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首页> 外文期刊>Journal of applied toxicology >Effect of metoclopramide and ranitidine on the inhibition of human AChE by VX in vitro.
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Effect of metoclopramide and ranitidine on the inhibition of human AChE by VX in vitro.

机译：甲氧氯普胺和雷尼替丁对VX体外抑制人AChE的影响。

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The repeated misuse of highly toxic organophosphorus-type (OP) chemical warfare agents ('nerve agents') emphasizes the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators ('oximes') is considered to be ineffective with certain nerve agents due to low oxime efficacy. Therefore, pretreatment with carbamate-type compounds, e.g. pyridostigmine, was recommended to improve antidotal efficacy. Recently, the clinically used reversible AChE inhibitors metoclopramide (MCP) and ranitidine (RAN) were shown to exhibit some protective effect against the OP pesticide paraoxon in vitro and in vivo. The present study was undertaken to investigate a potential protective effect of MCP and RAN against inhibition of human AChE by the nerve agent VX (O-ethyl S-[2-(diisopropylamino)ethyl)methylphosphonothioate). Hemoglobin-free human erythrocyte membranes were incubated with various, human relevant MCP (0.5-2 microm) and RAN (0.5-5 microm) concentrations starting 1 min before addition of VX (1-40 nm). Both compounds failed to increase VX IC(50) values. In addition, human AChE was incubated with higher than human relevant therapeutic concentrations of MCP (1 microm-1 mm) and RAN (1 microm-2.0 mm) and inhibited by 40 nm VX. At concentrations higher than 100 microm MCP and RAN caused a concentration dependent increase of residual AChE activity 15 min after addition of VX. These data indicate that MCP and RAN may be ineffective in protecting human AChE against inhibition by the nerve agent VX at human relevant doses.
机译：反复滥用高毒性有机磷型（OP）化学战剂（“神经毒剂”）强调了开发有效医学对策的必要性。阿托品和乙酰胆碱酯酶（AChE）激活剂（'肟'）的标准治疗由于肟功效低而被认为对某些神经药物无效。因此，用氨基甲酸酯型化合物，例如碳酸氢盐进行预处理。吡啶斯的明被推荐用于提高解毒功效。最近，临床上可逆的AChE抑制剂甲氧氯普胺（MCP）和雷尼替丁（RAN）已显示出对OP农药对氧磷的体外和体内保护作用。进行本研究以研究MCP和RAN对神经药VX（O-乙基S- [2-（二异丙基氨基）乙基）甲基硫代磷酸酯抑制人AChE的潜在保护作用。在加入VX（1-40 nm）之前1分钟，将无血红蛋白的人红细胞膜与各种与人相关的MCP（0.5-2 microm）和RAN（0.5-5 microm）浓度进行孵育。两种化合物都不能增加VX IC（50）值。此外，将人AChE与高于相关治疗浓度的MCP（1 microm-1 mm）和RAN（1 microm-2.0 mm）孵育，并用40 nm VX抑制。加入VX 15分钟后，浓度高于100微米的MCP和RAN会引起残留的AChE活性浓度依赖性地增加。这些数据表明，MCP和RAN在保护人类AChE免受人类相关剂量的神经毒剂VX抑制作用方面可能无效。

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