Non-Natural Nucleotides As Modulators of Atpases

Total Page:16

File Type:pdf, Size:1020Kb

Non-Natural Nucleotides As Modulators of Atpases NON-NATURAL NUCLEOTIDES AS MODULATORS OF ATPASES BY KEVIN ENG Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Anthony J. Berdis Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY May, 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ______________________________________________________ candidate for the ________________________________degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. This work is dedicated to my previous mentors, Silvana Gaetani, Danielle Piomelli, and Steve Barnett. You are the ones responsible for bringing me this far. Table of Contents Signature Sheet i Dedication ii Table of Contents 1 List of Figures 4 List of Tables 7 List of Abbreviations 8 Acknowledgements 9 Abstract 11 Chapter 1: Introduction 1.1 Overview of ATP and ATPases 13 The chemical properties of ATP and its role in biological systems Structural analysis of ATP binding pocket Existing drugs that target the ATP binding site 1.2 Non-natural Nucleotides as Therapeutic Agents 19 Non-natural nucleotides and translesion DNA synthesis Clinical importance of nucleoside analogs 1.3 Model Systems for Evaluating the Influence of 1 Non-Natural Nucleotides on ATP-dependent Processes 22 Sliding clamp loader ATPase P-glycoprotein 1.4 Statement of Purpose 31 Figures 32 Tables 68 Chapter 2: Selective inhibition of DNA replicase assembly by a non-natural nucleotide: Exploiting the structural diversity of ATP-binding sites 2.1 Abstract 69 2.2 Introduction 71 2.3 Materials and Methods 72 2.4 Results and Discussion 76 Figures 89 Tables 112 Chapter 3: A Novel Non-Natural Nucleoside that Influences P- glycoprotein Activity and Mediates Drug Resistance 3.1 Abstract 115 2 3.2 Introduction 116 3.3 Materials and Methods 118 3.4 Results 121 3.5 Discussion 128 Figures 134 Tables 150 Chapter 4: Conclusions and future directions 4.1 Overview 154 4.2 Chapter 2 Conclusions 155 4.3 Chapter 2 Future directions 156 4.4 Chapter 3 Conclusions 163 4.5 Chapter 3 Future directions 164 Figures 170 References 179 3 List of Figures Figure 1.1 Structures of ATP and dATP 33 Figure 1.2 Schematic of a molecular motor and actin assembly 35 Figure 1.3 Representation of a typical ATPase P-loop 37 Figure 1.4 Chemical mechanism of ATP hydrolysis. 39 Figure 1.5 Structures of ATP competitive inhibitors 41 Figure 1.6 Imatinib and cAbl kinase 43 Figure 1.7 Structures and electron density maps of non-natural nucleobases. 45 Figure 1.8 Schematic of translesion DNA synthesis 47 Figure 1.9 Structures of nucleoside analogs used in cancer chemotherapy 49 Figure 1.10 Structures of nucleoside analogs used in anti-viral chemotherapy 51 Figure 1.11 Schematic of replicase formation 53 Figure 1.12 Subunit compositions of clamp loaders from different species 55 Figure 1.13 Sample of the structural diversity of P-gp substrates 57 Figure 1.14 Model of P-glycoprotein transport 59 Figure 1.15 Structure of P-glycoprotein 61 Figure 1.16 ATP switch model 63 Figure 1.17 The occluded nucleotide model 65 Figure 1.18 Structures of the most recent P-glycoprotein inhibitors 67 Figure 2.1 Natural and non-natural nucleobases used in this study 90 Figure 2.2 Hydrolysis of nucleotide substrates by gp44/62 and the effect of r5-NITP and d5-NITP on gp44/62 ATPase activity 92 Figure 2.3 Effects of d5-NITP on T4 replicase formation and gp45 opening 94 4 Figure 2.4 Plot of K i values for various non-natural nucleotides as a function of their respective nucleobase size 96 Figure 2.5 Molecular modeling of the active sites of gp44/62 and γ-complex. 98 Figure 2.6 Alignment of the ATP-binding region of the bacteriophage T4 gp44/62, Saccharomyces cerevisiae RFC, and Escherichia coli γ-complex 100 Figure 2.7 Inhibition of T4 plaque formation by d5-NI 102 Figure 2.8 d5-NI is not bactericidal or bacteriostatic against E. coli . 