Nerve Agents
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Modifications on the Basic Skeletons of Vinblastine and Vincristine
Molecules 2012, 17, 5893-5914; doi:10.3390/molecules17055893 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Modifications on the Basic Skeletons of Vinblastine and Vincristine Péter Keglevich, László Hazai, György Kalaus and Csaba Szántay * Department of Organic Chemistry and Technology, University of Technology and Economics, H-1111 Budapest, Szt. Gellért tér 4, Hungary * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel: +36-1-463-1195; Fax: +36-1-463-3297. Received: 30 March 2012; in revised form: 9 May 2012 / Accepted: 10 May 2012 / Published: 18 May 2012 Abstract: The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties. Keywords: antitumor therapy; vinblastine; vincristine; derivatives 1. Introduction Vinblastine (1) and vincristine (2) are dimeric alkaloids (Figure 1) isolated from the Madagaskar periwinkle plant (Catharantus roseus), exhibit significant cytotoxic activity and are used in the antitumor therapy as antineoplastic agents. In the course of cell proliferation they act as inhibitors during the metaphase of the cell cycle and by binding to the microtubules inhibit the development of the mitotic spindle. In tumor cells these agents inhibit the DNA repair and the RNA synthesis mechanisms, blocking the DNA-dependent RNA polymerase. Molecules 2012, 17 5894 Figure 1. -
Carbamate Pesticides Aldicarb Aldicarb Sulfoxide Aldicarb Sulfone
Connecticut General Statutes Sec 19a-29a requires the Commissioner of Public Health to annually publish a list setting forth all analytes and matrices for which certification for testing is required. Connecticut ELCP Drinking Water Analytes Revised 05/31/2018 Microbiology Total Coliforms Fecal Coliforms/ E. Coli Carbamate Pesticides Legionella Aldicarb Cryptosporidium Aldicarb Sulfoxide Giardia Aldicarb Sulfone Carbaryl Physicals Carbofuran Turbidity 3-Hydroxycarbofuran pH Methomyl Conductivity Oxamyl (Vydate) Minerals Chlorinated Herbicides Alkalinity, as CaCO3 2,4-D Bromide Dalapon Chloride Dicamba Chlorine, free residual Dinoseb Chlorine, total residual Endothall Fluoride Picloram Hardness, Calcium as Pentachlorophenol CaCO3 Hardness, Total as CaCO3 Silica Chlorinated Pesticides/PCB's Sulfate Aldrin Chlordane (Technical) Nutrients Dieldrin Endrin Ammonia Heptachlor Nitrate Heptachlor Epoxide Nitrite Lindane (gamma-BHC) o-Phosphate Metolachlor Total Phosphorus Methoxychlor PCB's (individual aroclors) Note 1 PCB's (as decachlorobiphenyl) Note 1 Demands Toxaphene TOC Nitrogen-Phosphorus Compounds Alachlor Metals Atrazine Aluminum Butachlor Antimony Diquat Arsenic Glyphosate Barium Metribuzin Beryllium Paraquat Boron Propachlor Cadmium Simazine Calcium Chromium Copper SVOC's Iron Benzo(a)pyrene Lead bis-(2-ethylhexyl)phthalate Magnesium bis-(ethylhexyl)adipate Manganese Hexachlorobenzene Mercury Hexachlorocyclopentadiene Molybdenum Nickel Potassium Miscellaneous Organics Selenium Dibromochloropropane (DBCP) Silver Ethylene Dibromide (EDB) -
Pyridostigmine in the Treatment of Postural
Pyridostigmine in the Treatment of Postural Orthostatic Tachycardia: A Single-Center Experience KHALIL KANJWAL, M.D.,* BEVERLY KARABIN, PH.D.,* MUJEEB SHEIKH, M.D.,* LAWRENCE ELMER, M.D., PH.D.,† YOUSUF KANJWAL, M.D.,* BILAL SAEED, M.D.,* and BLAIR P. GRUBB, M.D.* From the *Electrophysiology Section, Division of Cardiology, Department of Medicine, The University of Toledo, Toledo, Ohio; and †Department of Neurology, The University of Toledo College of Medicine, Health Science Campus, Toledo, Ohio Background: The long-term efficacy of pyridostigmine, a reversible acetyl cholinesterase inhibitor, in the treatment of postural orthostatic tachycardia syndrome (POTS) patients remains unclear. We report our retrospective, single-center, long-term experience regarding the efficacy and adverse effect profile of pyridostigmine in the treatment of POTS patients. Methods: This retrospective study included an extensive review of electronic charts and data collection in regards to patient demographics, orthostatic parameters, side-effect profile, subjective response to therapy, as well as laboratory studies recorded at each follow-up visit to our institution’s Syncope