansaid, generic name and manufacturer, aged, the, ~ elderly 11 agranulocytosis antacids, 292 incidence, 7, 100-2 passim effect on drug absorption, 180, 181 in Sweden, 66, 67 NSAID interactions with, 185, 193 pyrazolone-induced, 7, 99-104 anthranilic acid, relative safety, 18 analytical epidemiological anti-arthritic drugs, ~ antirheumatic studies, 101-3 drugs
    [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]
  • Novel Composition for Treating Metabolic Syndrome
    (19) & (11) EP 2 494 967 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 05.09.2012 Bulletin 2012/36 A61K 31/155 (2006.01) A61K 31/60 (2006.01) A61K 45/06 (2006.01) A61K 31/4045 (2006.01) (21) Application number: 12170283.1 (22) Date of filing: 16.01.2008 (84) Designated Contracting States: (72) Inventor: Chen, Chien-Hung AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Forest Hills, NY New York 11375 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Coehn, Markus Fish & Richardson P.C. (30) Priority: 16.01.2007 US 885212 P Mies-van-der-Rohe-Strasse 8 80807 München (DE) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 08727718.2 / 2 118 279 This application was filed on 31-05-2012 as a divisional application to the application mentioned (71) Applicant: IPINTL, LLC under INID code 62. Flushing, NY 11354 (US) (54) Novel composition for treating metabolic syndrome (57) The invention relates to a composition that in- kinase (AMPK) activator; a second agent that possesses cludes a first agent selected from the group consisting anti-inflammatory activity; and a third agent that possess- of an oxidative phosphorylation inhibitor, an ionophore, es serotonin activity. and an adenosine 5’-monophosphate-activated Protein EP 2 494 967 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 494 967 A1 2 Description serotonin (e.g., serotonin sulfate, a serotonin creatinine sulfate complex, or serotonin hydrochloride) and a sero- CROSS-REFERENCE TO RELATED APPLICATION tonin re-uptake inhibitor.
    [Show full text]
  • 4-Methyl-2,2-Dioxo-1H-2Λ6,1-Benzothiazine-3-Carboxy Lic Acid
    Article 4-Methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxy lic Acid. Peculiarities of Preparation, Structure, and Biological Properties Igor V. Ukrainets 1, *, Ganna M. Hamza 1, Anna A. Burian 1, Svitlana V. Shishkina 2,3, Natali I. Voloshchuk 4 and Oxana V. Malchenko 4 1 Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska st., 61002 Kharkiv, Ukraine; [email protected] (G.M.H.); [email protected] (A.A.B.) 2 STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Nauki ave., 61001 Kharkiv, Ukraine; [email protected] 3 Department of Inorganic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq., 61077 Kharkiv, Ukraine 4 Department of Pharmacology, N. I. Pirogov Vinnitsa National Medical University, 56 Pirogov st., 21018 Vinnitsa, Ukraine; [email protected] (N.I.V.); [email protected] (O.V.M.) * Correspondence: [email protected]; Tel.: +38-0572-679-185 Received: 27 February 2018; Accepted: 6 March 2018; Published: 8 March 2018 Abstract: In order to determine the regularities of the structure–analgesic activity relationship, the peculiarities of obtaining, the spatial structure, and biological properties of 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid and some of its derivatives have been studied. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffraction analysis, it has been proven that varying the reaction conditions using alkaline hydrolysis of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate makes it possible to successfully synthesize a monohydrate of the target acid, its sodium salt, or 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine.
    [Show full text]
  • 2021 Equine Prohibited Substances List
    2021 Equine Prohibited Substances List . Prohibited Substances include any other substance with a similar chemical structure or similar biological effect(s). Prohibited Substances that are identified as Specified Substances in the List below should not in any way be considered less important or less dangerous than other Prohibited Substances. Rather, they are simply substances which are more likely to have been ingested by Horses for a purpose other than the enhancement of sport performance, for example, through a contaminated food substance. LISTED AS SUBSTANCE ACTIVITY BANNED 1-androsterone Anabolic BANNED 3β-Hydroxy-5α-androstan-17-one Anabolic BANNED 4-chlorometatandienone Anabolic BANNED 5α-Androst-2-ene-17one Anabolic BANNED 5α-Androstane-3α, 17α-diol Anabolic BANNED 5α-Androstane-3α, 17β-diol Anabolic BANNED 5α-Androstane-3β, 17α-diol Anabolic BANNED 5α-Androstane-3β, 17β-diol Anabolic BANNED 5β-Androstane-3α, 17β-diol Anabolic BANNED 7α-Hydroxy-DHEA Anabolic BANNED 7β-Hydroxy-DHEA Anabolic BANNED 7-Keto-DHEA Anabolic CONTROLLED 17-Alpha-Hydroxy Progesterone Hormone FEMALES BANNED 17-Alpha-Hydroxy Progesterone Anabolic MALES BANNED 19-Norandrosterone Anabolic BANNED 19-Noretiocholanolone Anabolic BANNED 20-Hydroxyecdysone Anabolic BANNED Δ1-Testosterone Anabolic BANNED Acebutolol Beta blocker BANNED Acefylline Bronchodilator BANNED Acemetacin Non-steroidal anti-inflammatory drug BANNED Acenocoumarol Anticoagulant CONTROLLED Acepromazine Sedative BANNED Acetanilid Analgesic/antipyretic CONTROLLED Acetazolamide Carbonic Anhydrase Inhibitor BANNED Acetohexamide Pancreatic stimulant CONTROLLED Acetominophen (Paracetamol) Analgesic BANNED Acetophenazine Antipsychotic BANNED Acetophenetidin (Phenacetin) Analgesic BANNED Acetylmorphine Narcotic BANNED Adinazolam Anxiolytic BANNED Adiphenine Antispasmodic BANNED Adrafinil Stimulant 1 December 2020, Lausanne, Switzerland 2021 Equine Prohibited Substances List . Prohibited Substances include any other substance with a similar chemical structure or similar biological effect(s).
    [Show full text]
  • Marrakesh Agreement Establishing the World Trade Organization
    No. 31874 Multilateral Marrakesh Agreement establishing the World Trade Organ ization (with final act, annexes and protocol). Concluded at Marrakesh on 15 April 1994 Authentic texts: English, French and Spanish. Registered by the Director-General of the World Trade Organization, acting on behalf of the Parties, on 1 June 1995. Multilat ral Accord de Marrakech instituant l©Organisation mondiale du commerce (avec acte final, annexes et protocole). Conclu Marrakech le 15 avril 1994 Textes authentiques : anglais, français et espagnol. Enregistré par le Directeur général de l'Organisation mondiale du com merce, agissant au nom des Parties, le 1er juin 1995. Vol. 1867, 1-31874 4_________United Nations — Treaty Series • Nations Unies — Recueil des Traités 1995 Table of contents Table des matières Indice [Volume 1867] FINAL ACT EMBODYING THE RESULTS OF THE URUGUAY ROUND OF MULTILATERAL TRADE NEGOTIATIONS ACTE FINAL REPRENANT LES RESULTATS DES NEGOCIATIONS COMMERCIALES MULTILATERALES DU CYCLE D©URUGUAY ACTA FINAL EN QUE SE INCORPOR N LOS RESULTADOS DE LA RONDA URUGUAY DE NEGOCIACIONES COMERCIALES MULTILATERALES SIGNATURES - SIGNATURES - FIRMAS MINISTERIAL DECISIONS, DECLARATIONS AND UNDERSTANDING DECISIONS, DECLARATIONS ET MEMORANDUM D©ACCORD MINISTERIELS DECISIONES, DECLARACIONES Y ENTEND MIENTO MINISTERIALES MARRAKESH AGREEMENT ESTABLISHING THE WORLD TRADE ORGANIZATION ACCORD DE MARRAKECH INSTITUANT L©ORGANISATION MONDIALE DU COMMERCE ACUERDO DE MARRAKECH POR EL QUE SE ESTABLECE LA ORGANIZACI N MUND1AL DEL COMERCIO ANNEX 1 ANNEXE 1 ANEXO 1 ANNEX
    [Show full text]
  • 2020 Equine Prohibited Substances List
    2020 Equine Prohibited Substances List . Prohibited Substances include any other substance with a similar chemical structure or similar biological effect(s). Prohibited Substances that are identified as Specified Substances in the List below should not in any way be considered less important or less dangerous than other Prohibited Substances. Rather, they are simply substances which are more likely to have been ingested by Horses for a purpose other than the enhancement of sport performance, for example, through a contaminated food substance. LISTED AS SUBSTANCE ACTIVITY BANNED 1-androsterone Anabolic BANNED 3β-Hydroxy-5α-androstan-17-one Anabolic BANNED 4-chlorometatandienone Anabolic BANNED 5α-Androst-2-ene-17one Anabolic BANNED 5α-Androstane-3α, 17α-diol Anabolic BANNED 5α-Androstane-3α, 17β-diol Anabolic BANNED 5α-Androstane-3β, 17α-diol Anabolic BANNED 5α-Androstane-3β, 17β-diol Anabolic BANNED 5β-Androstane-3α, 17β-diol Anabolic BANNED 7α-Hydroxy-DHEA Anabolic BANNED 7β-Hydroxy-DHEA Anabolic BANNED 7-Keto-DHEA Anabolic CONTROLLED 17-Alpha-Hydroxy Progesterone Hormone FEMALES BANNED 17-Alpha-Hydroxy Progesterone Anabolic MALES BANNED 19-Norandrosterone Anabolic BANNED 19-Noretiocholanolone Anabolic BANNED 20-Hydroxyecdysone Anabolic BANNED Δ1-Testosterone Anabolic BANNED Acebutolol Beta blocker BANNED Acefylline Bronchodilator BANNED Acemetacin Non-steroidal anti-inflammatory drug BANNED Acenocoumarol Anticoagulant CONTROLLED Acepromazine Sedative BANNED Acetanilid Analgesic/antipyretic CONTROLLED Acetazolamide Carbonic Anhydrase Inhibitor BANNED Acetohexamide Pancreatic stimulant CONTROLLED Acetominophen (Paracetamol) Analgesic BANNED Acetophenazine Antipsychotic BANNED Acetophenetidin (Phenacetin) Analgesic BANNED Acetylmorphine Narcotic BANNED Adinazolam Anxiolytic BANNED Adiphenine Antispasmodic BANNED Adrafinil Stimulant 25 November 2019, Lausanne, Switzerland 2020 Equine Prohibited Substances List . Prohibited Substances include any other substance with a similar chemical structure or similar biological effect(s).
    [Show full text]