DOCSLIB.ORG

The Identification of a Nitrosated Prodrug of the PDE-5 Inhibitor Aildenafil in a Dietary Supplement: a Viagra with A

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Identification of a Nitrosated Prodrug of the PDE-5 Inhibitor Aildenafil in a Dietary Supplement: a Viagra with A Journal of Pharmaceutical and Biomedical Analysis 54 (2011) 735–741 Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis journal homepage: www.elsevier.com/locate/jpba The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: A Viagra with a pop B.J. Venhuis a,∗, G. Zomer b, M. Hamzink b, H.D. Meiring b, Y. Aubin c, D. de Kaste a a National Institute for Public Health and the Environment, Postbox 1, 3721 MA, Bilthoven, The Netherlands b Netherlands Vaccine Institute, Postbox 457, 3720 AL, Bilthoven, The Netherlands c Biologics and Genetic Therapies Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, Canada K1A 0K9 article info abstract Article history: A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement pro- Received 13 August 2010 moted as a libido enhancing product. Using LC–DAD–MS, MS–MS, HRMS, IR and NMR the analogue Received in revised form was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydroly- 11 November 2010 sis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named Accepted 13 November 2010 nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of Available online 21 November 2010 aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Keywords: Sildenafil analogue Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coinci- Nitroso-prodenafil dental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines Aildenafil prodrug are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified Liquid chromatography–mass in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by spectrometry (LC–MS) producers of unapproved drugs. Nuclear magnetic resonance (NMR) © 2010 Elsevier B.V. All rights reserved. 1. Introduction drugs is illustrated by the identification of many unapproved PDE- 5 inhibitors [8]. Most of the unapproved PDE-5 inhibitors identified The erectile dysfunction (ED) drug Viagra (sildenafil citrate) are structural varieties (analogues) of the approved ED-drugs silde- or other PDE-5 inhibitors are not to be used coincidentally with nafil, vardenafil and tadalafil. Although many of these analogues are NO-donors [1–3]. NO-donating drugs are used in the treatment of disclosed in Pfizer, Bayer, or Lilly patents as PDE-5 inhibitors they angina pectoris (e.g. glyceryltrinitrate, isorbide nitrate) and act by were never selected for clinical development. As patent literature causing coronary vasodilatation. Originally, sildenafil was devel- is publicly accessible it can easily be misused. oped as an alternative treatment for angina pectoris because it The analogue identified in the current study is a cleverly raised NO-levels through PDE-5 inhibition. However, in clinical tri- designed nitrosated prodrug of aildenafil (Fig. 1). An N-methyl-N- als the vasodilatation caused in the corpus cavernosum of the penis nitroso-1,3-thiazole-5-amine moiety is linked to aildenafil through was more effective. Though the efficacy of sildenafil in inducing a hydrolyzable bond. The finding described in this article shows coronary vasodilatation was limited, coincidental use of drugs that that the producers of these pharmaceuticals evidently invest give off NO may cause a dangerous drop in blood pressure [4,5].ED time, resources and knowledge in the development of novel ana- patients using PDE-5 inhibitors are warned against the concomitant logues and are concomitantly prepared to take large health risks. use of NO-donating medicine and ‘poppers’ which are NO-releasing Nitrosamines may generate NO and enhance the vasodilating effect recreational (sex) drugs [6]. of a PDE-5 inhibitor with the risk of a dangerous drop in blood It has been estimated that for every two legitimate prescriptions pressure [9,10]. The potentially toxic nature of nitrosamines is illus- of an ED drug in Europe one third is purchased from illegal sources trated by the slimming drug nitroso-fenfluramine causing liver [7]. This ratio is expected to increase when adulterated dietary sup- failure on a large scale [11]. plements are also considered. The booming market for illegal ED 2. Materials and methods ∗ Corresponding author at: National Institute for Public Health and the Envi- 2.1. General ronment, Center for Quality of Chemical-Pharmaceutical Products, Anthonie van Leeuwenhoeklaan 9, 3721 MA, Bilthoven, The Netherlands. Tel.: +31 30 2744228; · · fax: +31 30 2744462. Reference sildenafil citrate, vardenafil HCl 3H2O and tadalafil E-mail address: [email protected] (B.J. Venhuis). were obtained from Pfizer, Bayer and Lilly, respectively. Methanol 0731-7085/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jpba.2010.11.020 736 B.J. Venhuis et al. / Journal of Pharmaceutical and Biomedical Analysis 54 (2011) 735–741 38 33 N O 32 34 N N 36 31 N S 35 37 N N 21 O 10 N N 4 S S 20 9 N 3 + + O 5 N N 2 m/z 112 m/z 124 19 14 18 6 N 8 1 7 30 11 17 16 15 OH 12 N + N + 25 24 S S 26 23 22 HN NOS 13 27 28 m/z 85 m/z 101 O 29 Fig. 1. The proposed structure of the new analogue prodrug and the suggested fragments for ‘Moiety142’. (HPLC supra-gradient; MeOH) was obtained from Biosolve 2.3. High resolution mass spectrometry (HRMS) (Valkenswaard, The Netherlands). Formic acid (p.a.), ammonium hydroxide (p.a.) and 2N NaOH were obtained from Merck (Darm- A small amount of the composite (20 mg) was dissolved in 1 ml stadt, Germany). Other chemicals were obtained from various of CHCl3. The clear supernatant was collected after centrifuga- commercial sources in the highest purity grade available. Water tion and evaporated to dryness. The residue was reconstituted in was demineralised and filtered using a Millipak® 200 0.22-␮m filter 100 ␮l of water/acetonitrile (3:1, v/v) + 0.1% (v/v) formic acid and from Millipore B.V. (Amsterdam, The Netherlands). Acidified water also containing 1 pmol/␮l of the peptide Angiotensin-III as inter- was prepared by addition of 2 ml of formic acid to 1000 ml of water nal lock mass calibrant at the m/z-value of the doubly charged ion and adjusting the pH to 4.0 using NH4OH. @ 466.26106 Da. A 10-␮l aliquot of this mixture was pipetted into One package with two capsules of the herbal dietary supple- a gold-coated borosilicate glass nanospray needle (manufactured ment was brought in for analysis. The product label listed 9 herbal in-house, essentially as described by Wilm and Mann [12]) and ingredients and a content of 560 mg per capsule. However, a cap- positioned in a static nanoelectrospray ion source (built in-house) sule contained, on average, 386 mg of a white powder. A composite that was mounted onto an LTQ Orbitrap XL mass spectrometer was prepared of the two capsules. (Thermo Scientific). The sample was continuously infused into the mass spectrometer operated in positive ion mode, using an electro- ◦ 2.2. LC–DAD–MS spray voltage of 800 V and a heated capillary temperature of 200 C. Automatic gain control was used to control the filling of the mass × 5 A stock solution of the sample was prepared by sonication analyzer at a full MS target of 5 10 ions in the Orbitrap mass of an amount of the composite equivalent to a quarter dosage analyzer (operated at a mass resolution of 100,000 FWHM @ m/z × 4 unit in 25 ml of MeOH. An aliquot of the supernatant liquid was 400 Da) or at a MS/MS target of 1 10 ions in the LTQ ion trap. diluted 100× using MeOH/acidified water (v/v = 50/50), which solu- Full scan MS spectra were acquired from m/z 150–1500 Da with 1 tion was subsequently used for LC–DAD–MSn analysis. All samples microscan and a maximum inject time of 150 ms. For structural elu- and solutions were filtered before use over a 0.45 ␮m Spartan 30 cidation, analyte ions of interest were fragmented in the ion trap filter (Whatman GmbH, Dassel, Germany). For chromatography with collision induced fragmentation (CID) and the resulting prod- and UV detection, a Surveyor instrumentation (Thermo Finnigan, uct ions were mass-analyzed in the Orbitrap analyzer at a mass Breda, The Netherlands) was used under the following condi- resolution of 100,000 FWHM @ m/z 400 Da. ® tions: XTerra MS C18 guard column (20 mm × 2.1 mm, 3.5 mm) ® × and XTerra MS C18 analytical column (100 mm 2.1 mm, 3.5 mm; 2.4. IR spectroscopy Waters Chromatography B.V., Etten-Leur, The Netherlands); elu- tion using solvent A—MeOH and solvent B—acidified water/MeOH The unknown compound was coated on KBr for IR analysis by (v/v = 50/50): 0–15 min isocratic (B = 100), 15–17 min gradient to mixing 20 mg KBr with 2 ml of the stock solution prepared under A/B = 60/40, 17–28 min isocratic A/B = 60/40, 28–33 min: isocratic Section 2.2. After evaporation of the MeOH under a stream of N a −1 ◦ 2 B = 100; flow rate at 0.25 ml min ; column temperature 25 C; sample of the dry powder was used for IR analysis (KBr) in a Bruker ␮ injection volume 20 l; ultraviolet light detection from 200 to IFS55 FT-IR spectrometer with a DTGS detector and OPUS software 450 nm.
