Acetylcholinesterase inhibition resulting from exposure to inhaled OP can be prevented by pretreatment with BChE in both macaques and minipigs.
Acetylcholinesterase inhibition resulting from exposure to inhaled OP can be prevented by pretreatment with BChE in both macaques and minipigs.
复制标题
在猕猴和小型猪中使用 BChE 进行预处理可以防止因吸入 OP 导致的乙酰胆碱酯酶抑制。
DOI：
10.1016/j.neuropharm.2020.108150
复制
发表时间：
2020
影响因子：
4.7
通讯作者：
Saxena,Ashima
中科院分区：
文献类型：
--
作者：
Rosenberg,Yvonne;Saxena,Ashima
越来越频繁和广泛的神经毒剂袭击突出表明，需要在接触有机磷之前和之后采取有效的应对措施，以保护军人和平民。由于OPs对中枢神经系统乙酰胆碱酯酶（AChE）的关键靶向作用，预防/减少中毒的预处理候选药物将是一种广泛作用的分子，在OPs到达其生理目标之前清除血液中的OPs。预防性人丁基胆碱酯酶（HuBChE）是主要的预处理候选物，在啮齿类动物、猕猴和小型猪中显示出对多种神经毒剂的LD50的保护作用。本文综述了HuBChE生物清除剂预处理的发展，从早期的概念验证研究到使用天然可注射酶的临床前研究，以及可通过吸入雾化器装置输送的重组酶的雾化形式的发展，以防止吸入OP神经毒剂和杀虫剂。早期的动物研究采用肠外暴露。然而，肺是大多数挥发性OP蒸气的入口，是OP中毒的主要途径。由此可见，IM注射预处理7.5 mg/kg的HuBChE可保护小型猪免受致命沙林蒸气的伤害，并可阻止血液中AChE的抑制。这类似于使用雾化器对雾化的对氧磷（估计为8毫克/公斤的估计人类剂量）雾化的rHuBChE对猕猴的5天保护作用。重要的是，相对于注射相同剂量，吸入OP的致死剂量可能更小，从而降低了HuBChE的保护性剂量，而HuBChE和暴露后肟的组合可能延长保护。
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 a broadly acting molecule 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 prevented 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.