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 Exposuredirected mutations in Hu PON1, the lack of knowledgeon the residues at the active site and the enzyme’sthree-dimensional structure, were recently overcomeby the work of Josse et al, 65,66 Harel et al, 77 Aharoni etal, 78 and Yeung et al. 79,80 Based on site-directed mutationsof amino acids believed to be at or near the activesite of Hu PON1 and on limited sequence homologywith a DFPase, Josse et al had postulated that the moleculehad the shape of a 6-fold beta propeller. Usinga mouse-rat-rabbit-human chimera of paraoxonase1 obtained through gene shuffling experiments andexpressed in bacteria, Harel et al 77 and Aharoni et al 78confirmed the postulated structure through X-raycrystallographic studies. Yeung et al have subsequentlycarried out site-directed mutation studies to identifyand “map” amino acid residues critical for binding andinvolved in catalytic activity. 79,80 Further studies haverevealed a degree of stereospecificity in the hydrolysisof soman by native Hu PON1, with the least toxic somanstereoisomer (C+P+) being hydrolyzed ~ 6 timesmore efficiently than the most toxic one (C−P−). 81 Theobserved stereospecificity is primarily due to preferentialbinding rather than to enhanced turnover of the(C+P+) stereoisomer by Hu PON1. All of these recentfindings support the goal of designing a recombinantversion of a naturally occurring human enzyme thatcan be developed as a catalytic biological scavenger toprotect against nerve agent poisoning.INTERAGENCY PARTNERSHIPS: PROJECT BIOSHIELDProject BioShield was signed into law by PresidentGeorge W Bush on July 21, 2004. It grants the secretariesof the US Department of Health and HumanServices and the US Department of Homeland Securityauthority to present the president and the director ofthe US Office of Management and Budget with recommendationsfor developing and procuring countermeasuresto chemical, biological, radiological, and nuclearthreats. Funding over 10 years was appropriated tothe Department of Homeland Security for Project Bio-Shield, establishing a new spending authority to spurdevelopment and procurement of “next generation”medical countermeasures (vaccines, therapeutics, anddiagnostics) against chemical, biological, radiological,and nuclear agents. It also authorizes the National Institutesof Health to speed research and developmentin promising areas of medical countermeasures tothese agents, grants increased flexibility and authorityto award contracts and grants under expedited peerreview procedures, and allows more rapid hiring oftechnical experts deemed necessary for research anddevelopment efforts. The Department of Defense isjoining in this effort to leverage interagency resources.The objectives are to develop dual-use technologiesand products that can be used to expand target populations(military and civilians) for US Food and DrugAdministration licensure. Project BioShield legislationrequires that products are manufactured under currentGood Manufacturing Practices (practices recognizedworld-wide that ensure the safe manufacturing, management,testing, and control of goods, foods, andpharmaceuticals) and have completed a successfulPhase I human clinical safety trial. Plasma-derived HuBChE is currently being produced from human CohnFraction IV-4 and will be used for preclinical safetyand toxicology testing with the intention of large-scaleproduction and more extensive testing to be carried outleading to licensure. The bioscavenger countermeasurehas been identified as a potential candidate for ProjectBioShield.Collaborating in the BioShield process requires theDepartment of Defense to expand the concept of useto first responders, healthcare workers, and civilians.One way to protect those groups may be to stockpilesufficient amounts of pHu BChE, which could then beused in conjunction with extensive decontaminationmeasures and personal protective equipment whenindicated. In some settings, pHu BChE may replacethe need for pyridostigmine bromide as a pretreatmentmedical countermeasure. Most studies tested theenzyme as a preventive countermeasure because oncethe nerve agent has reached the nerve synapse, pHuBChE becomes ineffective; at that point, interventionwould include the traditional countermeasures (atropine,pralidoxime, and anticonvulsant). Although themajority of bioscavenger use will be in the preexposuresetting, bioscavenger may also be useful in neutralizingon-going postexposure risks following skin absorption,which could lead to prolonged systemic exposure (ie,the “depot effect”).SUMMARYOP nerve agents represent a very real threat notonly to service members in the field but also to thepublic at large. Nerve agents have already been usedby terrorist groups against civilians and, because oftheir low cost and relative ease of synthesis, are likelyto be used again in the future. In addition, many commonlyused pesticides and chemical manufacturingby-products can act as anticholinesterases and may251
