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 Exposureform at temperatures 4° to 25°C. Similarly, the pharmacokineticproperties of the enzyme were not affectedupon storage at – 20°C for 3 years. Pretreatment withpHu BChE protected guinea pigs against a 5 times theLD 50of soman or VX. As expected, pHu BChE injectionin mice or monkeys elicited the production of highlevels of anti-BChE antibodies. No antibody responsewas detected following either of the two homologousmouse or monkey BChE injections. The observationthat the second injection of homologous BChE resultedin a pharmacokinetic profile that was similar to thatof the first injection is in agreement with the lack of ahumoral response to the injected enzyme.By nearly all criteria, the use of biological scavengersto protect against exposure to a lethal dose of anerve agent offers numerous advantages over conventionaltreatment therapies (Table 7-1). Developingan effective prophylactic to nerve agent exposure willgreatly reduce, if not eliminate, the need to know theprecise length of exposure in a crisis situation. Successfulprophylaxis will also preclude the need torepeatedly administer a host of pharmacologicallyactive drugs with short durations of action. Also,the need to use personal protective equipment toprotect against nerve agent exposure could be greatlyreduced, which is particularly significant for first respondershandling known casualties of nerve agentexposure. Finally, the appropriate scavenger wouldprotect against all current nerve agent threats, includingthose that are refractory to treatment by atropineand oxime therapy. In cases of lower doses of nerveagents or in response to agents that potentially exerta time-release depot effect, pHu BChE could be usedas a postexposure treatment to combat continuedtoxicity of the absorbed agent.Several challenges must be met before bioscavengerscan augment or replace the current therapeutic regimesfor nerve agent intoxication. The immunogenicity andserum half-life of the scavenger must be determinedin humans, and efforts may be required to minimizeany immune consequences and maximize the residencetime in circulation. Additionally, appropriate dosagesof scavenger must be determined that will, based onanimal models, protect against concentrations of nerveagents likely to be encountered in a wide range ofscenarios. While research efforts to date have resultedin the successful transition to preclinical trials of stoichiometricscavengers, the use of either naturally orgenetically engineered enzymes with catalytic activityto hydrolyze OPs holds the greatest theoretical promisefor the development of a broad specificity, high efficacy,prophylactic scavenger. Current research efforts arefocused on designing and expressing such enzymesand characterizing their in-vivo, antinerve agent efficacyin animal models acceptable to the Food andDrug Administration.AcknowledgmentSpecial thanks to Dr Doug Cerasoli, US Army Medical Research Institute of Chemical Defense, for hiscontributions to sections of the chapter.References1. Romano JA Jr, McDonough JH, Sheridan R, Sidell FR. Health effects of low-level exposure to nerve agents. In: SomaniSM, Romano JA, Jr, eds. Chemical Warfare Agents: Toxicity at Low Levels. New York, NY: CRC Press; 2002: 1–18.2. Yokoyama K, Araki S, Murata K, et al. Chronic neurobehavioral and central and autonomic nervous system effects ofTokyo subway sarin poisoning. J Physiol Paris. 1998;92:317–323.3. De Candole CA, Douglas WW, Evans CL, et al. The failure of respiration in death by anticholinesterase poisoning. BrJ Pharmacol Chemother. 1953;8:466–475.4. Stewart WC, Anderson EA. Effect of a cholinesterase inhibitor when injected into the medulla of the rabbit. J PharmacolExp Ther. 1968;162:309–318.5. Heffron PF, Hobbinger F. Relationship between inhibition of acetylcholinesterase and response of the rat phrenicnerve-diaphragm preparation to indirect stimulation at higher frequencies. Br J Pharmacol. 1979;66:323–329.6. Gray AP. Design and structure-activity relationships of antidotes to organophosphorus anticholinesterase agents. DrugMetab Rev. 1984;15:557–589.253
