a Bundeswehr Institute of Pharmacology and Toxicology , Neuherbergstraße 11, Munich , Germany.
Clin Toxicol (Phila). 2019 Jul;57(7):644-651. doi: 10.1080/15563650.2018.1540785. Epub 2019 Jan 30.
Nerve agents like sarin or VX have repeatedly been used in military conflicts or homicidal attacks, as seen in Syria or Malaysia 2017. Together with pesticides, nerve agents assort as organophosphorus compounds (OP), which inhibit the enzyme acetylcholinesterase. To counteract subsequent fatal symptoms due to acetylcholine (ACh) accumulation, oximes plus atropine are administered, a regimen that lacks efficacy in several cases of OP poisoning. New therapeutics are in development, but still need evaluation before clinical employment. Supportive treatment with already approved drugs presents an alternative, whereby compounds from COPD and asthma therapy are likely options. A recent pilot study by Chowdhury et al. included β2-agonist salbutamol in the treatment of OP-pesticide poisoned patients, yielding ambiguous results concerning the addition. Here, we provide experimental data for further investigations regarding the value of these drugs in OP poisoning. By video-microscopy, changes in airway area were analyzed in VX-poisoned rat precision cut lung slices (PCLS) after ACh-induced airway contraction and subsequent application of selected anticholinergics/β2-agonists. Glycopyrrolate and ipratropium efficiently antagonized an ACh-induced airway contraction in VX-poisoned PCLS (EC glycopyrrolate 15.8 nmol/L, EC ipratropium 2.3 nmol/L). β2-agonists formoterol and salbutamol had only negligible effects when solely applied in the same setting. However, combination of formoterol or salbutamol with low dosed glycopyrrolate or atropine led to an additive effect compared to the sole application [50.6 ± 8.8% airway area increase after 10 nmol/L formoterol +1 nmol/L atropine versus 11.7 ± 9.2% (10 nmol/L formoterol) or 8.6 ± 5.9% (1 nmol/L atropine)]. We showed antagonizing effects of anticholinergics and β2-agonists on ACh-induced airway contractions in VX-poisoned PCLS, thus providing experimental data to support a prospective comprehensive clinical study. Our results indicate that COPD and asthma therapeutics could be a valuable addition to the treatment of OP poisoning.
沙林或 VX 等神经毒剂在军事冲突或蓄意袭击中一再被使用，在叙利亚或 2017 年的马来西亚都能看到此类事件。与杀虫剂一起，神经毒剂被归类为有机磷化合物（OP），它会抑制乙酰胆碱酯酶。为了对抗随后由于乙酰胆碱（ACh）积累而产生的致命症状，会使用肟和阿托品，但是这种方案在 OP 中毒的几种情况下都没有效果。新的治疗方法正在开发中，但在临床应用之前仍需要进行评估。使用已经批准的药物进行支持性治疗是一种替代方法，其中 COPD 和哮喘治疗的化合物可能是可行的选择。Chowdhury 等人最近进行的一项试点研究在 OP 杀虫剂中毒患者的治疗中加入了β2-激动剂沙丁胺醇，但关于添加物的结果并不明确。在这里，我们提供了有关这些药物在 OP 中毒中价值的进一步研究的实验数据。通过视频显微镜，在 ACh 诱导的气道收缩后，分析了 VX 中毒的大鼠精密切割肺切片（PCLS）中的气道面积变化，随后应用了选定的抗胆碱能药/β2-激动剂。在 VX 中毒的 PCLS 中，格隆溴铵和异丙托溴铵有效地拮抗了 ACh 诱导的气道收缩（EC 格隆溴铵 15.8 nmol/L，EC 异丙托溴铵 2.3 nmol/L）。单独使用时，β2-激动剂福莫特罗和沙丁胺醇的作用可以忽略不计。然而，与单独使用相比，低剂量格隆溴铵或阿托品与福莫特罗或沙丁胺醇联合使用会产生附加作用[10 nmol/L 福莫特罗+1 nmol/L 阿托品后 50.6±8.8%气道面积增加，而 11.7±9.2%（10 nmol/L 福莫特罗）或 8.6±5.9%（1 nmol/L 阿托品）]。我们在 VX 中毒的 PCLS 中显示了抗胆碱能药和β2-激动剂对 ACh 诱导的气道收缩的拮抗作用，从而提供了支持全面临床研究的实验数据。我们的结果表明，COPD 和哮喘治疗可能是治疗 OP 中毒的有价值的补充。