Load more

Recommended publications
  • Nitroso and Nitro Compounds 11/22/2014 Part 1
    Hai Dao Baran Group Meeting Nitroso and Nitro Compounds 11/22/2014 Part 1. Introduction Nitro Compounds O D(Kcal/mol) d (Å) NO NO+ Ph NO Ph N cellular signaling 2 N O N O OH CH3−NO 40 1.48 molecule in mammals a nitro compound a nitronic acid nitric oxide b.p = 100 oC (8 mm) o CH3−NO2 57 1.47 nitrosonium m.p = 84 C ion (pKa = 2−6) CH3−NH2 79 1.47 IR: υ(N=O): 1621-1539 cm-1 CH3−I 56 Nitro group is an EWG (both −I and −M) Reaction Modes Nitro group is a "sink" of electron Nitroso vs. olefin: e Diels-Alder reaction: as dienophiles Nu O NO − NO Ene reaction 3 2 2 NO + N R h 2 O e Cope rearrangement υ O O Nu R2 N N N R1 N Nitroso vs. carbonyl R1 O O O O O N O O hυ Nucleophilic addition [O] N R2 R O O R3 Other reaction modes nitrite Radical addition high temp low temp nitrolium EWG [H] ion brown color less ion Redox reaction Photochemical reaction Nitroso Compounds (C-Nitroso Compounds) R2 R1 O R3 R1 Synthesis of C-Nitroso Compounds 2 O R1 R 2 N R3 3 R 3 N R N R N 3 + R2 2 R N O With NO sources: NaNO2/HCl, NOBF4, NOCl, NOSbF6, RONO... 1 R O R R1 O Substitution trans-dimer monomer: blue color cis-dimer colorless colorless R R NOBF OH 4 - R = OH, OMe, Me, NR2, NHR N R2 R3 = H or NaNO /HCl - para-selectivity ΔG = 10 Kcal mol-1 Me 2 Me R1 NO oxime R rate determining step Blue color: n π∗ absorption band 630-790 nm IR: υ(N=O): 1621-1539 cm-1, dimer υ(N−O): 1300 (cis), 1200 (trans) cm-1 + 1 Me H NMR (α-C-H) δ = 4 ppm: nitroso is an EWG ON H 3 Kochi et al.
    [Show full text]
  • ATSDR Case Studies in Environmental Medicine Nitrate/Nitrite Toxicity
    ATSDR Case Studies in Environmental Medicine Nitrate/Nitrite Toxicity Agency for Toxic Substances and Disease Registry Case Studies in Environmental Medicine (CSEM) Nitrate/Nitrite Toxicity Course: WB2342 CE Original Date: December 5, 2013 CE Expiration Date: December 5, 2015 Key • Nitrate toxicity is a preventable cause of Concepts methemoglobinemia. • Infants younger than 4 months of age are at particular risk of nitrate toxicity from contaminated well water. • The widespread use of nitrate fertilizers increases the risk of well-water contamination in rural areas. About This This educational case study document is one in a series of and Other self-instructional modules designed to increase the primary Case Studies care provider’s knowledge of hazardous substances in the in environment and to promote the adoption of medical Environmen- practices that aid in the evaluation and care of potentially tal Medicine exposed patients. The complete series of Case Studies in Environmental Medicine is located on the ATSDR Web site at URL: http://www.atsdr.cdc.gov/csem/csem.html In addition, the downloadable PDF version of this educational series and other environmental medicine materials provides content in an electronic, printable format. Acknowledgements We gratefully acknowledge the work of the medical writers, editors, and reviewers in producing this educational resource. Contributors to this version of the Case Study in Environmental Medicine are listed below. Please Note: Each content expert for this case study has indicated that there is no conflict of interest that would bias the case study content. CDC/ATSDR Author(s): Kim Gehle MD, MPH CDC/ATSDR Planners: Charlton Coles, Ph.D.; Kimberly Gehle, MD; Sharon L.
    [Show full text]
  • Systems Biology Reveals Reprogramming of the S-Nitroso
    www.nature.com/scientificreports OPEN Systems biology reveals reprogramming of the S‑nitroso‑proteome in the cortical and striatal regions of mice during aging process Maryam Kartawy, Igor Khaliulin & Haitham Amal* Cell aging depends on the rate of cumulative oxidative and nitrosative damage to DNA and proteins. Accumulated data indicate the involvement of protein S‑nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modifcation (PTM) of cysteine thiols, in diferent brain disorders. However, the changes and involvement of SNO in aging including the development of the organism from juvenile to adult state is still unknown. In this study, using the state‑of‑the‑ art mass spectrometry technology to identify S‑nitrosylated proteins combined with large‑scale computational biology, we tested the S‑nitroso‑proteome in juvenile and adult mice in both cortical and striatal regions. We found reprogramming of the S‑nitroso‑proteome in adult mice of both cortex and striatum regions. Signifcant biological processes and protein–protein clusters associated with synaptic and neuronal terms were enriched in adult mice. Extensive quantitative analysis revealed a large set of potentially pathological proteins that were signifcantly upregulated in adult mice. Our approach, combined with large scale computational biology allowed us to perform a system‑level characterization and identifcation of the key proteins and biological processes that can serve as drug targets for aging and brain disorders in future studies. Nitric oxide (NO) is produced in diferent organs and tissues, including the central and peripheral nervous sys- tem, and is one of the most important signaling molecules in the body1,2. At low concentrations, it participates in cell signaling and may have therapeutic value for brain injury 3.
    [Show full text]
  • C-Nitroso-Substituted Ligands of Poly(ADP-Ribose) Polymerase (Zinc Rmger/Drug-Induced Cell Death) WILLIAM G
    Proc. Nati. Acad. Sci. USA Vol. 89, pp. 7703-7707, August 1992 Pharmacology Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase (zinc rmger/drug-induced cell death) WILLIAM G. RICE*t, CHRISTOPHER D. HILLYERt, BRAD HARTEN*, CATHERINE A. SCHAEFFER*, MARK DORMINY*, DIXON A. LACKEY III*, EVA KIRSTEN§, JEROME MENDELEYEV§, KALMAN G. BUKI§, ALAEDDIN HAKAM§, AND ERNEST KUNt§ *Division of Hematology and Oncology, Department of Pediatrics, and tDepartment of Pathology and Laboratory of Medicine and the Winship Cancer Center, Emory University School of Medicine, Atlanta, GA 30322; and §Laboratory for Environmental Toxicology and Chemistry, The Romberg Tiburon Center, San Francisco State University, P.O. Box 855, Tiburon, CA 94920 Communicated by John Baldeschwieler, May 19, 1992 ABSTRACT 6-Nitroso-1,2-benzopyrone and 3-ni- Assays. For cell proliferation tests, cells were cultured in trosobenzamide, two C-nitroso compounds that inactivate the 96-well tissue culture plates at 3 x 103 cells per well (250-gl eukaryotic nuclear protein poly(ADP-ribose) polymerase total volume per well) for 2 hr (or the indicated length oftime) [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyl- in the absence or presence of various concentrations of transferase, ADPRT, EC 2.4.2.30] at one zinc-ringer site, NOBA or NOBP; thereafter 0.5 ,uCi of [methyl-3H]thymidine completely suppressed the proliferation of leukemic and other (85 Ci/mmol; 1 Ci = 37 GBq) was added per well and its malignant human cells and subsequently produced cell death. incorporation into DNA following an 18-hr incubation was Tumoricidal concentrations of the drugs were relatively harm- determined radiochemically (6).