and Autonomic Disorders Center. The response to pyridostigmine therapy was considered successful if patient had both symptom relief in addition to an objective response in orthostatic hemodynamic parameters (heart rate [HR] and blood pressure). Three hundred patients with POTS were screened for evaluation in this study. Of these 300, 203 patients with POTS who received pyridostigmine therapy were reviewed. Of these 203 patients, 168 were able to tolerate the medication after careful dose titration. The mean follow- up duration in this group of patients was 12 ± 3 (9–15) months. Pyridostigmine improved symptoms of orthostatic intolerance in 88 of 203 (43%) of total patients or 88 of 172 (51%) who were able to tolerate the drug. -
WO 2018/005077 Al O O© O
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/005077 Al 04 January 2018 (04.01.2018) W ! P O PCT (51) International Patent Classification: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, A61K 31/78 (2006.01) C08J 7/04 (2006.01) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. C08G 59/77 (2006.01) (84) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of regional protection available): ARIPO (BW, GH, PCT/US20 17/037 176 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (22) International Filing Date: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 13 June 2017 (13.06.2017) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (25) Filing Language: English MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (26) Publication Language: English KM, ML, MR, NE, SN, TD, TG). (30) Priority Data: 62/356,918 30 June 2016 (30.06.2016) US Published: — with international search report (Art. 21(3)) (71) Applicant: ELEMENTIS SPECIALTIES, INC. [US/US]; 469 Old Trenton Road, East Windsor, NJ 085 12 (US). (72) Inventors: IJDO, Wouter; 1224 Bridle Estates Dri ve, Yardley, PA 19067 (US). CHEN, Yanhui; 4 Hal- stead Place, Princeton, NJ 08540 (US). -
Potential Applicability of Assembled Chemical Weapons Assessment Technologies to RCRA Waste Streams and Contaminated Media EPA 542-R-00-004 August 2000
United States Solid Waste and EPA 542-R-00-004 Environmental Protection Emergency Response August 2000 Agency (5102G) www.epa.gov clu-in.org EPA Potential Applicability of Assembled Chemical Weapons Assessment Technologies to RCRA Waste Streams and Contaminated Media EPA 542-R-00-004 August 2000 POTENTIAL APPLICABILITY OF ASSEMBLED CHEMICAL WEAPONS ASSESSMENT TECHNOLOGIES TO RCRA WASTE STREAMS AND CONTAMINATED MEDIA U.S. Environmental Protection Agency Office of Solid Waste and Emergency Response Technology Innovation Office Washington, DC 20460 Potential Applicability of ACWA Technologies to RCRA Waste Streams and Contaminated Media NOTICE AND DISCLAIMER This document was prepared by the U.S. Environmental Protection Agency’s Technology Innovation Office with support under EPA Contract Number 68-W-99-003. It is intended to raise the awareness of the technologies included in the Assembled Chemical Weapons Assessment (ACWA) program, and presents an overview of each technology, including its applicability, performance, and other factors. Information about the technologies was obtained from the technology providers. No testing or evaluation was conducted by EPA during preparation of this document, and an independent assessment of this information was beyond EPA’s scope. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. For more information about this project, please contact: John Kingscott, U.S. Environmental Protection Agency, Technology Innovation Office, Ariel Rios Building, 1200 Pennsylvania Avenue, N.W. (MS 5102G), Washington, D.C., 20460; (703) 603-7189; e-mail: [email protected]. This document may be obtained from EPA’s web site at www.epa.gov/tio, or at clu-in.org. -
Verification of Chemical Warfare Agent Exposure in Human Samples