104 Figure 2.9 Kinetic model for the effects of a competitive inhibitor on the concurrent activity of two independent enzymes that possess different K m values for a common substrate and different K i values for a common competitive inhibitor 106 Figure 2.10 Comparison of the DNA replication mechanisms of E.coli and T4 bacteriophage 111 Figure 3.1 Structures and electrostatic potential models of non-natural nucleosides used in this study 135 Figure 3.2 Stimulation of P-gp ATPase activity by non-natural nucleosides 137 Figure 3.3 Stimulation of P-gp ATPase activity by increasing concentrations of calcein-AM in the presence and absence of d5-CHI or CsA 139 Figure 3.4 Modulation of drug resistance by d5-CHI in KB-V1 cells 141 Figure 3.5 Effects of d5-CHI, d5-CEI, and d5-PhI on the cytotoxicity of paclitaxel and vinblastine in KB-V1 cells 143 Figure 3.6 Effects of d5-CHI on cell viability. 145 Figure 3.7 Comparison of the structures of P-gp interacting compounds 147 Figure 3.8 Trend in ATPase V max /K m ratios and MDR modulation 149 5 Figure 4.1 Schematic of chapter 2 conclusions 171 Figure 4.2 Kinase profiling of non-natural nucleo(s)tides 173 Figure 4.3 Chemical structures of ligands for the 5HT2, histamine H2, adenosine, and melatonin receptors. 175 Figure 4.4 Schematic of model correlating changes in p-glycoprotein ATPase catalytic efficiency with changes in p-glycoprotein mediated drug resistance 177 6 List of Tables Table 1.1 Subunit compositions and functions of clamp loaders from various species 68 Table 2.1 Summary of inhibition constants for natural and non-natural nucleotides against the ATP-dependent clamp loaders from bacteriophage T4 (gp44/62) and Escherichia coli (γ-complex) 112 Table 2.2 Summary of inhibition constants for various non-natural nucleotides against wild-type, R175K, and R175L mutants of gp44/62 114 Table 3.1 Kinetic parameters for the stimulation in ATPase activity by drug substrates 150 Table 3.2 Permeability coefficients of substrates across MDCK and MDCK-MDR monolayers 151 Table 3.3 Effects of d5-CHI on the catalytic efficiency of drug-stimulated P-gp ATPase activity 152 Table 3.4 Effects of d5-CHI on the cytotoxicity of vinblastine (VBL), doxorubicin (DOX), colchicine (COLC), and paclitaxel (TAX) in KB-V1 cells and parental KB-3-1 cells 153 Table 4.1 ABC transporters involved in multidrug resistance and their known substrates 178 7 List of Abbreviations d4-NITP, 4-nitro-indolyl-2’-deoxyriboside triphosphate; d5-NITP, 5-nitro-indolyl-2’- deoxyriboside triphosphate; r5-NITP, 5-nitro-indolyl-2’-ribose triphosphate; d5-NI, 5-nitro- indolyl-2’-deoxyriboside; d6-NITP, 6-nitro-indolyl-2’-deoxyriboside triphosphate; d5-EtITP, 5-ethyl-indolyl-2’-deoxyriboside triphosphate; d5-EyITP, 5-ethylene-indolyl-2’-deoxyriboside triphosphate ; d5-EyInd, 5-ethylene-indolyl-2’-deoxyriboside; d5-FITP, 5-fluoro-indolyl-2’- deoxyriboside triphosphate; d5-FI, 5-fluoro-indolyl-2’-deoxyriboside; dITP, indolyl-2’- deoxyriboside triphosphate; Ind, indolyl-2’-deoxyriboside; d5-CHITP, 5-cyclohexyl-indolyl- 2’-deoxyriboside triphosphate; d5-AITP, 5-amino-indolyl-2’-deoxyriboside triphosphate; d5- CEITP, 5-cyclohexene-indolyl-2’-deoxyriboside triphosphate; d5-CITP, 5-carboxylate- indolyl-2’-deoxyriboside triphosphate; d5-PhITP, 5-phenyl-indolyl-2’-deoxyriboside triphosphate; AMP-PNP, 5'-adenylyl-beta,gamma-imidodiphosphate; gp44/62, bacteriophage T4 sliding clamp loader; gp45, bacteriophage T4 sliding clamp; gp43 exo -, exonuclease-deficient mutant of bacteriophage T4 DNA polymerase; γ complex, E. coli sliding clamp loader; β clamp, E. coli sliding clamp. d5-CEI, 5-cyclohexene indolyl 2’- deoxyribose; d5-CHI, 5-cyclohexyl indolyl 2’-deoxyribose; d5-PhI, 5-phenyl indolyl 2’- deoxyribose; AP→BL, apical to basolateral; BL→AP, basolateral to apical; CsA, cyclosporine A; MDR, multi drug resistance; MDCK, Madin Darby Canine Kidney; MTT, 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NIMH, National Institutes of Mental Health; PDSP, Psychoactive Drug Screening Program; Peff , permeability coefficient; P-gp, P-glycoprotein; SAR, structure activity relationship. 