Medical Aspects of Chemical Warfare (2008) - The Black Vault

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Nerve Agent Bioscavenger: Development of a New Approach to Protect Against Organophosphorus ExposureChapter 7NERVE AGENT BIOSCAVENGER:DEVELOPMENT OF A NEW APPROACHTO PROTECT AGAINST ORGANO-PHOSPHORUS EXPOSUREMichelle C. Ross, DVM, PhD*; Clarence A. Broomfield, PhD † ; Douglas M. Cerasoli, PhD ‡ ;Bhupendra P. Doctor, PhD § ; David E. Lenz, PhD ¥ ; Donald M. Maxwell, ms ; a n d Ashima Saxena, PhD **INTRODUCTIONPLASMA-DERIVED STOICHIOMETRIC BIOSCAVENGERSCholinesterasesPharmacokinetics and the Safety of Plasma-Derived Human ButyrylcholinesteraseIn Vitro and In Vivo Stability of Plasma-Derived Human ButyrylcholinesteraseEfficacy of Plasma-Derived Human ButyrylcholinesteraseImmunological Safety of Plasma-Derived ButyrylcholinesteraseBehavioral Safety of Plasma-Derived ButyrylcholinesteraseRECOMBINANT STOICHIOMETRIC BIOSCAVENGERSCATALYTIC BIOSCAVENGERSINTERAGENCY PARTNERSHIPS: PROJECT BIOSHIELDSUMMARY* Colonel, US Army; Director of CBRN Medical Defense Policy, Office of the Assistant Secretary of Defense for Health Affairs, 5111 Leesburg Pike,Skyline 5, Falls Church, Virginia 22041† Research Chemist, Research Division, Department of Pharmacology, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts PointRoad, Aberdeen Proving Ground, Maryland 21010‡ Research Microbiologist, Research Division, Department of Physiology and Immunology, US Army Medical Research Institute of Chemical Defense,3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010§Director, Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910¥Research Chemist, Research Division, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground,Maryland 21010 Research Chemist, Research Division, Department of Pharmacology, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts PointRoad, Aberdeen Proving Ground, Maryland 21010** Chief, Division of Biochemistry, Department of Molecular Pharmacology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, SilverSpring, Maryland 20910243
Medical Aspects of Chemical WarfareINTRODUCTIONNerve agents are highly lethal chemical agentthreats to the US population. Chemically, they belongto the organophosphorus (OP) compound groupand are among the most toxic substances identified.OP compounds were originally developed for useas insecticides, but their extreme toxicity and rapideffects on higher vertebrates have led to their adoptionas weapons of warfare. The OP compounds mostcommonly used as chemical weapons (referred toas “nerve agents”) are O-ethyl N,N-dimethyl phosphoramidocyanidate(tabun; North Atlantic TreatyOrganization [NATO] designation: GA), diisopropylphosphonofluoridate (sarin; NATO designation: GB),pinacoloxymethyl-fluorophosphonate (soman; NATOdesignation: GD), cyclohexylmethyl phosphonofluoridate(cyclosarin; NATO designation: GF), and ethyl-S-diisopropylaminoethyl methylphosphonothiolate(VX). Newer, nontraditional nerve agents pose evengreater dangers than these traditional ones.Nerve agents in aerosol or liquid form can enter thebody by inhalation or by absorption through the skin.Poisoning may also occur through the consumptionof liquids or foods contaminated with nerve agents.Nerve agents are lethal at extremely low levels; exposureto a high concentration of nerve agent can result indeath within minutes. Poisoning takes longer when thenerve agent is absorbed through the skin. The valuesfor the median lethal dose (LD 50) in mammals, includingestimates for humans, are in the mg/kg dose rangefor all routes of exposure except skin, in which LD 50values are in the mg/kg range. 1 Personnel may also beeffected through secondary contact with contaminatedvictims. Survivors may have long-term central nervoussystem dysfunction following intoxication. 2The acute toxicity of OPs is attributed to their bindingto and irreversible inhibition of acetylcholinesterase(AChE). The resulting increase in acetylcholineconcentration manifests at the cholinergic synapsesof both the peripheral and central nervous systemsby over-stimulation at the neuromuscular junctionsas well as alteration in the function of the respiratorycenter. 3–5 This precipitates a cholinergic crisis characterizedby miosis, increased tracheobronchial andsalivary secretions, bronchoconstriction, bradycardia,fasciculation, behavioral incapacitation, muscularweakness, and convulsions, culminating in death byrespiratory failure. 3Nerve agents are stable, easily dispersed, and can bemanufactured by readily available industrial chemicalprocesses, including OP pesticide production facilities,which can easily be converted to produce nerveagents. Even the most dangerous forms of nerve agentsare within the technical capability of sophisticatedterrorist networks. Nerve agents possessed by roguestates and other potential US adversaries have longbeen known to pose a serious threat to US forces. AumShinrikyo’s 1995 sarin attack in the Tokyo subway systemdemonstrated that nerve agents are also a real andpotent terrorist threat to civilian populations. Nerveagents are attractive chemical weapons for terroristuse because small quantities are fast-acting and cancause death or harm by multiple routes. Some types ofnerve agents are highly persistent, enabling terroriststo construct long-lasting hazards to target populations.For example, the administration of highly persistentnerve agents to frequently used public facilities, likesubway trains, can effect mass disruption by causingcitizens to fear using those facilities important toeveryday life. The use of nerve agents in combinationwith other weapons may also make differentiatingcausalities challenging and place first responders andlaw enforcement personnel at risk when entering acontaminated area.Current antidotal regimens