Toxichem Krimtech 2013;80(Special Issue):288 Verification of chemical warfare agent exposure in human samples Paul W. Elsinghorst, Horst Thiermann, Marianne Koller Institut für Pharmakologie und Toxikologie der Bundeswehr, München Abstract Aim: This brief presentation provides an overview of methods that have been developed for the verification of human exposure to chemical warfare agents. Methods: GC–MS detection of nerve agents (V- and G-type) has been carried out with respect to unreacted agents as well as enzyme-bound species and metabolites. Methods involving di- rect SPE from plasma, fluoride-induced release of protein-bound nerve agents in plasma and analysis of their metabolites in plasma and urine have been developed. Exposure to blistering agents, i.e., sulfur mustard, has been verified by GC–MS detection of the unreacted agent in plasma and by LC– and GC–MS analysis of its metabolites in urine. Results: After incorporation nerve agents quickly bind to proteins, e.g., acetylcholinesterase, butyrylcholinesterase or serum albumin, and only small parts remain freely circulating for a few hours (G-type) or up to 2 days (V-type). Concurrently they are converted to O-alkyl methylphosphonic acids by phosphotriesterases and/or simply by aqueous hydrolysis. As a re- sult, different biomarkers can be detected depending on the time passed between exposure and sampling. Unreacted V-type agents can be detected in plasma for 2 days, the O-alkyl methyl- phosphonic acids in plasma for about 2–4 days and in urine for up to 1 week. Fluoride-indu- ced release of protein-bound nerve agents can be carried out until 3 weeks post exposure. -
Corticosterone and Pyridostigmine/DEET Exposure
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Neurotoxicology Manuscript Author . Author Manuscript Author manuscript; available in PMC 2019 May 24. Published in final edited form as: Neurotoxicology. 2019 January ; 70: 26–32. doi:10.1016/j.neuro.2018.10.006. Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness Lindsay T. Michalovicza, Alicia R. Lockera, Kimberly A. Kellya, Julie V. Millera, Zachary Barnesb,c, Mary Ann Fletcherb,c, Diane B. Millera, Nancy G. Klimasb,c, Mariana Morrisb, Stephen M. Lasleyd, and James P. O’Callaghana,* aHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, USA bInstitute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA cMiami Veterans Affairs Medical Center, Miami, FL, USA dDepartment of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA Abstract Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. -
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. -
Warning: the Following Lecture Contains Graphic Images
What the новичок (Novichok)? Why Chemical Warfare Agents Are More Relevant Than Ever Matt Sztajnkrycer, MD PHD Professor of Emergency Medicine, Mayo Clinic Medical Toxicologist, Minnesota Poison Control System Medical Director, RFD Chemical Assessment Team @NoobieMatt #ITLS2018 Disclosures In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards, the American Nurses Credentialing Center’s Commission (ANCC) and the Commission on Accreditation for Pre-Hospital Continuing Education (CAPCE), states presenters must disclose the existence of significant financial interests in or relationships with manufacturers or commercial products that may have a direct interest in the subject matter of the presentation, and relationships with the commercial supporter of this CME activity. The presenter does not consider that it will influence their presentation. Dr. Sztajnkrycer does not have a significant financial relationship to report. Dr. Sztajnkrycer is on the Editorial Board of International Trauma Life Support. Specific CW Agents Classes of Chemical Agents: The Big 5 The “A” List Pulmonary Agents Phosgene Oxime, Chlorine Vesicants Mustard, Phosgene Blood Agents CN Nerve Agents G, V, Novel, T Incapacitating Agents Thinking Outside the Box - An Abbreviated List Ammonia Fluorine Chlorine Acrylonitrile Hydrogen Sulfide Phosphine Methyl Isocyanate Dibotane Hydrogen Selenide Allyl Alcohol Sulfur Dioxide TDI Acrolein Nitric Acid Arsine Hydrazine Compound 1080/1081 Nitrogen Dioxide Tetramine (TETS) Ethylene Oxide Chlorine Leaks Phosphine Chlorine Common Toxic Industrial Chemical (“TIC”). Why use it in war/terror? Chlorine Density of 3.21 g/L. Heavier than air (1.28 g/L) sinks. Concentrates in low-lying areas. Like basements and underground bunkers. Reacts with water: Hypochlorous acid (HClO) Hydrochloric acid (HCl). -
Title 16. Crimes and Offenses Chapter 13. Controlled Substances Article 1
