Nordgren I, Karlén B, Kimland M, Palmér L, Holmstedt B
Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
Pharmacol Toxicol. 1992 May;70(5 Pt 1):384-8. doi: 10.1111/j.1600-0773.1992.tb00492.x.
Intoxications with organophosphorus compounds are normally treated with a mixture of atropine and an enzyme regenerating oxime. The addition of diazepam to the conventional drug therapy is reported to greatly improve the antidotal effect. The implication of the cholinergic system in such intoxications prompted us to study the effect of different combinations of antidotes on the acetylcholine (ACh) synthesizing system in mouse brain in vivo. The antidotes studied in this paper are diazepam, HI-6 and 1-hyoscyamine, the active enantiomer of atropine. Diazepam decreases the synthesis rate of ACh both when administered separately and in combination with 1-hyoscyamine and HI-6. This is in contrast to 1-hyoscyamine which, in addition to blocking muscarinic receptors, also increases the release and rate of synthesis of ACh, which probably is an unfavourable effect of the antidote. This might at least partly explain the advantage of combining 1-hyoscyamine and an oxime with diazepam in intoxications with anticholinesterases. Mice administered soman (0.75 x LD50), after pretreatment with the three-drug combination of antidotes, show no cholinergic symptoms despite a 50% increase in endogenous ACh. The rate of synthesis of ACh in these mice is in the same range as in animals administered diazepam alone. Mice administered the same dose of soman with no antidotal pretreatment suffer from severe tremor and salivation, and have a strongly reduced synthesis rate of ACh.
有机磷化合物中毒通常用阿托品和一种酶再生肟的混合物进行治疗。据报道，在传统药物治疗中加入地西泮可大大提高解毒效果。胆碱能系统在这类中毒中的作用促使我们研究不同解毒剂组合对小鼠脑内乙酰胆碱（ACh）合成系统的体内效应。本文研究的解毒剂是地西泮、HI - 6和1 - 莨菪碱，阿托品的活性对映体。地西泮单独给药以及与1 - 莨菪碱和HI - 6联合给药时，均会降低ACh的合成速率。这与1 - 莨菪碱相反，1 - 莨菪碱除了阻断毒蕈碱受体外，还会增加ACh的释放和合成速率，这可能是解毒剂的不利作用。这可能至少部分解释了在抗胆碱酯酶中毒时将1 - 莨菪碱和一种肟与地西泮联合使用的优势。用三种解毒剂联合预处理后给予梭曼（0.75×LD50）的小鼠，尽管内源性ACh增加了50%，但未出现胆碱能症状。这些小鼠中ACh的合成速率与单独给予地西泮的动物处于相同范围。未进行解毒预处理而给予相同剂量梭曼的小鼠会出现严重震颤和流涎，且ACh的合成速率大幅降低。
