DOCSLIB.ORG

Reaction of Drugs with Nitrous Acid As a Source of Carcinogenic Nitrosamines1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Reaction of Drugs with Nitrous Acid As a Source of Carcinogenic Nitrosamines1 [CANCER RESEARCH 34, 255-258, Januarv 1974] Brief Communication Reaction of Drugs with Nitrous Acid as a Source of Carcinogenic Nitrosamines1 William Lijinsky Carcinogenesis Program, Biology Division, Oak Ridge National Laboratory. Oak Ridge, Tennessee 37830 SUMMARY tischistosomiasis), cyclizine (for motion sickness), disul- firam (antialcoholic), and methadone (narcotic). Twelve common drugs that are tertiary amines react with nitrite in aqueous solution at ph 3 to 4 to form dialkylni- trosamines that are known carcinogens. Aminopyrine gave MATERIALS AND METHODS dimethylnitrosamine in 30% yield or higher at all concentra tions down to 50 ppm (with 25 ppm nitrite); the other Aminopyrine (dimethylaminoantipyrine) was from Al- product of this reaction was the nitrite salt of 4-hydroxyan- drich Chemical Co. (Milwaukee, Wis.), quinacrine hydro- tipyrine. The other drugs, when present at 0.01 Mwith 0.04 chloride and methapyrilene hydrochloride were from Sigma Mnitrite, formed nitrosamines in yields ranging from 0.03% Chemical Co. (St. Louis, Mo.), and methadone hydrochlo from dextropropoxyphene to 2.4% from lucanthorre in 4 hr ride was from Mallinckrodt Chemical Works (St. Louis, at 37°. Mo.). The remaining compounds were kindly supplied gratis by the manufacturers as follows: chlorpheniramine (Schering Corp., Bloomfield, N. J.), chlorpromazine (Smith, Kline and French, Philadelphia, Pa.), dextro INTRODUCTION propoxyphene (Eli Lilly and Co., Indianapolis, Ind.), lucan thone (Sterling-Winthrop Pharmaceutical Co., Rensselaer, Some preliminary studies of the interaction of tertiary N. Y.), tolazamide (Upjohn Co., Kalamazoo, Mich.), amines with nitrous acid have indicated that formation of disulfiram (Ayerst Laboratories, New York, N. Y.), cycli dialkylnitrosamines by nitrosative dealkylation is a reaction zine (Burroughs-Wellcome, Research Triangle Park, N. usually undergone by tertiary amines at moderately acid pH C.), and oxytetracycline hydrochloride (Pfizer Pharmaceuti (6). Such reactions taking place in the stomach of man cals, Groton, Conn.). might be a source of carcinogenic nitrosamines (3), since Reactions were carried out in 20- to 40-ml volumes of nitrite is commonly used as a curing and preserving agent in aqueous solution containing the drug, 0.5 to 1.0 ml acetic meat and fish and can be formed by reduction of nitrate. A acid (as a convenient acidifying agent), and sodium nitrite (4 significant exposure of man to tertiary amines is in the form to 8 moles/mole of amine). The pH of the solution was of the many drugs commonly taken (a large proportion of taken at the beginning and end of the reaction. Reactions which are tertiary amines). A short report of reactions of a were carried out at 90°under reflux or at 37°in corked few drugs with nitrous acid has been made (4), and a flasks. At the end of the allotted time the reactions were biological study of the reaction of one tertiary amine, stopped by addition of a few pellets of sodium hydroxide aminopyrine, has demonstrated the formation of large (this made the solutions alkaline), and the aqueous solutions amounts of dimethylnitrosamine in this way (5). were extracted twice with double volumes of méthylène Here are reported further studies on the reactions of chloride; this was adequate to extract almost completely all aminopyrine and other commonly used drugs with nitrous of the nitrosamine present (the partition coefficient for acid, with special