Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor
Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor
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DOI：
10.1016/j.neuro.2016.05.006
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发表时间：
2016-07-01
期刊：
影响因子：
3.4
通讯作者：
Antonijevic, Biljana
中科院分区：
文献类型：
--
作者：
Antonijevic, Evica;Musilek, Kamil;Antonijevic, Biljana
由于肟基结构是有机磷（OP）抑制的乙酰胆碱酯酶（AChE）的唯一致病解毒剂，因此大多数研究都是针对其合成和测试。在这项研究中，实验bispyridinium肟K 027和K203，这在过去的十年中的研究显示出有前途的结果，在体内研究其治疗和再激活能力，在急性中毒的直接乙酰胆碱酯酶抑制剂敌敌畏（DDVP），用作二甲基OP结构模型。此外，肟K 027和K203的功效与已经用于功效实验和人类医学的四种肟（解磷定、三甲肟、双肟和HI-6）的功效进行了比较。为了评估治疗功效，将Wistar大鼠组用等毒性剂量的肟（5%LD 50，i. m.）和/或阿托品（10 mg/kg，i.m.）在s.c.敌敌畏攻毒（4-6剂）。使用相同的解毒方案，在s.c.后60分钟测量红细胞、膈肌和脑中的AChE活性。敌敌畏暴露（75% LD 50）。肟K 027对敌敌畏诱导的大鼠致死作用最强，肟K203的作用强于三甲肟、解磷定和HI-6。只有肟K 027或肟K 027与阿托品合用才能显著地激活AChE。此外，急性I. M.肟K 027对大鼠的毒性低于其它所有肟类化合物。本研究的结果支持先前的研究，认为肟K 027是一种有前途的实验肟结构，可用于进一步测试结构不同的OP化合物。(C)© 2016 Elsevier B. V.版权所有。
As oxime-based structures are the only causal antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE), the majority of studies on these have been directed towards their synthesis and testing. In this study, experimental bispyridinium oximes K027 and K203, which have shown promising results in the last decade of research, were examined in vivo for their therapeutic and reactivating ability in acute poisoning by the direct AChE-inhibitor dichlorvos (DDVP), used as a dimethyl OP structural model. Additionally, the efficacy of oximes K027 and K203 was compared with the efficacy of four oximes (pralidoxime, trimedoxime, obidoxime and HI-6), already used in efficacy experiments and human medicine. To evaluate therapeutic efficacy, groups of Wistar rats were treated with equitoxic doses of oximes (5% LD50, i.m.) and/or atropine (10 mg/kg, i.m.) immediately after s.c. DDVP challenge (4-6 doses). Using the same antidotal protocol, AChE activity was measured in erythrocytes, diaphragm and brain 60 min after s.c. DDVP exposure (75% LD50). The oxime K027 was the most efficacious in reducing the DDVP induced lethal effect in rats, while the oxime K203 was more efficacious than trimedoxime, pralidoxime and HI-6. Significant reactivation of DDVP inhibited AChE was achieved only with oxime K027 or its combination with atropine in erythocytes and the diaphragm. Moreover, the acute i.m. toxicity of oxime K027 in rats was lower than all other tested oximes. The results of this study support previous studies considering the oxime K027 as a promising experimental oxime structure for further testing against structurally-different OP compounds. (C) 2016 Elsevier B.V. All rights reserved.