Harris L W, Talbot B G, Anderson D R, Lennox W J, Green M D
Life Sci. 1987 Feb 9;40(6):577-83. doi: 10.1016/0024-3205(87)90372-9.
The generally accepted explanation for the effects of oximes in countering organophosphorus (OP) anticholinesterase is reactivation of the inhibited acetylcholinesterase (AChE). With soman, the inhibited AChE rapidly becomes resistant to oxime reactivation due to a phenomenon called aging. Thus, pretreatment with pyridostigmine (Py) or physostigmine (Ph) followed by atropine sulfate therapy is required to achieve significant protection against soman; the effectiveness of a pretreatment/therapy (P/T) regimen can be further increased against certain OPs (e.g. sarin and VX) by including an oxime in the therapy regimen. The P/T regimen is clouded by a controversy concerning the use of oximes in the treatment of carbamate intoxication, because 2-PAM has been reported to exacerbate intoxication by some carbamates and to have no effect on decarbamylation rates. To better understand the role of oxime therapy in the theory of pretreatment of OP intoxication we examined the effects of 2-PAM and HI-6 on the rate of decarbamylation of Py-inhibited erythrocyte AChE in vitro and in vivo, and studied the effects of atropine plus 2-PAM or HI-6 on Py toxicity. In decarbamylation experiments, Py-inhibited guinea pig erythrocytes were washed free of excess Py and incubated with vehicle or oxime (2 X 10(-4) M, pH 7.3 and 37 degrees C). Aliquots were assayed for AChE activity at various times during a 60 min incubation period. Rate constants were calculated and compared to determine whether the presence of oxime affected decarbamylation. The data from in vitro and in vivo experiments revealed that oximes accelerated the decarbamylation (p less than 0.05) of inhibited AChE. Lethality data for Py-treated guinea pigs showed that treatment with atropine (23 mumoles/kg, im) plus 2-PAM or HI-6 (145 mumoles/kg, im) at one min after injection of Py increased the protective ratio from 4.2 (atropine only) to 5.1 and 12.2, respectively. It is suggested that the enhanced therapeutic efficacy of atropine by oximes against Py intoxication is related to oxime-induced reactivation.
肟类化合物对抗有机磷（OP）抗胆碱酯酶作用的普遍公认解释是使受抑制的乙酰胆碱酯酶（AChE）重新活化。对于梭曼，由于一种称为老化的现象，受抑制的AChE会迅速变得对肟类重新活化产生抗性。因此，需要用吡啶斯的明（Py）或毒扁豆碱（Ph）预处理，随后进行硫酸阿托品治疗，以获得对梭曼的显著保护；通过在治疗方案中加入肟类，针对某些有机磷（如沙林和VX）的预处理/治疗（P/T）方案的有效性可进一步提高。由于有报道称2-解磷定可加重某些氨基甲酸酯类中毒且对脱氨基甲酰化速率无影响，P/T方案因肟类在氨基甲酸酯类中毒治疗中的使用存在争议而变得模糊不清。为了更好地理解肟类治疗在OP中毒预处理理论中的作用，我们研究了2-解磷定和HI-6对体外和体内Py抑制的红细胞AChE脱氨基甲酰化速率的影响，并研究了阿托品加2-解磷定或HI-6对Py毒性的影响。在脱氨基甲酰化实验中，将Py抑制的豚鼠红细胞洗涤以去除过量的Py，并与赋形剂或肟类（2×10⁻⁴ M，pH 7.3和37℃）一起孵育。在60分钟孵育期内的不同时间对等分试样进行AChE活性测定。计算速率常数并进行比较，以确定肟类的存在是否影响脱氨基甲酰化。体外和体内实验的数据表明，肟类加速了受抑制AChE的脱氨基甲酰化（p＜0.05）。Py处理的豚鼠的致死率数据表明，在注射Py后1分钟用阿托品（23微摩尔/千克，肌肉注射）加2-解磷定或HI-6（145微摩尔/千克，肌肉注射）治疗，保护率分别从4.2（仅阿托品）提高到5.1和12.2。提示肟类增强阿托品对Py中毒的治疗效果与肟类诱导的重新活化有关。