8 Acknowledgements This work would not be possible without the contributions of several individuals. First and foremost, my advisor Dr. Anthony Berdis for providing support and guidance throughout my training. I would also like to thank my committee members Dr. Chris Dealwis, Dr. Shigemi Matsuyama, and Dr. Robert Bonomo whose insights were invaluable to my professional development and Dr. John Mieyal for his guidance. Special thanks to Edward Motea, Xuemei Zhang, and Sandra Craig for their time and effort in providing non- natural nucleotides of the highest quality used throughout all my studies. I am also grateful to Dr. Irene Lee for teaching me the principles of protein purification. I would also like to thank Dr. Babho Devadoss for providing me with the invaluable guidance of a senior graduate. I am also indebted to my undergraduate student, Raphael Bendriem, for his fresh insights to the P-glycoprotein project which helped shape the project as it is today. Special thanks to members of the Berdis lab (past and present); Jackelyn Golden, Andrea Ramos, Asim Sherrif, Robert Bowers, Dave McCutcheon, and Kevin Costanzo for making every workday more enjoyable. Several researchers have provided me with their advice and expertise throughout my studies: Philip Kiser, David Lodowski, Jim Fairman, Jay Prendergast, Seunghwan Lim, Vivian Gama, Jose Gomez, Reema Wahdan, Andrea Moomaw, and Monica Montano. During my time here at Case, I have been truly blessed with many great friends: Eric Lam, Vaibhav Pathak, Chohee Yun, Charlotte Chung, Alejandro Colozo, Paul Park, Debarshi Mustafi, Rod Nibbe, Dasha Hajkova-Leary, Ndiya Ogba, the Marksz family, Stasha Razack, Jared Klaus, and Joe Dea.
Recommended publications
  • Chapter Four – TRPA1 Channels: Chemical and Temperature Sensitivity
    CHAPTER FOUR TRPA1 Channels: Chemical and Temperature Sensitivity Willem J. Laursen1,2, Sviatoslav N. Bagriantsev1,* and Elena O. Gracheva1,2,* 1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA 2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA *Corresponding author: E-mail: elena.gracheva@yale.edu, sviatoslav.bagriantsev@yale.edu Contents 1. Introduction 90 2. Activation and Regulation of TRPA1 by Chemical Compounds 91 2.1 Chemical activation of TRPA1 by covalent modification 91 2.2 Noncovalent activation of TRPA1 97 2.3 Receptor-operated activation of TRPA1 99 3. Temperature Sensitivity of TRPA1 101 3.1 TRPA1 in mammals 101 3.2 TRPA1 in insects and worms 103 3.3 TRPA1 in fish, birds, reptiles, and amphibians 103 3.4 TRPA1: Molecular mechanism of temperature sensitivity 104 Acknowledgments 107 References 107 Abstract Transient receptor potential ankyrin 1 (TRPA1) is a polymodal excitatory ion channel found in sensory neurons of different organisms, ranging from worms to humans. Since its discovery as an uncharacterized transmembrane protein in human fibroblasts, TRPA1 has become one of the most intensively studied ion channels. Its function has been linked to regulation of heat and cold perception, mechanosensitivity, hearing, inflam- mation, pain, circadian rhythms, chemoreception, and other processes. Some of these proposed functions remain controversial, while others have gathered considerable experimental support. A truly polymodal ion channel, TRPA1 is activated by various stimuli, including electrophilic chemicals, oxygen, temperature, and mechanical force, yet the molecular mechanism of TRPA1 gating remains obscure. In this review, we discuss recent advances in the understanding of TRPA1 physiology, pharmacology, and molecular function.
