Tuovinen K, Kaliste-Korhonen E, Raushel F M, Hänninen O
Department of Physiology, University of Kuopio, Finland.
Toxicology. 1999 Jun 15;134(2-3):169-78. doi: 10.1016/s0300-483x(99)00029-3.
The acute toxicity of organophosphorus (OP) compounds in mammals is due to their irreversible inhibition of acetylcholinesterase (AChE) in the nervous system, which leads to increased synaptic acetylcholine levels. The protective actions of intravenously (i.v.) administered pyridostigmine, physostigmine, eptastigmine, and an organophosphate hydrolase, phosphotriesterase, in acute sarin intoxication were studied in mice. The acute intragastric (i.g.) toxicity (LD50) of sarin with and without the pretreatments was tested by the up-and-down method. The mice received pyridostigmine (0.06 mg/kg body weight), physostigmine (0.09 mg/kg body weight), the physostigmine derivative eptastigmine (0.90 mg/kg body weight) or phosphotriesterase (104 U/g, 10.7 microg/g body weight) 10 min prior to the i.g. administration of sarin. Physostigmine was also administered with phosphotriesterase. Phosphotriesterase was the most effective antidote in sarin intoxication. The LD50 value for sarin increased 3.4-fold in mice receiving phosphotriesterase. Physostigmine was the most effective carbamate in sarin exposure. The protective ratios of physostigmine and pyridostigmine were 1.5- and 1.2-1.3-fold, respectively. Eptastigmine did not give any protection against sarin toxicity. Both the phosphotriesterase and physostigmine treatments protected the brain AChE activities measured 24 h after sarin exposure. In phosphotriesterase and physostigmine-treated mice, a 4- and 2-fold higher sarin dose, respectively, was needed to cause a 50% inhibition of brain AChE activity. Moreover, the combination of phosphotriesterase-physostigmine increased the LD50 value for sarin 4.3-fold. The animals pretreated with phosphotriesterase-ephysostigmine tolerated four times the lethal dose in control animals, furthermore their survival time was 2-3 h in comparison to 20 min in controls. In conclusion, phosphotriesterase and physostigmine were the most effective treatments against sarin intoxication. However, eptastigmine did not provide any protection against sarin toxicity.
有机磷（OP）化合物对哺乳动物的急性毒性是由于它们不可逆地抑制神经系统中的乙酰胆碱酯酶（AChE），从而导致突触乙酰胆碱水平升高。研究了静脉注射（i.v.）给予的吡啶斯的明、毒扁豆碱、依他斯的明和一种有机磷酸酯水解酶磷酸三酯酶对小鼠急性沙林中毒的保护作用。采用上下法测试了有无预处理情况下沙林的急性胃内（i.g.）毒性（LD50）。在胃内给予沙林前10分钟，小鼠接受吡啶斯的明（0.06mg/kg体重）、毒扁豆碱（0.09mg/kg体重）、毒扁豆碱衍生物依他斯的明（0.90mg/kg体重）或磷酸三酯酶（104U/g，10.7μg/g体重）。毒扁豆碱也与磷酸三酯酶一起给药。磷酸三酯酶是沙林中毒最有效的解毒剂。接受磷酸三酯酶的小鼠中沙林的LD50值增加了3.4倍。毒扁豆碱是沙林暴露中最有效的氨基甲酸酯类药物。毒扁豆碱和吡啶斯的明的保护率分别为1.5倍和1.2 - 1.3倍。依他斯的明对沙林毒性没有任何保护作用。磷酸三酯酶和毒扁豆碱处理均能保护沙林暴露后24小时测得的脑AChE活性。在磷酸三酯酶和毒扁豆碱处理的小鼠中，分别需要高4倍和2倍的沙林剂量才能导致脑AChE活性50%的抑制。此外，磷酸三酯酶 - 毒扁豆碱组合使沙林的LD50值增加了4.3倍。用磷酸三酯酶 - 依他斯的明预处理的动物能耐受对照动物致死剂量的四倍，此外，它们的存活时间为2 - 3小时，而对照动物为20分钟。总之，磷酸三酯酶和毒扁豆碱是对抗沙林中毒最有效的治疗方法。然而，依他斯的明对沙林毒性没有提供任何保护作用。