regard to the extent of interaction at dimethylnitrosamine between méthylènechloride and rather low concentrations, to offer some indication of the water, or dilute alkali, is 3.5:1, and higher than this for other magnitude of the hazard to man from such interactions. nitrosamines). The méthylènechlorideextracts were back- The drugs examined were aminopyrine (analgesic), chlor- extracted with a small volume of 5 N hydrochloric acid and pheniramine and methapyrilene (antihistaminics), chlorpro- were evaporated to a small volume at room temperature in a mazine and dextropropoxyphene (tranquilizers), tolazamide stream of nitrogen. The residual solutions were made to 5 or (hypoglycémie),quinacrine (antimalarial), lucanthone (an- 10 ml in volumetric flasks, and the nitrosamines were 1Research jointly sponsored by the National Cancer Institute and the estimated by gas-liquid chromatography on 8.4% diethyl- United States Atomic Energy Commission under contract with Union eneglycol succinate on Chromosorb (analyses were carried Carbide Corporation. out by the Analytical Chemistry Division, Oak Ridge Received June 21, 1973; accepted September 24, 1973. National Laboratory, and by Dr. George Singer of the JANUARY 1974 255 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1974 American Association for Cancer Research. William Lijinsky Biology Division). Identification of the product as the drug to nitrite of 1:1 or 1:2 are given in Table 1; the nitrosamine was based on the retention time in a gas-liquid concentration in the reaction mixture and the fraction of the chromatogram and was in most cases confirmed by mass theoretical yield are given. In all cases the expected volatile spectrometry carried out on the products of the reactions on nitrosamine was formed from the tertiary amine. No a larger scale, as for cyclizine (Table 1) and in Ref. 4. A attempt was made to identify the other products of the Coulson nitrogen-specific detector was used for the estima reactions, among which must have been the other possible tion of concentration; this eliminated possible over-estima nitrosamine formed by cleavage of one of the small alkyl tion of nitrosamine because of the presence of by-products groups. having the same retention time, among which is acetic acid In Table 2 are the results of similar reactions of the drugs with the same retention time as dimethylnitrosamine. The with nitrite, but under identical conditions of concentration yields given are minimal because of inevitable losses in the of amine and of nitrite, each solution being 0.01 Min amine extraction and evaporation procedures. Recovery of the and 0.04 Min nitrite. The acid was acetic acid, and the pH's most easily lost nitrosamine, dimethylnitrosamine, was 75 of the solutions were all 3.3 to 3.4. Again the yields of to 80%. volatile nitrosamine are given in /ug/ml of solution and as a percentage of theoretical. Because the reaction of aminopyrine with nitrous acid RESULTS was so much more vigorous than that of any other tertiary amine we have examined, this reaction was explored more The yields of nitrosamine by reaction of the several drugs thoroughly. Table 3 shows the yield of dimethylnitrosamine with nitrite at arbitrary concentrations and with a ratio of at quite low concentrations of aminopyrine with various Table 1 Nitrosamines formed by interaction of drugs with nitrite in acetic acid nitrosamineTemper of tion of drug tion of DrugAminopyrineOxytetracyclineChlorpromazineDextropropoxypheneChlorpheniramineMethadoneMethapyrileneDisulfiramQuinacrineLucanthoneTolazamideCyclizineConcentra(mg/ml)0.2581555555555555555540ConcentraNaNO2 ature37°37373790379037903790379037379037903790Time(hr)24241444441412444434PH3.23.03.23.43.43.33.53.53.53.33.33.43.43.63.53.53.63.63.13.7Mg/ml33200.5103821712522691754.51.512104070155DMN"DMNDMNDMNDMNDMNDMNDMNDMNDMNDMNDMNDMNDiethylnitros-amineDiethylnitros-amineDiethylnitros-amineDiethylnitros-amineDiethylnitros-amineNHMIDNP%of (mg/ml)0.251611010101010101010101010101010101036Yield theoretical40150.30.883.30.161.50.071.80.182.40.7140.30.151.20.73.03.48.2 'DMN, dimethylnitrosamine; NHMI, nitrosohexamethyleneimine; DNP. dinitrosopiperazine. 