Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes
Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes
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DOI：
10.1016/j.fct.2018.08.065
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发表时间：
2018-11-01
影响因子：
4.3
通讯作者：
Antonijevic, Biljana
中科院分区：
文献类型：
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作者：
Antonijevic, Evica;Musilek, Kamil;Antonijevic, Biljana
乙酰胆碱酯酶（AChE）抑制是有机磷农药和神经毒剂引起的一个重要分子事件，是人类健康的重要问题。在实验性肟类药物（OP中毒的潜在解毒剂）的疗效测试中，OP抑制的AChE的再激活被用作特定终点。然而，据我们所知，到目前为止，肟还没有定量评估的综合基准剂量（BMD）的方法，这将提高识别和量化的效果，并允许更严格的比较功效。因此，我们已经研究了在体内的剂量-反应关系的两个有前途的实验肟，K203和K 027，关于再激活红细胞乙酰胆碱酯酶抑制敌敌畏（DDVP）。各组Wistar大鼠在敌敌畏（DDVP）攻击（s.c.）后立即用6种不同剂量的肟（i.m.）处理，60 min后测定AChE。通过PROAST软件65.5（RIVM，荷兰）进行剂量-反应建模。BMD-协变量方法导致四参数模型从指数和希尔模型家族作为最佳估计的AChE活性和肟剂量之间的关系，与效能参数是肟依赖性的。考虑到与BMD 58-K203 = 100 μ mol/kg相比，BMD 58-K 027 = 52 μ mol/kg剂量下AChE活性增加了58%，肟K 027的效力是1.929倍。
Inhibition of acethylcholinesterase (AChE) as a key molecular event induced by organophosphate (OP) pesticides and nerve agents presents a human health concern. In efficacy testing of experimental oximes, potential antidotes in OP poisoning, reactivation of OP-inhibited AChE is used as specific endpoint. However, according to our best knowledge, so far oximes have not been quantitatively evaluated by comprehensive benchmark dose (BMD) approach, that would improve both identification and quantification of the effect and allow more rigorous comparison of efficacies. Thus, we have examined in vivo dose-response relationship for two promising experimental oximes, K203 and K027, concerning reactivation of erythrocyte AChE inhibited by dichlorvos (DDVP). Groups of Wistar rats were treated with six different doses of oximes (i.m) immediately after DDVP challenge (s.c) and AChE was measured 60 min later. Dose-response modeling was done by PROAST software 65.5 (RIVM, The Nederlands). BMD-covariate method resulted in four-parameter model from both exponential and Hill model families as the best estimate of relationship between AChE activity and oxime dose, with potency parameter being oxime-dependent. Oxime K027 was shown to be 1.929-fold more potent considering that 58% increase in AChE activity was achived with the dose BMD58-K027 = 52 mu mol/kg in contrast to BMD58-K203 = 100 mu mol/kg.