Medical Aspects of Chemical Warfare7. Lipp JA. Effect of diazepam upon soman-induced seizure activity and convulsions. Electroencephalogr Clin Neurophysiol.1972;32:557–560.8. Dirnhuber P, French MC, Green DM, Leadbeater L, Stratton JA. The protection of primates against soman poisoningby pretreatment with pyridostigmine. J Pharm Pharmacol. 1979;31:295–299.9. McLeod CG Jr. Pathology of nerve agents: perspectives on medical management. Fundam Appl Toxicol. 1985;5:S10–S16.10. Dunn MA, Sidell FR. Progress in medical defense against nerve agents. JAMA. 1989;262:649–652.11. Doctor BP, Maxwell DM, Ashani Y, Saxena A, Gordon RK. New approaches to medical protection against chemicalwarfare nerve agents. In: Somani SM, Romano JA Jr, eds. Chemical Warfare Agents: Toxicity at Low Levels. New York,NY: CRC Press; 2002: 191–214.12. Wolfe AD, Rush RS, Doctor BP, Koplovitz I, Jones D. Acetylcholinesterase prophylaxis against organophosphate toxicity.Fundam Appl Toxicol. 1987;9:266–270.13. Maxwell DM, Castro CA, De La Hoz DM, et al. Protection of rhesus monkeys against soman and prevention of performancedecrement by pretreatment with acetylcholinesterase. Toxicol Appl Pharmacol. 1992;115:44–49.14. Maxwell DM, Brecht KM, Doctor BP, Wolfe AD. Comparison of antidote protection against soman by pyridostigmine,HI-6 and acetylcholinesterase. J Pharmacol Exp Ther. 1993;264:1085–1089.15. Broomfield CA, Maxwell DM, Solana RP, Castro CA, Finger AV, Lenz DE. Protection by butyrylcholinesterase againstorganophosphorus poisoning in nonhuman primates. J Pharmacol Exper Ther. 1991;259:633–638.16. Raveh L, Ashani Y, Levy D, De La Hoz D, Wolfe AD, Doctor BP. Acetylcholinesterase prophylaxis against organophosphatepoisoning. Quantitative correlation between protection and blood-enzyme level in mice. Biochem Pharmacol.1989;38:529–534.17. Ashani Y, Shapira S, Levy D, Wolfe AD, Doctor BP, Raveh L. Butyrylcholinesterase and acetylcholinesterase prophylaxisagainst soman poisoning in mice. Biochem Pharmacol. 1991;41:37–41.18. Raveh L, Grunwald J, Marcus D, Papier Y, Cohen E, Ashani Y. Human butyrylcholinesterase as a general prophylacticantidote for nerve agent toxicity. In vitro and in vivo quantitative characterization. Biochem Pharmacol. 1993;45:2465–2474.19. Raveh L, Grauer E, Grunwald J, Cohen E, Ashani Y. The stoichiometry of protection against soman and VX toxicityin monkeys pretreated with human butyrylcholinesterase. Toxicol Appl Pharmacol. 1997;145:43–53.20. Wolfe AD, Blick DW, Murphy MR, et al. Use of cholinesterases as pretreatment drugs for the protection of rhesusmonkeys against soman toxicity. Toxicol Appl Pharmacol. 1992;117:189–193.21. Augstinsson KB. Electrophoretic separation and classification of blood plasma esterases. Nature. 1958;151:1786–1789.22. Scott DF, Chacko TL, Maxwell DM, Schlager JJ, Lanclos KD. Expression and partial purification of a recombinantsecretory form of human liver carboxylesterase. Protein Expr Purifi. 1999;17:16–25.23. Maxwell DM, Brecht KM, O’Neill BL. The effect of carboxylesterase inhibition on interspecies differences in soman toxicity.Toxicol Lett. 1987;39:35–42.24. Li B, Sedlacek M, Manoharan I, et al. Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase,are present in human plasma. Biochem Pharmacol. 2005;70:1673–1684.25. Maxwell DM, Wolfe AD, Ashani Y, Doctor BP. Cholinesterase and carboxylesterase as scavengers for organophosphorusagents, In: Massoulie J, Bacou F, Bernard E, Chatonnet A, Doctor BP, Quinn DM, eds. Cholinesterases: Structure,Function, Mechanism, Genetics, and Cell Biology. Washington, DC: American Chemical Society; 1991: 206.254
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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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Nerve Agentsimpairment such as whee
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Nerve Agentssuboptimal, manner. The
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Nerve Agentsthan those who did not.
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Nerve Agentssible for binding nerve
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Nerve Agentsfor comparison was not
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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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