Creation of a protective pulmonary bioshield against inhaled organophosphates using an aerosolized bioscavenger

摘要

In addition to the global use of organophosphate (OP) pesticides for agriculture, OP nerve agents and pesticides have been employed on battlefields and by terrorists (e.g., the recent sarin attack in Syria). These occurrences highlight the need for an effective countermeasure against OP exposure. Human butyrylcholinesterase (HuBChE) is a leading candidate, but injection of the high doses required for protection present pharmacokinetic challenges. An aerosolized recombinant from (aer-rHuBChE) that can neutralize inhaled OPs at their portal of entry has been assessed for its efficacy to protect macaques against respiratory toxicity following inhalation exposure to the pesticide paraoxon (aer-Px). While protection in macaques has been demonstrated using a Microsprayer delivery device, administration to humans will likely employ a vibrating mesh nebulizer (VMN). Compared to the 50–70% lung deposition achieved in adult humans with a VMN, deposition in macaques is < 5%, an initial major obstacle to demonstrating protection. Such problems have been partly overcome by using a more efficient modified VMN and proportionally higher doses, which together generate an effective rHuBChE pulmonary bioshield and protect against high levels of inhaled Px.