Acetylcholinesterase inhibition resulting from exposure to inhaled OP can be prevented by pretreatment with BChE in both macaques and minipigs.

Abstract More frequent and widespread nerve agent attacks highlight the need for efficacious pre- and post-exposure organophosphate (OP) counter-measures to protect military and civilian populations. Because of critical targeting of acetylcholinesterase (AChE) in the CNS by OPs, a pre-treatment candidate for preventing/reducing poisoning will be broadly acting molecules that scavenges OPs in blood before they reach their physiological targets. Prophylactic human butyrylcholinesterase (HuBChE), the leading pretreatment candidate, has been shown to protect against multiple LD50's of nerve agents in rodents, macaques, and minipigs. This review describes the development of a HuBChE bioscavenger pretreatment from early proof-of-concept studies to pre-clinical studies with the native injectable enzyme and the development of aerosolized forms of recombinant enzyme, which can be delivered by inhalation nebulizer devices, to effect protection against inhaled OP nerve agents and insecticides. Early animal studies utilized parenteral exposure. However, lungs are the portal of entry for most volatile OP vapors and represent the major means of OP intoxication. In this regard, pretreat-ment with 7.5 mg/kg of HuBChE by IM injection protected minipigs against lethal sarin vapor and preventing AChE inhibition in the blood. This is similar to the five-day protection in macaques by an aerosolized rHuBChE using a nebulizer against aerosolized paraoxon (estimated to be an 8 mg/kg estimated human dose). Importantly, lethal inhaled doses of OP may be smaller relative to the same dose delivered by injection, thus reducing the protective HuBChE dose while a combination of HuBChE and post-exposure oxime may prolong protection.