    [Show full text]
  • The Emerging Role of Transient Receptor Potential Channels in Chronic Lung Disease
    BACK TO BASICS | TRANSIENT RECEPTOR POTENTIAL CHANNELS IN CHRONIC LUNG DISEASE The emerging role of transient receptor potential channels in chronic lung disease Maria G. Belvisi and Mark A. Birrell Affiliation: Respiratory Pharmacology Group, Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK. Correspondence: Maria G. Belvisi, Respiratory Pharmacology Group, Airway Disease Section, National Heart and Lung Institute, Imperial College, Exhibition Road, London SW7 2AZ, UK. E-mail: m.belvisi@imperial.ac.uk @ERSpublications Transient receptor potential channels are emerging as novel targets for chronic lung diseases with a high unmet need http://ow.ly/GHeR30b3hIy Cite this article as: Belvisi MG, Birrell MA. The emerging role of transient receptor potential channels in chronic lung disease. Eur Respir J 2017; 50: 1601357 [https://doi.org/10.1183/13993003.01357-2016]. ABSTRACT Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis are a major and increasing global health burden with a high unmet need. Drug discovery efforts in this area have been largely disappointing and so new therapeutic targets are needed. Transient receptor potential ion channels are emerging as possible therapeutic targets, given their widespread expression in the lung, their role in the modulation of inflammatory and structural changes and in the production of respiratory symptoms, such as bronchospasm and cough, seen in chronic lung disease. Received: Jan 08 2017 | Accepted after revision: April 14 2017 Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com Copyright ©ERS 2017 https://doi.org/10.1183/13993003.01357-2016 Eur Respir J 2017; 50: 1601357 TRANSIENT RECEPTOR POTENTIAL CHANNELS IN CHRONIC LUNG DISEASE | M.G.
    [Show full text]
  • Nerve Agent - Lntellipedia Page 1 Of9 Doc ID : 6637155 (U) Nerve Agent
    This document is made available through the declassification efforts and research of John Greenewald, Jr., creator of: The Black Vault The Black Vault is the largest online Freedom of Information Act (FOIA) document clearinghouse in the world. The research efforts here are responsible for the declassification of MILLIONS of pages released by the U.S. Government & Military. Discover the Truth at: http://www.theblackvault.com Nerve Agent - lntellipedia Page 1 of9 Doc ID : 6637155 (U) Nerve Agent UNCLASSIFIED From lntellipedia Nerve Agents (also known as nerve gases, though these chemicals are liquid at room temperature) are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. The disruption is caused by blocking acetylcholinesterase, an enzyme that normally relaxes the activity of acetylcholine, a neurotransmitter. ...--------- --- -·---- - --- -·-- --- --- Contents • 1 Overview • 2 Biological Effects • 2.1 Mechanism of Action • 2.2 Antidotes • 3 Classes • 3.1 G-Series • 3.2 V-Series • 3.3 Novichok Agents • 3.4 Insecticides • 4 History • 4.1 The Discovery ofNerve Agents • 4.2 The Nazi Mass Production ofTabun • 4.3 Nerve Agents in Nazi Germany • 4.4 The Secret Gets Out • 4.5 Since World War II • 4.6 Ocean Disposal of Chemical Weapons • 5 Popular Culture • 6 References and External Links --------------- ----·-- - Overview As chemical weapons, they are classified as weapons of mass destruction by the United Nations according to UN Resolution 687, and their production and stockpiling was outlawed by the Chemical Weapons Convention of 1993; the Chemical Weapons Convention officially took effect on April 291997. Poisoning by a nerve agent leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles.
    [Show full text]
  • * * * Chemical Agent * * * Instructor's Manual
    If you have issues viewing or accessing this file contact us at NCJRS.gov. · --. -----;-:-.. -----:-~------ '~~~v:~r.·t..~ ._.,.. ~Q" .._L_~ •.• ~,,,,,.'.,J-· .. f.\...('.1..-":I- f1 tn\. ~ L. " .:,"."~ .. ,. • ~ \::'J\.,;;)\ rl~ lL/{PS-'1 J National Institute of Corrections Community Corrections Division * * * CHEMICAL AGENT * * * INSTRUCTOR'S MANUAL J. RICHARD FAULKNER, JR. CORRECTIONAL PROGRAM SPECIALIST NATIONAL INSTITUTE OF CORRECTIONS WASIHNGTON, DC 20534 202-307-3106 - ext.138 , ' • 146592 U.S. Department of Justice National Institute of Justice This document has been reproduced exactly as received from the person or organization originating it. Points of view or opinions stated In tl]!::; document are those of the authors and do not necessarily represent the official position or policies of the National Institute of Justice. Permission to reproduce this "'"P 'J' ... material has been granted by Public Domain/NrC u.s. Department of Justice to the National Criminal Justice Reference Service (NCJRS). • Further reproduction outside of the NCJRS system reqllires permission of the f ._kt owner, • . : . , u.s. Deparbnent of Justice • National mstimte of Corrections Wtulringttm, DC 20534 CHEMICAL AGENTS Dangerous conditions that are present in communities have raised the level of awareness of officers. In many jurisdictions, officers have demanded more training in self protection and the authority to carry lethal weapons. This concern is a real one and administrators are having to address issues of officer safety. The problem is not a simple one that can be solved with a new policy. Because this involves safety, in fact the very lives of staff, the matter is extremely serious. Training must be adopted to fit policy and not violate the goals, scope and mission of the agency.
    [Show full text]
  • Nitrous Oxide (N2O) Isotopic Composition in the Troposphere: Instrumentation, Observations at Mace Head, Ireland, and Regional Modeling
    Nitrous oxide (N2O) isotopic composition in the troposphere: instrumentation, observations at Mace Head, Ireland, and regional modeling by Katherine Ellison Potter B.S. Chemistry & Environmental Science College of William and Mary, 2004 SUBMITTED TO THE DEPARTMENT OF EARTH, ATMOSPHERIC, AND PLANETARY SCIENCES IN PARTIAL FULFULLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CLIMATE PHYSICS AND CHEMISTRY AT THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY SEPTEMBER 2011 © 2011 Massachusetts Institute of Technology. All rights reserved. Signature of Author: _____________________________________________________________ Department of Earth, Atmospheric, and Planetary Sciences 19 August 2011 Certified by: ___________________________________________________________________ Ronald G. Prinn TEPCO Professor of Atmospheric Chemistry Thesis Supervisor Certified by: ___________________________________________________________________ Shuhei Ono Assistant Professor Thesis Co-Supervisor Accepted by: ___________________________________________________________________ Maria T. Zuber E.A. Griswold Professor of Geophysics and Planetary Science Department Head 2 Nitrous oxide (N2O) isotopic composition in the troposphere: instrumentation, observations at Mace Head, Ireland, and regional modeling by Katherine Ellison Potter Submitted to the Department of Earth, Atmospheric, and Planetary Sciences on 19 August 2011 in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Climate Physics and Chemistry Abstract Nitrous
    [Show full text]
  • Ambient Formaldehyde Measurements Made at A
    Ambient formaldehyde measurements made at a remote marine boundary layer site during the NAMBLEX campaign ? a comparison of data from chromatographic and modified Hantzsch techniques T. J. Still, S. Al-Haider, P. W. Seakins, R. Sommariva, J. C. Stanton, G. Mills, S. A. Penkett To cite this version: T. J. Still, S. Al-Haider, P. W. Seakins, R. Sommariva, J. C. Stanton, et al.. Ambient formaldehyde measurements made at a remote marine boundary layer site during the NAMBLEX campaign ? a comparison of data from chromatographic and modified Hantzsch techniques. Atmospheric Chemistry and Physics, European Geosciences Union, 2006, 6 (9), pp.2711-2726. hal-00295970 HAL Id: hal-00295970 https://hal.archives-ouvertes.fr/hal-00295970 Submitted on 6 Jul 2006 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Atmos. Chem. Phys., 6, 2711–2726, 2006 www.atmos-chem-phys.net/6/2711/2006/ Atmospheric © Author(s) 2006. This work is licensed Chemistry under a Creative Commons License. and Physics Ambient formaldehyde measurements made at a remote marine boundary layer site during the NAMBLEX campaign – a comparison of data from chromatographic and modified Hantzsch techniques T.
    [Show full text]
  • CLINICAL REVIEW Management of the Effects of Exposure to Tear
    CLINICAL REVIEW For the full versions of these articles see bmj.com Management of the effects of exposure to tear gas Pierre-Nicolas Carron, Bertrand Yersin Service of Emergency Medicine, Despite the frequent use of riot control agents by Eur- solvent, and delivered with a dispersion vehicle (a University Hospital Center and opean law enforcement agencies, limited information pyrotechnically delivered aerosol or spray University of Lausanne, 1011 exists on this subject in the medical literature. The solution).45 Tear gases are not currently considered as Lausanne CHUV, Switzerland Correspondence to: P-N Carron effects of these agents are typically limited to minor chemical weapons by Western countries. Since the Pierre-Nicolas.Carron@chuv.ch and transient cutaneous inflammation, but serious 1950s, they have been mainly used by law enforcement complications and even deaths have been reported. agencies for crowd control purposes in most European Cite this as: BMJ 2009;338:b2283 doi:10.1136/bmj.b2283 During the 1999 World Trade Organisation meeting countries, including the United Kingdom, France, and at the 2001 Summit of the Americas in Quebec, Germany, and Switzerland. Tear gases are also used exposure to tear gas was the most common reason for in military training exercises to test the rapidity or effi- medical consultations.12 Primary and emergency care cacy of protective measures in the event of a chemical physicians play a role in the first line management of attack. patients as well as in the identification of those at risk of Of the known disabling chemical irritants (of which complications from exposure to riot control agents.
    [Show full text]
  • Fluorescent Micro Sphere^ U.S
    [111 4,413,070 [451 Nov. I, 3983 [54] PQLYACRQLEIN MICRQSPHERES 4,210,565 7/1980 Emrnons ............................. 526/315 4,230,772 10/1980 Swift et al. .......................... 526/315 [75] Inventor: Alan Rembaum, Pasadena, Calif. 4,267,091 5/1981 Geelhaar et al. ................... 526/315 [73] Assignee: California Institute of Technology, OTHER PUBLICATIONS Pasadena, Calif. “Characteristics of Fine Particles” Chemical Engineer- [21] Appl. No.: 248,899 ing, Jun. 11, 1962, p. 207. E221 Filed: Mar. 30, 1981 Primary Examiner-Wilbert J. Briggs, Sr. Assistant Examiner-A. H. Koeckert [51] Int. (3.3 .......................... C08F 2/54; C08F 16/34 Attorney, Agent, or Firm-Marvin E. Jacobs [52] U.S. Cl. ............................... 523/223; 204A59.21; 435/180; 526/315; 526/303.1; 252/301.36; [571 ABSTRACT 252/62.54; 424/82; 525/377; 525/380; 525/382 Microspheres of acrolein homopolymers and co- [58] Field of Search ........................ 526/315; 523/223; polymer with hydrophillic comonomers such as meth- 435/180 acrylic acid and/or hydroxyethylmethacrylate are pre- 1561 References Cited pared by cobalt gamma irradiation of dilute aqueous solutions of the monomers in presence of suspending U.S. PATENT DOCUMENTS agents, especially alkyl sulfates such as sodium dodecyl 3,105,801 10/1963 Bell et al. ............................ 204/154 sulfate. Amine or hydroxyl modification is achieved by 3,819,555 6/1974 Kaufman ............................. 526/315 forming adducts with diamines or alkanol amines. Car- 3,936,423 2/1976 Randazzo ............................ 526/315 boxyl modification is effected by oxidation with perox- 3,957,741 5/1978 Rembaum ...................... 204/159.15 ides. Pharmaceuticals or other aldehyde reactive mate- 3,988,505 10/1976 Evans et al.
    [Show full text]
  • An Ayurvedic Approach to the Use of Cannabis to Treat Anxiety By: Danielle Bertoia at (Approximately) Nearly 5000 Years Old, Ay
    An Ayurvedic Approach to the use of Cannabis to treat Anxiety By: Danielle Bertoia At (approximately) nearly 5000 years old, Ayurveda is touted as being one of, if not the oldest healing modality on the planet. The word Ayurveda translates from Sanskrit to “The Science of Life” and is based on the theory that each of us are a unique blend of the 5 elements that make up the known Universe and our planet. Earth, air, fire, water and ether all combine together to create our physical form. When living in harmony with the rhythms of nature and in accordance to our unique constitution, health prevails. When we step outside of our nature by eating foods that are not appropriate, exposing ourselves to outside stressors, and by ignoring the power of our internal knowing, we then leave ourselves vulnerable to dis-ease. Doshic theory reveals to us that these 5 elements then combine with one another to create 3 Doshas. Air and Ether come together to create Vata, Fire and Water to create Pitta and Earth and Water to create Kapha. As we take our first breath upon birth, we settle into our Primary, Secondary and Tertiary doshas, also known as our Prakruti. This becomes our initial blueprint, our Health Touchstone if you will, which we will spend our lifetimes endeavoring to preserve. As time and experience march on, we may begin to experience a distancing from this initial blueprint, a disconnect from our true health, also known as our Vikruti. Outside stress, incorrect food choices, our personal karma and incorrect seasonal diet can all contribute to an imbalanced state within the doshas.
    [Show full text]
  • CS Gas Exposure in a Crowded Night Club: the Consequences for an Accident and Emergency Department
    56 Case reports 9 Selbst SM, De Maio JG, Boenning D. Mouth wash poison- 13 Simon HK, Cox JM, Sucov A, Linakis JG. Ethanol ing. Clin Pediatr 1985;24:162-3. clearance in intoxicated children and adolescents present- 10 Wright J. Ethanol-induced hypoglycaemia. Br J Alcohol ing to the ED. Acad Emerg Med 1994;1:520-4. Alcoholism 1979;14:174-6. 14 Gibson PJ, Cant AJ, Mant TGK. Ethanol poisoning. Acta 11 Ricci LR, Hoffman S. Ethanol induced hypoglycaemic Paediatr Scand 1985;74:977-8. J Accid Emerg Med: first published as 10.1136/emj.15.1.56 on 1 January 1998. Downloaded from coma in a child. Ann Emerg Med 1982;1 1:203-4. 15 Pollack CV, Jorden RC, Carlton FB, Baker ML. Gastric 12 Gershman H, Steeper J. Rate of clearance of ethanol from emptying in the acutely inebriated patient. J Emerg Med the blood of intoxicated patients in the emergency depart- 1992; 10: 1-5. ment. J Emerg Med 199 1;9:307-1 1. See also letters on p00 CS gas exposure in a crowded night club: the consequences for an accident and emergency department A Breakell, G G Bodiwala Abstract respiratory problems, seven required supple- A case is reported of deliberate release of mental oxygen. Two of these patients suffered CS gas (O-chlorobenzylidene malononi- from asthma. Clinically none of the patients trile) in an enclosed space and the conse- developed wheeze but one asthmatic patient quences for an accident and emergency required a nebuliser for chest tightness. One department. patient was admitted to hospital with persistent (7AccidEmergMed 1998;15:56-64) chest tightness and sore throat.
    [Show full text]
  • Acrylonitrile
    ACRYLONITRILE This substance was considered by previous Working Groups, in February 1978 (IARC, 1979) and March 1987 (IARC, 1987a). Since that time, new data have become available, and these have been incorporated into the monograph and taken into consi- deration in the present evaluation. 1. Exposure Data 1.1 Chemical and physical data 1.1.1 Nomenclature Chem. Abstr. Serv. Reg. No.: 107-13-1 Chem. Abstr. Name: 2-Propenenitrile Synonyms: AN; cyanoethylene; propenenitrile; VCN; vinyl cyanide 1.1.2 Structural and molecular formulae and relative molecular mass H2 CCHCN C3H3N Relative molecular mass: 53.06 1.1.3 Chemical and physical properties of the pure substance (a) Description: Colourless liquid (Verschueren, 1996) (b) Boiling-point: 77.3°C (Lide, 1995) (c) Melting-point: –83.5°C (Lide, 1995) 20 (d) Density: d4 0.8060 (Lide, 1995) (e) Spectroscopy data: Infrared, nuclear magnetic resonance and mass spectral data have been reported (Sadtler Research Laboratories, 1980; Brazdil, 1991) (f) Solubility: Soluble in water (7.35 mL/100 mL at 20°C); very soluble in acetone, benzene, diethyl ether and ethanol (Lide, 1995; Budavari, 1996) (g) Volatility: Vapour pressure, 13.3 kPa at 23°C; relative vapour density (air = 1), 1.83 (Verschueren, 1996) (h) Stability: Flash-point (open cup), 0°C; flammable; polymerizes spontaneously, particularly in the absence of oxygen, on exposure to visible light and in contact with concentrated alkali (Budavari, 1996) (i) Explosive limits: Lower, 3.05%; upper, 17.0% (Budavari, 1996) (j) Octanol/water partition coefficient (P): log P, 0.25 (Hansch et al., 1995) –43– 44 IARC MONOGRAPHS VOLUME 71 (k) Conversion factor: mg/m3 = 2.17 × ppm1 1.1.4 Technical products and impurities Acrylonitrile of 99.5–99.7% purity is available commercially, with the following specifications (ppm by weight, maximum): acidity (as acetic acid), 10; acetone, 75; ace- tonitrile, 300; acrolein, 1; hydrogen cyanide, 5; total iron, 0.1; oxazole, 10; peroxides (as hydrogen peroxide), 0.2; water, 0.5%; and nonvolatile matter, 100.
    [Show full text]
  • FCC 10, Second Supplement the Following Index Is for Convenience and Informational Use Only and Shall Not Be Used for Interpretive Purposes
    Index to FCC 10, Second Supplement The following Index is for convenience and informational use only and shall not be used for interpretive purposes. In addition to effective articles, this Index may also include items recently omitted from the FCC in the indicated Book or Supplement. The monographs and general tests and assay listed in this Index may reference other general test and assay specifications. The articles listed in this Index are not intended to be autonomous standards and should only be interpreted in the context of the entire FCC publication. For the most current version of the FCC please see the FCC Online. Second Supplement, FCC 10 Index / Allura Red AC / I-1 Index Titles of monographs are shown in the boldface type. A 2-Acetylpyrrole, 21 Alcohol, 90%, 1625 2-Acetyl Thiazole, 18 Alcohol, Absolute, 1624 Abbreviations, 7, 3779, 3827 Acetyl Valeryl, 608 Alcohol, Aldehyde-Free, 1625 Absolute Alcohol (Reagent), 5, 3777, Acetyl Value, 1510 Alcohol C-6, 626 3825 Achilleic Acid, 25 Alcohol C-8, 933 Acacia, 602 Acid (Reagent), 5, 3777, 3825 Alcohol C-9, 922 ªAccuracyº, Defined, 1641 Acid-Hydrolyzed Milk Protein, 22 Alcohol C-10, 390 Acesulfame K, 9 Acid-Hydrolyzed Proteins, 22 Alcohol C-11, 1328 Acesulfame Potassium, 9 Acid Calcium Phosphate, 240 Alcohol C-12, 738 Acetal, 10 Acid Hydrolysates of Proteins, 22 Alcohol C-16, 614 Acetaldehyde, 11 Acidic Sodium Aluminum Phosphate, Alcohol Content of Ethyl Oxyhydrate Acetaldehyde Diethyl Acetal, 10 1148 Flavor Chemicals (Other than Acetaldehyde Test Paper, 1636 Acidified Sodium Chlorite
    [Show full text]