Lorke Dietrich E, Nurulain Syed M, Hasan Mohamed Y, Kuča Kamil, Petroianu Georg A
Department of Cellular Biology & Pharmacology, Florida International University, Miami, Florida, USA; Department of Anatomy, FMHS, UAE University, Al Ain, United Arab Emirates.
J Appl Toxicol. 2014 Oct;34(10):1096-103. doi: 10.1002/jat.2939. Epub 2013 Oct 18.
Poisoning with organophosphorus compounds (OPCs) poses a serious threat worldwide. OPC-induced mortality can be significantly reduced by prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors. The only American Food and Drug Administration (FDA)-approved substance for such pre-treatment (to soman exposure) is presently pyridostigmine, although its efficacy is controversial. In search for more efficacious and broad-spectrum alternatives, we have assessed in vivo the mortality-reducing efficacy of a group of five compounds with known AChE inhibitory activity (pyridostigmine, physostigmine, ranitidine, tacrine and K-27), when given in equitoxic dosage (25% of LD01 ) 30 min before exposure to the OPC terbufos sulfone. Protection was quantified in rats by determining the relative risk of death (RR) using Cox analysis, with RR = 1 for animals given only terbufos sulfone, but no pre-treatment. All tested AChE inhibitors reduced terbufos sulfone-induced mortality significantly (p ≤ 0.05) as compared with the non-treatment group (RR = 1: terbufos sulfone only). Best in vivo protection from terbufos sulfone-induced mortality was achieved, when K-27 was given before terbufos sulfone exposure (RR = 0.06), which was significantly (P ≤ 0.05) superior to the pre-treatment with all other tested compounds, for example tacrine (RR = 0.21), pyridostigmine (RR = 0.28), physostigmine (RR = 0.29) and ranitidine (RR = 0.33). The differences in efficacy between tacrine, pyridostigmine, physostigmine and ranitidine were not statistically significant. Prophylactic administration of an oxime (such as K-27) in case of imminent OPC exposure may be a viable option.
有机磷化合物（OPC）中毒在全球范围内构成严重威胁。预防性给予可逆性乙酰胆碱酯酶（AChE）抑制剂可显著降低OPC引起的死亡率。目前，美国食品药品监督管理局（FDA）批准的用于此类预处理（针对梭曼暴露）的唯一物质是吡啶斯的明，但其疗效存在争议。为了寻找更有效和广谱的替代品，我们评估了一组五种具有已知AChE抑制活性的化合物（吡啶斯的明、毒扁豆碱、雷尼替丁、他克林和K-27）在等毒性剂量（LD01的25%）下于暴露于OPC特丁硫磷砜前30分钟给予时降低死亡率的疗效。通过使用Cox分析确定死亡相对风险（RR）来对大鼠的保护作用进行量化，仅给予特丁硫磷砜但未进行预处理的动物RR = 1。与未治疗组（RR = 1：仅特丁硫磷砜）相比，所有测试的AChE抑制剂均显著降低了特丁硫磷砜诱导的死亡率（p≤0.05）。在特丁硫磷砜暴露前给予K-27时，对特丁硫磷砜诱导的死亡率的体内保护效果最佳（RR = 0.06），这显著（P≤0.05）优于用所有其他测试化合物进行的预处理，例如他克林（RR = 0.21）、吡啶斯的明（RR = 0.28）、毒扁豆碱（RR = 0.29）和雷尼替丁（RR = 0.33）。他克林、吡啶斯的明、毒扁豆碱和雷尼替丁之间疗效的差异无统计学意义。在即将接触OPC的情况下预防性给予肟（如K-27）可能是一种可行的选择。