256 CANCER RESEARCH VOL. 34 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1974 American Association for Cancer Research. Nitrosamines from Drugs and Nitrous Acid Table 2 Formation of nitrosamines from drugs at 0.01 M amine and 0.04 M nitrite Yield of nitrosamine" DrugChlorpromazineChlorpheniramineDextropropoxypheneMethadoneMethapyrileneQuinacrineLucanthoneDisuinramTolazamideTrimethylamineTemperature90°37903790379037903790379037373737Time(hr)14141414141414334pH3.43.43.43.43.33.33.43.43.43.33.33.33.33.33.33.theoretical0.060.050.70.20.40.030.40.040.70.080.15O.I1.92.40.080.61.4 -33.3Jig/ml0.50.3551.630.230.350.61.5119240.8810.5DMNDMNDMNDMNDMNDMNDMNDMNDMNDMNDiethylnitros-amineDiethylnitros-amineDiethylnitros-amineDiethylnitros-amineDiethylnitros-amineNHMIDMN%of " DMN, dimethylnitrosamine; NHMI, nitrosohexamethyleneimine. Table 3 corresponds quite well with the composition 52.59% C, Reaction of aminopyrine with nitrite in acetic acid at 37°in I hr 5.21% H, 16.72% N for CuHnNaO«. It is reasonable to deduce that the yellow product of reaction of aminopyrine Concentrationof aminopyrinemg/ml0.0.0.0.0.0.050.050.05mM0.430.430.430.430.430.220.220.22ConcentrationofNaNOmg/mlO.I0.0750.050.0250.0120.050.0250.012imM1.45I.I0.70.350.170.70.350.17Dimethylnitrosawith nitrous acid is the nitrite salt of the compound shown mineyield(% below (4-hydroxyantipyrine), formed by oxidativedeamina- of theoretical)5554482613523522tion of aminopyrine (Chart 1). A yellow compound was precipitated by addition of sodium nitrite to an acid solution of 4-hydroxyantipyrine. This had a UV absorption spectrum similar to that of the compound derived from aminopyrine and had the same melting point, a mixture of the 2 products showed no depression of melting point, and the mass spectra of the 2 products were the same. The 2 products seem identical. concentrations of nitrite. At high concentrations of
Load more

Recommended publications
  • Diphenhydramine Hydrochloride (CASRN 147-24-0) in F344/N Rats
    NATIONAL TOXICOLOGY PROGRAM Technical Report Series No. 355 TOXICOLOGY AND CARCINOGENESIS STUDIES OF DIPHENHYDRAMINE HYDROCHLORIDE (CAS NO. 147-24-0) IN F344/N RATS AND B6C3F1 MICE (FEED STUDIES) LJ.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health NTP ‘TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF DIPHENHYDRAMINE HYDROCHLORIDE (CAS NO. 147-24-0) IN F344/N RATS AND B6C3F1 MICE (FEED STUDIES) R. Melnick, Ph.D., Study Scientist NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 September 1989 NTP TR 355 NIH Publication No. 89-2810 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health CONTENTS PAGE ABSTRACT ................................................................ 3 EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY .................. 6 CONTRIBUTORS ............................................................ 7 PEERREVIEWPANEL ........................................................ 8 SUMMARY OF PEER REVIEW COMMENTS ......................................... 9 I. INTRODUCTION ........................................................ 11 I1. MATERIALS AND METHODS .............................................. 21 III. RESULTS ............................................................. 35 RATS ............................................................. 36 MICE ............................................................. 45 GENETIC TOXICOLOGY ............................................... 53 IV.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,569,369 B2 Kramer Et Al
