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

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