    [Show full text]
  • N-Nitroso Compounds in the Diet
    Mutation Research 443Ž. 1999 129±138 www.elsevier.comrlocatergentox Community address: www.elsevier.comrlocatermutres N-Nitroso compounds in the diet William Lijinsky 11398 High Hay DriÕe, Columbia, MD 21044, USA Received 7 October 1998; received in revised form 12 February 1999; accepted 12 February 1999 Abstract N-Nitroso compounds were known almost 40 years ago to be present in food treated with sodium nitrite, which made fish meal hepatotoxic to animals through formation of nitrosodimethylamineŽ. NDMA . Since that time, N-nitroso compounds have been shown in animal experiments to be the most broadly acting and the most potent group of carcinogens. The key role of nitrite and nitrogen oxides in forming N-nitroso compounds by interaction with secondary and tertiary amino compounds has led to the examination worldwide of foods for the presence of N-nitroso compounds, which have been found almost exclusively in those foods containing nitrite or which have become exposed to nitrogen oxides. Among these are cured meats, especially baconÐand especially when cooked; concentrations of 100 mgkgy1 have been found or, more usually, near 10 mgkgy1. This would correspond to consumption of 1 mg of NDMA in a 100-g portion. Much higher concentrations of NDMAŽ. but lower ones of other nitrosamines have been found in Japanese smoked and cured fish Ž more than 100 mg kgy1. Beer is one source of NDMA, in which as much as 70 mg ly1 has been reported in some types of German beer, although usual levels are much lowerŽ 10 or 5 mg ly1. ; this could mean a considerable intake for a heavy beer drinker of several liters per day.
    [Show full text]
  • A Mitochondria-Targeted S-Nitrosothiol Modulates Respiration, Nitrosates Thiols, and Protects Against Ischemia-Reperfusion Injury
    A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury Tracy A. Primea, Frances H. Blaikieb, Cameron Evansb, Sergiy M. Nadtochiyc, Andrew M. Jamesa, Christina C. Dahma, Dario A. Vitturid, Rakesh P. Pateld, C. Robin Hileye, Irina Abakumovaa, Raquel Requejoa, Edward T. Chouchania, Thomas R. Hurda, John F. Garveyf, Cormac T. Taylorf, Paul S. Brookesc, Robin A. J. Smithb, and Michael P. Murphya,1 aMRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, United Kingdom; bDepartment of Chemistry, University of Otago, P. O. Box 56, Dunedin 9054, New Zealand; cDepartment of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642; dDepartment of Pathology and Center for Free Radical Biology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294; eDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom; and fConway Institute, University College, Dublin, Dublin 4, Ireland Edited by Salvador Moncada, University College London, London, United Kingdom, and approved May 1, 2009 (received for review March 25, 2009) Nitric oxide (NO•) competitively inhibits oxygen consumption by phonium (TPP) cationic moiety, which has been used to target mitochondria at cytochrome c oxidase and S-nitrosates thiol pro- molecules to mitochondria both in vitro and in vivo (11). The teins. We developed mitochondria-targeted S-nitrosothiols (MitoS- delocalized positive charge and lipophilic surface enables TPP NOs) that selectively modulate and protect mitochondrial function. cations to cross biological membranes rapidly without a require- The exemplar MitoSNO1, produced by covalently linking an S- ment for a carrier protein, and to accumulate several hundred- nitrosothiol to the lipophilic triphenylphosphonium cation, was fold in energized mitochondria in vivo driven by the membrane rapidly and extensively accumulated within mitochondria, driven potential (⌬␺) (12).