    USOO856.9369B2 (12) United States Patent (10) Patent No.: US 8,569,369 B2 Kramer et al. (45) Date of Patent: *Oct. 29, 2013 (54) AMINO ACID COMPOUNDS OTHER PUBLICATIONS (75) Inventors: Ronald Kramer, Phoenix, AZ (US); Jablecka et al., MedSci Monit 10(I):CR29-32 (2004). Alexander Nikolaidis, New Kallikratia Maynard et al., J. Nutr. 131:287-290 (2001). (GR) Ruel et al., J. Thorac Cardiovasc. Surg 135:762-77, 2008. Rytlewski et al., European Journal of Obstetrics & Gynecology and (73) Assignee: Thermolife International, LLC, Reproductive Biology 138:23-28 (2008). Phoenix, AZ (US) Schwedheim et al., Br J Clin Pharmacol 65(1):51-59 (2007). Smith et al., J. Thorac Cardiovasc. Surg 132:58-65 (2006). (*) Notice: Subject to any disclaimer, the term of this Rytlewski et al., Eur J. Clin Invest 35 (1):32-37 (2005). patent is extended or adjusted under 35 Ming et al., Circulation 110:3708-3714 (2004). U.S.C. 154(b) by 0 days. Romero et al., Cardiovascular Drug Reviews 24(3-4):275-290 (2006). This patent is Subject to a terminal dis Oka et al., Vasc Med 10:265-274 (2005). claimer. Hayashi et al., PNAS 102(38): 13681-13686 (2005). Grasemann et al., Eur Respir J 25:62-68 (2005). (21) Appl. No.: 13/468,231 Boger, J. Nutr 137:1650S-1655S (2007). Beghetti et al., J. Thorac Cardiovasc. Surg 132(6): 1501-1502 (2006). (22) Filed: May 10, 2012 Larsen et al., B. Acta Physiol 191(1):59-66 (2007). Berge, Journal of Pharmaceutical Sciences, Jan. 1977, vol.
    [Show full text]
  • Guidance for Identification and Naming of Substance Under REACH
    Guidance for identification and naming of substances under 3 REACH and CLP Version 2.1 - May 2017 GUIDANCE Guidance for identification and naming of substances under REACH and CLP May 2017 Version 2.1 2 Guidance for identification and naming of substances under REACH and CLP Version 2.1 - May 2017 LEGAL NOTICE This document aims to assist users in complying with their obligations under the REACH and CLP regulations. However, users are reminded that the text of the REACH and CLP Regulations is the only authentic legal reference and that the information in this document does not constitute legal advice. Usage of the information remains under the sole responsibility of the user. The European Chemicals Agency does not accept any liability with regard to the use that may be made of the information contained in this document. Guidance for identification and naming of substances under REACH and CLP Reference: ECHA-16-B-37.1-EN Cat. Number: ED-07-18-147-EN-N ISBN: 978-92-9495-711-5 DOI: 10.2823/538683 Publ.date: May 2017 Language: EN © European Chemicals Agency, 2017 If you have any comments in relation to this document please send them (indicating the document reference, issue date, chapter and/or page of the document to which your comment refers) using the Guidance feedback form. The feedback form can be accessed via the EVHA Guidance website or directly via the following link: https://comments.echa.europa.eu/comments_cms/FeedbackGuidance.aspx European Chemicals Agency Mailing address: P.O. Box 400, FI-00121 Helsinki, Finland Visiting address: Annankatu 18, Helsinki, Finland Guidance for identification and naming of substances under 3 REACH and CLP Version 2.1 - May 2017 PREFACE This document describes how to name and identify a substance under REACH and CLP.
