Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, P O Box 127788, Abu Dhabi, UAE.
Herbert Wertheim College of Medicine, Department of Cellular Biology & Pharmacology, Florida International University, University Park GL 495, 11200 SW 8th St, Miami, FL 33199, USA.
Molecules. 2020 Mar 27;25(7):1521. doi: 10.3390/molecules25071521.
Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome.
Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure.
Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens.
Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.
有机磷化合物（OPC）作为农药非常有用，但也对健康构成严重威胁。目前的阿托品标准治疗和已建立的肟类酶重激活剂治疗并不令人满意。实验数据表明，在接触 OPC 之前使用可逆的胆碱酯酶抑制剂进行治疗可以获得更好的治疗效果。在比较了 5 种这样的胆碱酯酶抑制剂（毒扁豆碱、吡哆醇、雷尼替丁、他克林或 K-27）的保护效果后，我们观察到实验肟 K-27 的保护效果最佳。本研究旨在确定在 OPC（对氧磷）接触后立即给予额外的 K-27 是否可以改善结果。
通过 Cox 生存分析在 48 小时内确定相对死亡风险（RR）来评估治疗效果。将仅接受预处理和对氧磷的动物与接受预处理和对氧磷后立即给予对氧磷的动物进行比较。
用毒扁豆碱（RR = 0.30）和 K-27（RR = 0.34）预处理可观察到对氧磷诱导的死亡率的最佳保护。这两种物质的效果明显优于他克林（RR = 0.67）、雷尼替丁（RR = 0.72）和吡哆醇（RR = 0.76），后者的效果较差，但与未治疗组（仅对氧磷）相比，仍显著降低 RR。在接触对氧磷后立即给予 K-27（后处理）并不能进一步降低死亡率。对仅在接触对氧磷之前进行预处理和在接触对氧磷后立即进行预处理加 K-27 进行预处理的统计学分析显示，任何预处理方案之间均无显著差异。
如果在接触亚致死剂量的对氧磷之前预防性给予毒扁豆碱或 K-27，可获得最佳结果。此后立即进行额外的肟治疗并不能进一步改善治疗效果。
