Bajgar J
Military Medical Academy, Hradec Králové, Czechoslovakia.
Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove. 1991;34(1):5-77.
Literature survey dealing with cholinesterases and effects of highly toxic organophosphorus compounds suitable for use as chemical weapons is given in introductory part of this work. There are nerve paralytical agents (NPA)--sarin, soman, VX and a model compound O-ethyl-S-(2-dimethylaminoethyl)-methyl-phosphonothioate (EDMM). On the base of described scheme of intoxication with NPA, inhibition effect on cholinesterases, preferably on AChE as the most important factor involved in the mechanism of acute intoxication with NPA was studied. Intoxication of mice or rats with sarin and soman (2 x LD50) showed that time course of poisoning is faster than that for VX or EDMM. Inhibition of AChE in the blood was in good correlation with symptoms of intoxication and also with inhibition of AChE in the brain. The differences between inhibition effect of soman preferably uniform character of inhibition in the brain parts) and sarin (selective inhibition in the brain parts, with maximum in the frontal cortex and pontomedullar area) were observed. This selectivity was most marked for VX and EDMM intoxication (maximal inhibition in the part of the pontomedullar area containing reticular formation). The dose causing inhibition effect in the brain was assessed to be about 1% of the dose administered. The study of the effect of antidotal therapy (combination of atropine and reactivator) in vivo showed in mice and rats intoxicated with sarin non-uniform increase of AChE activity in the pontomedullar part depending on the dose and type of reactivator. The most marked effect was observed for methoxime. It was demonstrated that there exists good correlation between survival of experimental animals and the rest AChE activity in the pontomedullar part of the brain. AChE activity level critical for survival or death of the organism poisoned with NPA was assessed from these experiments; it was about 1-5% of normal values. By means of original method allowing continual monitoring of AChE activity in the blood, similar AChE reactivation was demonstrated, with highest effect for trimedoxime and methoxime. Using continual determination of the blood AChE activity following sarin, soman, VX and EDMM intoxication demonstrated that only a part of the dose administered caused inhibition effect in the blood; this part was determined to be practically 100% (i. v. administration); for other routes of administration this ratio was as follows: 50-80% (i. m.), 20-40% (i. p.), 6-16% (p. o.) and 1-5% (p. c.), respectively. Using this continual monitoring, the detoxication of sarin and soman was demonstrated. Detoxication of VX and EDMM was not observed.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究的引言部分对胆碱酯酶以及适合用作化学武器的剧毒有机磷化合物的影响进行了文献综述。其中包括神经麻痹剂（NPA）——沙林、梭曼、VX以及一种模型化合物O-乙基-S-(2-二甲基氨基乙基)-甲基硫代磷酸酯（EDMM）。基于所描述的NPA中毒方案，研究了其对胆碱酯酶的抑制作用，尤其关注乙酰胆碱酯酶（AChE），因为它是NPA急性中毒机制中最重要的因素。用沙林和梭曼（2倍半数致死剂量）对小鼠或大鼠进行中毒实验，结果表明中毒进程比VX或EDMM更快。血液中AChE的抑制与中毒症状以及脑中AChE的抑制密切相关。观察到梭曼（脑中抑制作用性质较为均匀）和沙林（脑部分区域选择性抑制，额叶皮质和脑桥延髓区域抑制作用最强）在抑制效果上的差异。这种选择性在VX和EDMM中毒时最为明显（脑桥延髓区域含有网状结构的部分抑制作用最强）。导致脑中出现抑制作用的剂量估计约为给药剂量的1%。对体内解毒治疗（阿托品和复活剂联合使用）效果的研究表明，在沙林中毒的小鼠和大鼠中，脑桥延髓部分AChE活性的增加并不均匀，这取决于复活剂的剂量和类型。甲氧肟的效果最为显著。实验证明，实验动物的存活与脑桥延髓部分剩余的AChE活性之间存在良好的相关性。通过这些实验评估了NPA中毒生物体存活或死亡的关键AChE活性水平；约为正常值的1 - 5%。采用能够持续监测血液中AChE活性的原始方法，也证明了类似的AChE复活情况，三甲肟和甲氧肟的效果最佳。在沙林、梭曼、VX和EDMM中毒后持续测定血液中的AChE活性表明，所给药剂量中只有一部分在血液中产生抑制作用；静脉注射时这部分剂量几乎为100%；其他给药途径的比例分别为：肌肉注射50 - 80%、腹腔注射20 - 40%、口服6 - 16%、皮下注射1 - 5%。通过这种持续监测，证明了沙林和梭曼的解毒情况。未观察到VX和EDMM的解毒情况。（摘要截取自400字）