    [Show full text]
  • WL-13 Safety Data Sheet, Canada (SDS-WL-13-CA
    WL- 13 Safety Data Sheet according to the Hazardous Products Regulation (February 11, 2015) SECTION 1: Identification 1.1. Product identifier Product form : Mixture Product name : WL- 13 1.2. Recommended use and restrictions on use No additional information available 1.3. Supplier Swagelok Supplier: 29495 F.A. Lennon Drive Distributor, add your contact information 44139 Solon, OH - United States T 440-349-5600 - F 440-519-3304 www.swagelok.com 1.4. Emergency telephone number Emergency number : Infotrac: North America: 1-800-535-5053 International: 1-352-323-3500 SECTION 2: Hazard identification 2.1. Classification of the substance or mixture Classification (GHS-CA) Not classified 2.2. GHS Label elements, including precautionary statements GHS-CA labeling No labeling applicable 2.3. Other hazards No additional information available 2.4. Unknown acute toxicity (GHS-CA) No data available SECTION 3: Composition/Information on ingredients 3.1. Substances Not applicable 3.2. Mixtures Name Chemical name / Synonyms Product identifier % Classification (GHS-CA) Molybdenum(IV) sulfide Molybdenum disulfide / Molybdenum (CAS-No.) 1317-33-5 <= 10 Comb. Dust disulphide / Molybdenum sulfide / Molybdenum sulfide (MoS2) / Manganese tetroxide Sodium nitrite Diazotizing salts / Nitrous acid, (CAS-No.) 7632-00-0 <= 1.8 Acute Tox. 3 (Oral), H301 sodium salt / Nitrous acid, sodium Aquatic Acute 1, H400 salt (1:1) / SODIUM NITRITE Full text of hazard classes and H-statements: see section 16 SECTION 4: First-aid measures 4.1. Description of first aid measures First-aid measures after inhalation : Allow victim to breathe fresh air. Allow the victim to rest. First-aid measures after skin contact : Remove affected clothing and wash all exposed skin area with mild soap and water, followed by warm water rinse.
    [Show full text]
  • Acids and Bases
    Name Date Class CHAPTER 14 REVIEW Acids and Bases SECTION 1 SHORT ANSWER Answer the following questions in the space provided. 1. Name the following compounds as acids: sulfuric acid a. H2SO4 sulfurous acid b. H2SO3 hydrosulfuric acid c. H2S perchloric acid d. HClO4 hydrocyanic acid e. hydrogen cyanide 2. H2S Which (if any) of the acids mentioned in item 1 are binary acids? 3. Write formulas for the following acids: HNO2 a. nitrous acid HBr b. hydrobromic acid H3PO4 c. phosphoric acid CH3COOH d. acetic acid HClO e. hypochlorous acid 4. Calcium selenate has the formula CaSeO4. H2SeO4 a. What is the formula for selenic acid? H2SeO3 b. What is the formula for selenous acid? 5. Use an activity series to identify two metals that will not generate hydrogen gas when treated with an acid. Choose from Cu, Ag, Au, Pt, Pd, or Hg. 6. Write balanced chemical equations for the following reactions of acids and bases: a. aluminum metal with dilute nitric acid ϩ → ϩ 2Al(s) 6HNO3(aq) 2Al(NO3)3(aq) 3H2(g) b. calcium hydroxide solution with acetic acid ϩ → ϩ Ca(OH)2(aq) 2CH3COOH(aq) Ca(CH3COO)2(aq) 2H2O(l ) MODERN CHEMISTRY ACIDS AND BASES 117 Copyright © by Holt, Rinehart and Winston. All rights reserved. Name Date Class SECTION 1 continued 7. Write net ionic equations that represent the following reactions: a. the ionization of HClO3 in water ϩ → ϩ ϩ Ϫ HClO3(aq) H2O(l ) H3O (aq) ClO3 (aq) b. NH3 functioning as an Arrhenius base ϩ → ϩ ϩ Ϫ NH3(aq) H2O(l ) ← NH4 (aq) OH (aq) 8.