for OP poisoning consistof a combination of pretreatment with a spontaneouslyreactivating AChE inhibitor, such as pyridostigminebromide, and postexposure therapy with an anticholinergicdrug, such as atropine sulfate, and an oxime,such as 2-pralidoxime chloride 6 and an anticonvulsantsuch as diazepam, 7 if needed. Although these antidotalregimens effectively prevent lethality and, inbest cases, reverse toxicity following exposure, theydo not prevent the exposed individual from becominga casualty. Moreover, no current therapies for nerveagent exposure can provide sustained protection toan individual; they have to be readministered withinminutes or hours and are therefore limited by practicaland logistical issues. Treated patients often show signsof postexposure incapacitation, convulsions, and performancedeficits or, in the case of recurring seizures,permanent brain damage. 8–10 Some nerve agents, suchas soman, present an additional challenge because ofthe rapid dealkylation of soman-inhibited AChE thatis resistant to therapeutic reversal by an oxime.An urgent need exists for new medical countermeasuresto nerve agent exposure that provide highersurvival rates, eliminate or reduce enduring adverse effectsto survivors, and significantly reduce or eliminatethe need for repeated administration of therapeuticdrugs. Ideally, medical treatment should be administeredwithin approximately 1 minute after exposureand should be effective for all OP compounds. Thesechallenges stimulated the development of enzymebioscavengers as a pretreatment therapy to sequester244
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The Coat of Arms1818Medical Departm
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Textbooks of Military MedicinePubli
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MEDICAL ASPECTS o fCHEMICAL WARFARE
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ContentsContributorsForeword by The
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ContributorsMICHAEL ADLER, PhDResea
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DONALD M. MAXWELL, MSResearch Chemi
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ForewordThe US military has been co
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PrefaceA significant concern for th
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PrologueThe original edition of Med
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xxii
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Medical Aspects of Chemical Warfare
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Nerve AgentsChapter 5NERVE AGENTSFR
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Nerve AgentsAbout 10,000 to 30,000
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Nerve Agentsphorofluoridate (DFP) w
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Nerve AgentsFig. 5-2. This schemati
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Nerve AgentsExhibit 5-1 continuedis
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Nerve Agentsactivity but only 15% t
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Nerve AgentsTABLE 5-3CHEMICAL, PHYS
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Nerve AgentsTABLE 5-4EFFECTS OF EXP
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Nerve Agentsaffecting the other eye
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Nerve Agentsmay cause severe rhinor
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Nerve Agentsof jerks and tremor.Cen
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Nerve Agentsand they were decreased
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Nerve Agentsnerve agent toxicity on
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Nerve Agentspatient. Decontaminatio
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Nerve AgentsFig. 5-5. The Mark I ki
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Nerve Agentsadministered intramuscu
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Nerve Agentsthat hydroxamine reacti
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Nerve AgentsOral administration may
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Nerve AgentsTABLE 5-7RECOMMENDED TH
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Page 228 and 229: Nerve Agentstivity of smooth muscle
Page 230 and 231: Nerve Agents38. Grob D, Lilienthal
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Page 234 and 235: Nerve Agents117. McLeod CG Jr, Sing
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Page 238 and 239: Nerve Agents193. Funckes AJ. Treatm
Page 240 and 241: Nerve Agents235. Suzuki T, Morita H
Page 242: Nerve Agents274. Pellegrini JE, Bak
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PROCESSMedical Aspects of Chemical
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Triage of Chemical CasualtiesChapte
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Triage of Chemical Casualtiesreceiv
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Triage of Chemical Casualtiesentran
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Triage of Chemical Casualtiescatego
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Triage of Chemical CasualtiesIn a f
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Triage of Chemical Casualtiesnose)
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Triage of Chemical CasualtiesWith n
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Triage of Chemical Casualties14. Sa
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Decontamination of Chemical Casualt
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• Analyze using GC-MS with methan
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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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