TITLE 16. CRIMES AND OFFENSES CHAPTER 13. CONTROLLED SUBSTANCES ARTICLE 1. GENERAL PROVISIONS § 16-13-1. Drug related objects (a) As used in this Code section, the term: (1) "Controlled substance" shall have the same meaning as defined in Article 2 of this chapter, relating to controlled substances. For the purposes of this Code section, the term "controlled substance" shall include marijuana as defined by paragraph (16) of Code Section 16-13-21. (2) "Dangerous drug" shall have the same meaning as defined in Article 3 of this chapter, relating to dangerous drugs. (3) "Drug related object" means any machine, instrument, tool, equipment, contrivance, or device which an average person would reasonably conclude is intended to be used for one or more of the following purposes: (A) To introduce into the human body any dangerous drug or controlled substance under circumstances in violation of the laws of this state; (B) To enhance the effect on the human body of any dangerous drug or controlled substance under circumstances in violation of the laws of this state; (C) To conceal any quantity of any dangerous drug or controlled substance under circumstances in violation of the laws of this state; or (D) To test the strength, effectiveness, or purity of any dangerous drug or controlled substance under circumstances in violation of the laws of this state. (4) "Knowingly" means having general knowledge that a machine, instrument, tool, item of equipment, contrivance, or device is a drug related object or having reasonable grounds to believe that any such object is or may, to an average person, appear to be a drug related object. -
Medical Control of the Glaucomas
Br J Ophthalmol: first published as 10.1136/bjo.56.3.272 on 1 March 1972. Downloaded from 272 call these cases of malignant glaucoma, using the old term in a new broader sense, or whether we devise a new terminology to describe such phenomena should perhaps await further experimentation. Conclusion Many questions still remain in regard to malignant glaucoma, and it is to be hoped that future observations will gradually elucidate them. Today, however, medical therapy consisting of the concurrent use of mydriatic-cycloplegic drops, carbonic anhydrase inhibitors, and hyperosmotic agents is available, and is proving to be effective in half the cases when continued for 5 days. In addition, the vitreous surgery described above is in our opinion a safe and reliable surgical procedure in cases of malignant glaucoma which are not relieved by medical therapy. COMMENTARY MALIGNANT GLAUCOMA Chandler's anterior chamber deepening procedure with gonioscopy used for diagnosis of the extent of synaechial closure of the angle does not seem to predispose to malignant glaucoma. Even though it is known that there is a predisposition to malignant glaucoma in the fellow eye, this eye should always be treated with a peripheral iridectomy as early as possible after the onset of malignant glaucoma in the opposite eye. No medical treatment of any sort should be given before the peripheral iridectomy, since both miotics and mydriatics may be dangerous before surgerycopyright. is performed. If the fellow eye has been operated upon when the angle has been completely open, then malignant glaucoma has not occurred. However, if angle-closure is present in the fellow eye at the time of surgery, then malignant glaucoma becomes very common. -
Nerve Agent Hydrolysis Activity Designed Into a Human Drug Metabolism Enzyme
Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme Andrew C. Hemmert1, Tamara C. Otto2, Roberto A. Chica3¤, Monika Wierdl4, Jonathan S. Edwards1, Steven L. Lewis1, Carol C. Edwards4, Lyudmila Tsurkan4, C. Linn Cadieux2, Shane A. Kasten2, John R. Cashman5, Stephen L. Mayo3, Philip M. Potter4, Douglas M. Cerasoli2, Matthew R. Redinbo1* 1 Department of Biochemistry/Biophysics and Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 2 United States Army Medical Research Institute for Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America, 3 Department of Biology and Chemistry, California Institute of Technology, Pasadena, California, United States of America, 4 Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America, 5 Human BioMolecular Research Institute, San Diego, California, United States of America Abstract Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme’s native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates.