COPD and asthma therapeutics for supportive treatment in organophosphate poisoning

Context: 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 beta 2-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. Methods: 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/beta 2-agonists. Results: Glycopyrrolate and ipratropium efficiently antagonized an ACh-induced airway contraction in VX-poisoned PCLS (EC50 glycopyrrolate 15.8 nmol/L, EC50 ipratropium 2.3 nmol/L). beta 2-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)]. Discussion: We showed antagonizing effects of anticholinergics and beta 2-agonists on ACh-induced airway contractions in VX-poisoned PCLS, thus providing experimental data to support a prospective comprehensive clinical study. Conclusions: Our results indicate that COPD and asthma therapeutics could be a valuable addition to the treatment of OP poisoning.