Bosković B
Fundam Appl Toxicol. 1981 Mar-Apr;1(2):203-13. doi: 10.1016/s0272-0590(81)80059-0.
Soman is a highly toxic organophosphorus chemical warfare nerve agent which is characterized by (1) extremely rapid ageing of the phosphonylated enzyme, (2) poor reactivation of inhibited AChE due to a steric factor, (3) pronounced CNS effects, and (4) tentative direct toxic biochemical effects. By studies of Soman and its thiocholine-like analog (which yield the same type of phosphonylated enzyme), it has been established that (1) the steric factor is at least as responsible as ageing in the failure of oximes to reactivate effectively AChE inhibited by Soman, (2) that its dealkylation is catalyzed by the anionic site of the enzyme, and (3) that the velocity of reactivation and ageing of AChE is dependent on the orientation of the phosphonyl group at the enzyme surface. It has been found that PiMeP-Cl (O-pinacolyl methylphosphonochloridate) may serve as a good model in the evaluation of Soman toxicity and in the selection of adequate oximes in the treatment of its poisoning. The opposite effects of TMB-4 and HI-6, as group representatives, on PiMeP-Cl toxicity in mice (strong potentiation by TMB-4 and antagonism by HI-6) were mainly ascribed to the rates of decomposition of their corresponding O-pinacolyl methylphosphonylated products formed in vivo. They are considered to be slow with potentiators and instantaneous with antagonists, respectively. This assumption was confirmed by the finding that the most powerful oximes in Soman poisoned mice were HI-6, HGG-42 and BDB-27, which, contrary to TMB-4, possess an oxime group in position 2 and the CH2-O-CH2 linking chain. The remarkable influence of diazepam and sodium n-dipropylacetate on the survival time in Soman poisoned rats treated by atropine and bis-pyridinium oximes points to their antagonistic action at the biochemical level (decrease of elevated cGMP in CNS), not possessed by atropine. Essential antidotes in experimental treatment of Soman poisoning today are the powerful reactivators of Soman-inhibited AChE (e.g. HI-6, HGG-42 and BDB-27) and atropine. The treatment may be further improved by the use of symptomatic agents capable of counteracting biochemical changes in Soman poisoning not antagonized by atropine (e.g. diazepam), and theoretically for now, by retardation of ageing and by overcoming steric disturbances.
梭曼是一种剧毒的有机磷化学战神经毒剂，其特点是：（1）磷酰化酶老化极快；（2）由于空间因素，被抑制的乙酰胆碱酯酶（AChE）再活化能力差；（3）对中枢神经系统有明显作用；（4）可能有直接的毒性生化作用。通过对梭曼及其硫代胆碱类似物（产生相同类型的磷酰化酶）的研究，已确定：（1）在肟不能有效再活化被梭曼抑制的AChE的情况中，空间因素至少与老化起着同样的作用；（2）其脱烷基作用由酶的阴离子部位催化；（3）AChE的再活化和老化速度取决于磷酰基在酶表面的取向。已发现甲基毗呐磷氯（O-频哪基甲基膦酰氯）可作为评估梭曼毒性和选择治疗其中毒的合适肟类药物的良好模型。作为组代表的TMB-4和HI-6对小鼠甲基毗呐磷氯毒性有相反作用（TMB-4有强增效作用，HI-6有拮抗作用），这主要归因于它们在体内形成的相应O-频哪基甲基膦酰化产物的分解速率。它们分别被认为对增效剂来说是缓慢的，对拮抗剂来说是瞬间的。这一假设被以下发现所证实：在梭曼中毒小鼠中最有效的肟类药物是HI-6、HGG-42和BDB-27，与TMB-4相反，它们在2位有一个肟基和CH2-O-CH2连接链。地西泮和二丙基乙酸钠对用阿托品和双吡啶肟治疗的梭曼中毒大鼠存活时间有显著影响，这表明它们在生化水平上有拮抗作用（降低中枢神经系统中升高的环鸟苷酸），而阿托品没有这种作用。目前在梭曼中毒实验治疗中的重要解毒剂是能有效再活化被梭曼抑制的AChE的药物（如HI-6、HGG-42和BDB-27）和阿托品。使用能够对抗梭曼中毒中未被阿托品拮抗的生化变化的对症药物（如地西泮），从理论上讲，通过延缓老化和克服空间干扰，可进一步改善治疗效果。