    [Show full text]
  • Dietary Nitrates, Nitrites, and N-Nitroso Compounds and Cancer Risk: a Review of the Epidemiologic Evidence Monika Eichholzer, M.D., M
    Lead Review Article April 1998: 95-105 Dietary Nitrates, Nitrites, and N-Nitroso Compounds and Cancer Risk: A Review of the Epidemiologic Evidence Monika Eichholzer, M.D., M. Sc., M. Sc., and Felix Gutzwiller, M.D., Dr.P.H. Experimental animal studies have shown N-nitroso daily intake of nitrate, with high levels in lettuce, spinach, compounds (NOC) to be potent carcinogens. celery, beetroot, turnip greens, etc. The nitrate concentra- Epidemiologic evidence of the carcinogenic tion of drinking water varies widely depending on the potential of dietary NOC and precursor nitrates source (high concentrations in private water supplies), and nitrites in humans remains inconclusive with season, and proximity to arable land. Nitrate and nitrite are regard to the risk of stomach, brain, esophageal, often added as preservatives to processed (cured) meat, and nasopharyngeal cancers. Inadequate available meat products, and fish. Nitrites are also found naturally data could obscure a small to moderate effect of in some grains and vegetables. Nitrosodimethylaminehas NOC. been found in various processed meats (salted, cured, or smoked) and fish and in beer.3s6s7 Introduction Stomach Cancer Various N-nitroso compounds (NOC) have been found to Large differences in the incidence of stomach cancer exist be carcinogenic to multiple organs in at least 40 animal worldwide. The highest incidence rates are found in Ja- species including higher primates.’ The cellular and mo- pan and China; Switzerland and France have intermediate lecular changes induced by some NOC in animals have rates; and North America and Greece have the lowest rates. been shown to be very similar to those in human tissues? The continuous decline of stomach cancer rates over the In addition to exposure to preformed NOC (e.g., tobacco past several decades and the results of migrant studies use, certain occupational environments, diet),2’ humans suggest a predominant etiologic role for external environ- are exposed to nitrogen-containing compounds and mental factors generally believed to be dietary.
    [Show full text]
  • Health Hazards of Nitrite Inhalants, 83
    Health Hazards of Nitrite Inhalants U.S. DEPARMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Health Hazards of Nitrite Inhalants Editors: Harry W. Haverkos, M.D. Divlsion of Clinical Research National Institute on Drug Abuse John A. Dougherty, Ph.D. Veterans Administration Medical Center Lexington, KY NIDA Research Monograph 83 1988 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5500 Fishers Lane Rockville, MD 20857 For Sale by the Superitendent of Documents, U.S. Government Printing Office Washington, DC 20402 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. MARY L. JACOBSON Temple Universlty School of Medicine National Federation of Parents for Philadelphia, Pennsylvania Drug-Free Youth Omaha, Nebraska SYDNEY ARCHER, Ph.D. Rensselaer Polytechnic Institute Troy, New York REESE T. JONES, M.D. Langley Porter Neuropsychiatric lnstitute RICHARD E. BELLEVILLE, Ph.D. San Francisco, California NB Associates, Health Sciences RockviIle, Maryland DENISE KANDEL, Ph.D. KARST J. BESTEMAN College of Physicians and Surgeons of Alcohol and Drug Problems Association Columbia University of North America New York, New York Washington, D.C GILBERT J.
    [Show full text]
  • Synthetic Uses of S-Nitrosothiols in Organic Chemistry
    SYNTHETIC USES OF S-NITROSOTHIOLS IN ORGANIC CHEMISTRY By TYLER DAVID BIGGS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY WASHINGTON STATE UNIVERSITY Department of Chemistry MAY 2017 © Copyright by TYLER DAVID BIGGS, 2017 All Rights Reserved © Copyright by TYLER DAVID BIGGS, 2017 All Rights Reserved To the Faculty of Washington State University: The members of the Committee appointed to examine the dissertation of TYLER DAVID BIGGS find it satisfactory and recommend that it be accepted. Ming Xian, Ph.D., Chair Cliff E. Berkman, Ph.D. Aurora Clark, Ph.D. Jeffery Jones, Ph.D. ii ACKNOWLEDGMENT I would like to thank Dr. Ming Xian for his supervision, help, and guidance over the course of my Ph.D. study. His challenges and questions kept me on track, and forced me to constantly reevaluate myself critically. I would also like to thank Dr. Ronald for helping to kindle my interest and passion in chemistry. I would like to thank my committee members for sharing their time and knowl- edge. I would also like to thank the Washington State University Chemistry depart- ment for the resources and equipment provided, and those in the front office who keep things running. Finally I would like to thank my fellow students who have supported me. Ryan Joseph, for his help and enthusiasm in chemistry and LATEX. Nelmi Devarie, for talks of cooking and science. Laksiri, Hua Wang, and Chung-Min Park for their help in training me in the basics. Most importantly are my family and friends, with out their support I would have never started this journey, or have a place to go up on finishing it, without their help and commitment.