Medical Aspects of Chemical Warfarebe a low-dose exposure threat to workers in a varietyof professions. Anticholinesterase pesticides may alsobe used against civilians in a terrorist context. Currenttherapeutic regimes for acute nerve agent exposureare generally effective in preventing fatalities if administeredin an appropriate time period. For acutemulti-LD 50levels of OP exposure, pyridostigminepretreatment coupled with postexposure administrationof an oxime, atropine, and an anticonvulsant doesnot prevent substantial behavioral incapacitation or, insome cases, permanent brain damage. It is thereforeimportant from both military and domestic securityperspectives to develop novel defenses against nerveagents, including the use of bioscavenger molecules,that avoid many of the difficulties associated withcurrent treatments. While the use of nerve agents onthe battlefield may be somewhat predictable, nerveagent use in a terrorist situation will be, in all probability,a surprise event. The potential to afford longtermprotection to first-responders exposed to toxicor incapacitating concentrations of OPs is a notableadvantage of biological scavengers.Recent efforts have focused on identifying proteinsthat can act as biological scavengers of OP compoundsand can remain stable in circulation for long periodsof time. By prophylactically inactivating OPs beforethey inhibit central nervous system AChE, this approachavoids the side effects associated with currentantidotes and the requirement for their rapid administration.Ideally, the scavenger should enjoy a longresidence time in the blood stream (11–15 days), shouldbe biologically inert in the absence of nerve agent, andshould not present an antigenic challenge to the immunesystem. Taken together, pharmacological safety,toxicity, stability, and efficacy data strongly supportpHu BChE as a safe pretreatment for chemical agentintoxication. Pharmacokinetic parameters of pHuBChE in mice, guinea pigs, and monkeys suggest thata single dose of enzyme can maintain blood BChE at atherapeutic concentration for at least 4 days. Safety andtoxicity studies demonstrate that pHu BChE, even ata dose that is 30 times the therapeutic dose, is devoidof tissue toxicity and is safe for human use. PlasmaHu BChE has a long shelf life (2 years) in lyophilizedTable 7-1Protection by Human butyrylcholinesterase against Nerve Agent PoisoningTreatment Test Species Nerve Agent Protection* (LD 50) Impairment RecoverypHu BChE Rat gD 1.5 none ImmediatepHu BChE Guinea pig gD 5.5 none ImmediatepHu BChE Guinea Pig VX 5.0 none ImmediatepHu BChE Rhesus monkey gD 3.3 4 of 8 15 min to 2 hpHu BChE Rhesus monkey VX 2.1 2 of 4 20 min to 20 hpHu BChE Cynomolgus monkey GD 5.5 1 of 5 4 of 6 †rHu BChE Guinea pig gD 5.5 none ImmediaterHu BChE Guinea pig VX 5.5 immediateATR/2-PAM/DZP Guinea pig gD 1.5 4 of 4 2 of 4, days ‡ATR/2-PAM/DZP Guinea pig VX 1.5 10 of 10 10 of 10, days ‡*Values represent multiples of median lethal doses (LD 50s) of nerve agent survived after BChE administration.† One animal died after the third dose of soman and one was impaired and later euthanized after 48 hours. The remaining four animals werenormal, survived, and were held for long-term observations.‡ Two animals died in the first hour, while the other two remained impaired for 2 to 4 days.2-PAM: 2-pyridine aldoxime methyl chlorideATR: atropineDZP: diazepamHu BChE: human butyrylcholinesteraseLD 50: median lethal dosepHu BChE: plasma-derived human butyrylcholinesteraserHu BChE: recombinant human butyrylcholinesteraseData sources: (1) Genovese RF, Doctor BP. Behavioral and pharmacological assessment of butyrylcholinesterase in rats. Pharmacol BiochemBehav. 1995;51:647–654. (2) Lenz DE, Maxwell DM, Koplovitz I, et al. Protection against soman or VX poisoning by human butyrylcholinesterasein guinea pigs and cynomolgus monkeys. Chem Biol Interact. 2005;157–158:205–210. (3) Raveh L, Grauer E, Grunwald J, Cohen E,Ashani Y. The stoichiometry of protection against soman and VX toxicity in monkeys pretreated with human butyrylcholinesterase. ToxicolAppl Pharmacol. 1997;145:43–53. (4) Garcia GE, Moorad-Doctor D, Doctor BP, et al. Glycan structure comparison of native human plasmabutyrylcholinesterase (Hu-BChE) and transgenic goat produced Hu-BChE. FASEB J. 2005;19:A867.252
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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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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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