    [Show full text]
  • Mechanisms of Nitric Oxide Reactions Mediated by Biologically Relevant Metal Centers
    Struct Bond (2014) 154: 99–136 DOI: 10.1007/430_2013_117 # Springer-Verlag Berlin Heidelberg 2013 Published online: 5 October 2013 Mechanisms of Nitric Oxide Reactions Mediated by Biologically Relevant Metal Centers Peter C. Ford, Jose Clayston Melo Pereira, and Katrina M. Miranda Abstract Here, we present an overview of mechanisms relevant to the formation and several key reactions of nitric oxide (nitrogen monoxide) complexes with biologically relevant metal centers. The focus will be largely on iron and copper complexes. We will discuss the applications of both thermal and photochemical methodologies for investigating such reactions quantitatively. Keywords Copper Á Heme models Á Hemes Á Iron Á Metalloproteins Á Nitric oxide Contents 1 Introduction .................................................................................. 101 2 Metal-Nitrosyl Bonding ..................................................................... 101 3 How Does the Coordinated Nitrosyl Affect the Metal Center? .. .. .. .. .. .. .. .. .. .. .. 104 4 The Formation and Decay of Metal Nitrosyls ............................................. 107 4.1 Some General Considerations ........................................................ 107 4.2 Rates of NO Reactions with Hemes and Heme Models ............................. 110 4.3 Mechanistic Studies of NO “On” and “Off” Reactions with Hemes and Heme Models ................................................................................. 115 4.4 Non-Heme Iron Complexes ..........................................................
    [Show full text]
  • Methapyrilene Hydrochloride (CAS No
    National Toxicology Program Toxicity Report Series Number 46 NTP Technical Report on the Hepatotoxicity Studies of the Liver Carcinogen Methapyrilene Hydrochloride (CAS No. 135-23-9) Administered in Feed to Male F344/N Rats July 2000 U.S. Department of Health and Human Services Public Health Service National Institutes of Health FOREWORD The National Toxicology Program (NTP) is made up of four charter agencies of the U.S. Department of Health and Human Services (DHHS): the National Cancer Institute (NCI), National Institutes of Health; the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center for Toxicological Research (NCTR), Food and Drug Administration; and the National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention. In July 1981, the Carcinogenesis Bioassay Testing Program, NCI, was transferred to the NIEHS. The NTP coordinates the relevant programs, staff, and resources from these Public Health Service agencies relating to basic and applied research and to biological assay development and validation. The NTP develops, evaluates, and disseminates scientific information about potentially toxic and hazardous chemicals. This knowledge is used for protecting the health of the American people and for the primary prevention of disease. The studies described in this Toxicity Study Report were performed under the direction of the NIEHS and were conducted in compliance with NTP laboratory health and safety requirements and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use were in accordance with the Public Health Service Policy on Humane Care and Use of Animals.
    [Show full text]
  • Amino-Nitrogen Contents of Wool and Collagen
    U. S. DEPARTMENT OF COMMERCE NATIONAL BUREAU OF STANDARDS RESEARCH PAPER RP787 Part of Journal of Research of the National Bureau of Standards, Volume 14, May 1935 AMINO-NITROGEN CONTENTS OF WOOL AND COLLAGEN By Joseph R. Kanagy 1 and Milton Harris 2 ABSTRACT When wool, collagen, and arginine were treated with nitrous acid, increasing amounts of nitrogen were evolved with time. The continued evolution of nitro­ gen was due to the action of nitrous acid on the guanidine nuclei of these materials. A new method for the determination of the arginine content of a protein is given. The method is based on the relative rates of evolution of nitrogen from the guanidine nuclei in a protein and in arginine. Evidence is presented t o show that the action of nitrous acid on the guanidine nucleus is different from its action on a free amino group. The free amino-nitro­ gen contents of wool and collagen were calculated by subtracting from the total nitrogen evolved that portion of nitrogen which came from the guanidine nuclei. The values obtained for the percentages of the total nitrogen as amino nitrogen are 2.53 for wool and 2.77 for collagen. CONTENTS Page I. Introduction ___ _____________ __________________________________ _ 563 II. Materials and methods _____________________________________ ____ _ 564 III. 566 IV. 569 Conclu~on _____________________________ __ _____________________ _ V. ~frc~~~~~~~~~~======================= ===== ========= =========== 573 VI. References __ _____ ___________ _____ ___________________ _______ ___ _ 573 I. INTRODUCTION The free amino groups in wool and collagen have been related to the combination of these materials with acids, dyes, and tannins by various investigators.
    [Show full text]
  • A Comparison of Drug Use in Driver Fatalities and Similarly Exposed Drivers
    DOT HS-802 488 A COMPARISON OF DRUG USE IN DRIVER FATALITIES AND SIMILARLY EXPOSED DRIVERS Contract No. DOT-HS-4-00941 July 1977 Final Report PREPARED FOR: U.S. DEPARTMENT OF TRANSPORTATION NATIONAL HIGHWAY TRAFFIC SAFETY ADMINISTRATION WASHINGTON, D.C. 20590 Document is available to the public through the National Technical Information Service, Springfield, Virginia 22161 This document is disseminated under the sponsorship of the Department of Transportation in the interest of information exchange. The United States Govern­ ment assumes no liability for its contents or use thereof. Technical Report Documentation Page 1. Report No. 2. Goeemm.nt Accession No. 3. Recipient's Catalog No. DOT HS-802 488 -^. 1. Title and Subtitle 5. Report Date July 1977 A COMPARISON OF DRU^ USE IN DRIVER FATALITIES 6. Performing Organization Code AND SIMILARLY EXPOSED DRIVERS . B. Performing Organization Report No. 7. Authorrs) Robert R. Blackburn, Edward J. Woodhouse 3963-D 9. Performing Organization Name and Address 10. Worb Unit No. (TRAIS) Midwest Research Institute I). Contract at Grant No. 425 Volker Boulevard DOT-HS-4-00941 Kansas City, Missouri 64110 13. Type of Report and Period Covered 12. Sponsoring Agency Name and Address 28 June 1974-25 March 1977 i U.S. Department of Transportation National Highway Traffic Safety Administration Final Report Washington, D.C. 20590 14. Sponsoring Agency Code 15. supplementary Notes 16. Abstract Crash information, urine, blood and bile samples from 900 fatally injured drivers were collected by medical examiners in 22 areas of the country. Ran­ domly selected living drivers were interviewed at times and places of recent fatal crashes in Dallas, Texas, and Memphis, Tennessee and breath, urine, and blood samples were obtained.
    [Show full text]
  • With [3H]Mepyramine (Trieyclic Antidepressants/Antihistamine/Neurotransmitter/Amitriptyline) VINH TAN TRAN, RAYMOND S
    Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 6290-6294,, December 1978 Neurobiology Histamine H1 receptors identified in mammalian brain membranes with [3H]mepyramine (trieyclic antidepressants/antihistamine/neurotransmitter/amitriptyline) VINH TAN TRAN, RAYMOND S. L. CHANG, AND SOLOMON H. SNYDER* Departments of Pharmacology and Experimental Therapeutics, and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Communicated by Julius Axelrod, August 30,1978 ABSTRACT The antihistamine [3H mepyramine binds to Male Sprague-Dawley rats (150-200 g) were killed by cer- HI histamine receptors in mammalian brain membranes. vical dislocation, their brains were rapidly removed and ho- Potencies of H1 antihistamines at the binding sites correlate mogenized with a Polytron for 30 min (setting 5) in 30 vol of with their pharmacological antihistamine effects in the guinea pig ileum. Specific [3Himepyramine binding is saturable with ice-cold Na/K phosphate buffer (50 mM, pH 7.5), and the a dissociation constant of about 4 nM in both equilibrium and suspension was centrifuged (50,000 X g for 10 min). The pellet kinetic experiments and a density of 10pmolper gram ofwhole was resuspended in the same volume of fresh buffer and cen- brain. Some tricyclic antidepressants are potent inhibitors of trifuged, and the final pellet was resuspended in the original secific [3Hmepamine binding. Regional variations of volume of ice-cold buffer by Polytron homogenization. Calf [3Hjmepyramine ing do not correlate with variations in brains were obtained from a local abattoir within 2 hr after the endogeneous histamine and histidine decarboxylase activity. death of the animals and transferred to the laboratory in ice- Histamine is a neurotransmitter candidate in mammalian brain cold saline.
    [Show full text]
  • The Sandmeyer Reaction: Substitution for an NH2 on an Aromatic Ring
    Sandmeyer Reaction 59 The Sandmeyer Reaction: Substitution for an NH2 on an Aromatic Ring + General Sandmeier Reaction: Substitution for NH2 Group on a Benzene, via Diazonium ArN2 ArCN CuCN CuBr ArBr NaNO2, HCl HONO + - CuCl ArNH2 ArN2 Cl ArCl diazonium salt + H2O, H , heat ArOH H3PO2 ArH Intro The “Sandmeyer Reaction” is a versatile method for replacing the amine group of a primary aromatic amine with a number of different substitutents. The amine is treated with “nitrous acid” (HNO2) under acidic conditions, which produces the diazonium ion. The diazonium can then undergo substitution reaction with various reactants, particularly copper(I) substrates. Although the substitution can be simplistically viewed as a direct ionic substitution reaction (anion as nucleophile, molecular N2 as a premier leaving group), the actual mechanism is actually more complicated and involves radicals. HONO - Cl + NH2 NaNO2, HCl, H2O N2 Cl + N2 Sodium Nitrite CuCl mw = 69.1 g/mol copper(I) chloride p-chlorotoluene p-toluidine diazonium NaCl mw = 126.6 g/mol mw = 107.2 g/mol salt NaHSO bp = 162ºC mp = 45ºC 3 + NaOH density = 1.07 g/mL H2O, H , heat OH CuSO4-(H2O)5 copper(II) sulfate 249.7 g/mol Phenol Side Product Today’s Reaction: Synthesis of p-Chlorotoluene In today’s experiment, we will use copper(I) chloride (CuCl) as our “nucleophile”, to produce the chloride product. The diazonium ion has limited stability in water; it tends to react to give phenols (ArOH) upon standing or unnecessary warming. The principle organic side product will be the phenol resulting from competing reaction with water.
    [Show full text]
  • Different Nitrous Acid Sources in the Air Quality Levels
    Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | Atmos. Chem. Phys. Discuss., 10, 28183–28230, 2010 Atmospheric www.atmos-chem-phys-discuss.net/10/28183/2010/ Chemistry ACPD doi:10.5194/acpd-10-28183-2010 and Physics 10, 28183–28230, 2010 © Author(s) 2010. CC Attribution 3.0 License. Discussions Different nitrous acid This discussion paper is/has been under review for the journal Atmospheric Chemistry sources in the air and Physics (ACP). Please refer to the corresponding final paper in ACP if available. quality levels The impact of different nitrous acid M. Gonc¸alves et al. sources in the air quality levels of the Title Page Iberian Peninsula Abstract Introduction Conclusions References M. Gonc¸alves1,2, D. Dabdub3, W. L. Chang3, F. Saiz3, O. Jorba2, and J. M. Baldasano1,2 Tables Figures 1Environmental Modeling Laboratory, Projects Department, Technical University of Catalonia, Barcelona, Spain J I 2Earth Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain J I 3Department of Mechanical and Aerospace Engineering, University of California, Irvine, Irvine, California, USA Back Close Received: 21 October 2010 – Accepted: 5 November 2010 – Published: 17 November 2010 Full Screen / Esc Correspondence to: M. Gonc¸alves ([email protected]) Printer-friendly Version Published by Copernicus Publications on behalf of the European Geosciences Union. Interactive Discussion 28183 Discussion Paper | Discussion Paper | Discussion Paper | Discussion Paper | Abstract ACPD Hydroxyl radical (OH) is a primary oxidant in the atmosphere and affects both gas- phase pollutants and particulate matter levels. Nitrous acid (HONO) acts as an impor- 10, 28183–28230, 2010 tant source of OH in the urban atmosphere.
    [Show full text]