    [Show full text]
  • Control of Nitrosamine Impurities in Human Drugs
    Control of Nitrosamine Impurities in Human Drugs Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Fe bruary 2021 Pharmaceutical Quality/ Manufacturing Standards/ Current Good Manufacturing Practice (CGMP) Revision 1 Control of Nitrosamine Impurities in Human Drugs Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: [email protected] https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Fe bruary 2021 Pharmaceutical Quality/ Manufacturing Standards/ Current Good Manufacturing Practice (CGMP) Revision 1 Preface FDA is implementing this guidance without prior public comment because the Agency has determined that prior public participation is not feasible or appropriate (see Section 701(h)(1)(C)(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 10.115(g)(2) and (g)(3)). FDA made this determination because of the importance of providing timely information to manufacturers regarding risk assessments, testing, and other appropriate actions they should take to reduce and mitigate nitrosamine impurities in active pharmaceutical ingredients (APIs) 1 and drug products. This guidance document is being implemented immediately, but it remains subject to comment in accordance with the Agency’s good guidance practices.
    [Show full text]
  • 1 Structure and Activity of N-Nitroso Compounds (NOC)
    Structure and activity of N‐Nitroso Compounds (NOC) and overview on endogeneous nitrosation (bio)chemistry Gerhard Eisenbrand – Chairman of the DFG‐SKLM University of Kaiserslautern, Department of Chemistry, Division of Food Chemistry and Toxicology, Erwin‐Schroedinger‐Str., 67663 Kaiserslautern, Germany History More than 50 years ago N‐nitrosodimethylamine (NDMA) has been reported by Peter Magee and his colleague M.J. Barnes (1956) to induce primary liver tumours in rats. This finding originated from an investigation into the potential causes of hepatotoxicity in workers in the rubber industry, where the compound had been explored for suitability as a solvent in the vulcanization process (Barnes and Magee, 1954). Sporadic case reports on accidental (Freund, 1937) or intentional fatal intoxications (Cooper& Kimbrough, 1980; Fussgänger & Ditschuneit,1980) by NDMA published before or later described human postmortem findings, especially acute liver necrosis and haematological toxicity similar to those seen in experimental animals at lethal dosage. NDMA is a quite polar, low molecular weight water soluble compound, significantly different from the lipophilic carcinogens of higher molecular mass known at that time such as polycyclic aromatic hydrocarbons (PAH), aromatic amines or pyrrolizidines. The seminal finding by Magee & Barnes (1956) was confirmed by Schmähl & Preussmann (1959) who also showed the next homologue, N‐ nitrosodiethylamine (NDEA) to be at least as potent a carcinogen as NDMA (Schmähl et al., 1960). Subsequently, research into biological activities of N‐nitroso compounds (NOC) rapidly gained momentum and a wide range of NOC, including certain nitrosamides such as N‐methyl‐N‐nitrosourea or N‐methyl‐N‐nitrosorurethane (Schoental, 1960; Druckrey et al., 1961), were identified as potent carcinogens.
    [Show full text]
  • A Study of Some Nitroso Compounds. Cilton Watson Tate Louisiana State University and Agricultural & Mechanical College
    Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 1954 A Study of Some Nitroso Compounds. Cilton Watson Tate Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Part of the Chemistry Commons Recommended Citation Tate, Cilton Watson, "A Study of Some Nitroso Compounds." (1954). LSU Historical Dissertations and Theses. 8076. https://digitalcommons.lsu.edu/gradschool_disstheses/8076 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Historical Dissertations and Theses by an authorized administrator of LSU Digital Commons. For more information, please contact [email protected]. A STUDY OF SOME MXTROSQ COMPOUNDS PART I * Oxidation of Nitroso Compounds to the corresponding Mitro Cosh pounds. PART IX - Development of Chromat©graphic and Spectrophotoiaetric Methods for the Separation, Identification and Estimation of some Mitros© and Related Compounds. PART XXX- Influences of Mitre Compounds on the Decomposition of Nitroso Compounds. A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy The Department o f Chemistry by C ilton Watson Tate M.S. Louisiana State University, 1950 Aug., 1953 UMI Number: DP69454 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted.
    [Show full text]