Zwitterionic oxime (RS194B) to reverse advanced symptoms and lethality of organophosphate pesticide exposure

摘要 神经肌肉接头、外周自主神经和中枢神经元对AChE的抑制作用 突触和循环中的红细胞与所有有机磷的毒性有关 杀虫剂。治疗通常包括毒扁豆碱拮抗剂(阿托品)与 一种能够重新激活OP-2的吡啶醛肟类化合物，如解磷定(2-PAM)和奥比定。 抑制AChE，加/不加抗惊厥药(安定)以控制癫痫发作。然而，动物 模型研究和最近对农药中毒个体进行的临床试验显示，情况参差不齐。 这些肟类的临床益处甚至是危害，因此它们作为解毒剂的真正效果一直是fi 辩论过了。目前使用的肟要么重新激活不良，不容易通过血脑屏障，而且是 迅速从循环中清除。因此，必须反复给药。最近，Dr。 加州大学圣迭戈分校帕尔默·泰勒的实验室已经开发出结构简单的两性离子肟，如fi RS194B，有效地穿过血脑屏障(BBB)，导致OP-2迅速重新激活 对暴露的小鼠和猕猴的AChE抑制和严重临床症状的显著逆转 使用杀虫剂或神经毒剂。在最近的一项PlantVax猕猴研究中，观察到一种 吸入致死剂量的OP杀虫剂对氧磷会引起非常严重的临床症状。 与杀虫剂中毒人群中的情况相似。这很可能是不寻常的 猕猴雾化OP的沉积主要分布在胃和肺 和小孩子，这与成年人的情况形成了鲜明对比。 了解不同药物的急性和慢性影响及治疗面临的挑战 有机磷农药的体内毒代动力学和肟类有显著的变异。 在相同或不同动物物种中的反应性。一般而言，抑制和重新激活 不同有机磷杀虫剂(PX)或神经对猪、大鼠和豚鼠痛觉的影响 药物(沙林、环沙林、VX)比人类和非人类灵长类的速度慢。此阶段I 提案，是第一个评估中枢作用的肟类RS194B重新激活的效果 硫代磷杀虫剂的体外和体内研究。最初，猕猴和猕猴的肟类重新激活 一组二乙基和二甲基硫代磷杀虫剂都能抑制人的RACH 接受评估并随后应用RS194B重新激活AChE并逆转临床体征的疗效 将对暴露于选定常用杀虫剂的猕猴进行评估。类似的 猕猴和人类的生化/药理学特性和再激活动力学 杀虫剂中毒后的共同临床症状应该允许合理的动物- 人类外推，并为利用猴子进行RS194B的体内评估提供支持。

ABSTRACT Inhibition of AChE in the neuromuscular junction, peripheral autonomic and central neuron synapses, and on circulating red blood cells is associated with the toxicity for all organophosphate insecticides. Treatment typically involves the muscarinic antagonist (atropine) in combination with a pyridinium aldoxime, eg pralidoxime (2-PAM) and obidoxime, capable of reactivating the OP- inhibited AChE, with/without an anti-convulsant (diazepam) to control seizures. However, animal model studies and recent clinical trials using pesticide-poisoned individuals have shown uneven clinical benefits of these oximes and even harm so their true efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the BBB and are rapidly cleared from the circulation. Hence, they must be repeatedly administered. Recently, Dr. Palmer Taylor's lab at UCSD has developed zwitterionic oximes of simplified structure eg RS194B, that efficiently cross the blood-brain-barrier (BBB) resulting in rapid reactivation of OP- inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticide or nerve agents. In a recent PlantVax macaque study, it was observed that a lethal dose of the OP insecticide paraoxon, delivered by inhalation, caused clinical symptoms very similar to those in insecticide poisoned people. This probably is a consequence of the unusual deposition of nebulized OP predominantly in the stomach in addition to the lungs in macaques and small children in contrast to that seen in adult humans. The challenges to understanding the acute and chronic effects of and treatments for different OP pesticides result from significant variability in their in vivo toxicokinetics and oxime responsiveness in the same or different animal species. In general, the inhibition and reactivation kinetics with swine, rat and guinea pig AChE exposed to a variety of OP insecticides (Px) or nerve agents (sarin, cyclosarin, VX) are slower than for humans and non-human primates. This Phase I proposal, is the first to evaluate the efficacy of a centrally acting oxime RS194B to reactivate phosphorothioate insecticides in vitro and in vivo. Initially, oxime reactivation of macaque and human rAChE inhibited by a panel of both diethyl- and dimethylphosphorothioate insecticides will be assessed and subsequently, RS194B efficacy to reactivate AChE and reverse clinical signs in macaques exposed to selected commonly used insecticides will be assessed. The similar biochemical/pharmacological properties and reactivation kinetics in macaques and humans and the shared clinical symptoms following insecticide poisoning should allow a reasonable animal-to- human extrapolation and provide support for the use of monkeys for in vivo evaluation of RS194B.