Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates.
Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi P.O. Box 127788, United Arab Emirates.
Int J Mol Sci. 2021 Mar 17;22(6):3072. doi: 10.3390/ijms22063072.
Poisoning with organophosphorus compounds (OPCs) represents an ongoing threat to civilians and rescue personal. We have previously shown that oximes, when administered prophylactically before exposure to the OPC paraoxon, are able to protect from its toxic effects. In the present study, we have assessed to what degree experimental (K-27; K-48; K-53; K-74; K-75) or established oximes (pralidoxime, obidoxime), when given as pretreatment at an equitoxic dosage of 25% of LD, are able to reduce mortality induced by the OPC azinphos-methyl. Their efficacy was compared with that of pyridostigmine, the only FDA-approved substance for such prophylaxis. Efficacy was quantified in rats by Cox analysis, calculating the relative risk of death (RR), with RR=1 for the reference group given only azinphos-methyl, but no prophylaxis. All tested compounds significantly ( ≤ 0.05) reduced azinphos-methyl-induced mortality. In addition, the efficacy of all tested experimental and established oximes except K-53 was significantly superior to the FDA-approved compound pyridostigmine. Best protection was observed for the oximes K-48 (RR = 0.20), K-27 (RR = 0.23), and obidoxime (RR = 0.21), which were significantly more efficacious than pralidoxime and pyridostigmine. The second-best group of prophylactic compounds consisted of K-74 (RR = 0.26), K-75 (RR = 0.35) and pralidoxime (RR = 0.37), which were significantly more efficacious than pyridostigmine. Pretreatment with K-53 (RR = 0.37) and pyridostigmine (RR = 0.52) was the least efficacious. Our present data, together with previous results on other OPCs, indicate that the experimental oximes K-27 and K-48 are very promising pretreatment compounds. When penetration into the brain is undesirable, obidoxime is the most efficacious prophylactic agent already approved for clinical use.
有机磷化合物（OPC）中毒一直是平民和救援人员面临的威胁。我们之前的研究表明，肟类化合物在接触 OPC 对氧磷之前进行预防性给药，能够保护免受其毒性作用。在本研究中，我们评估了实验性肟类化合物（K-27；K-48；K-53；K-74；K-75）或已确立的肟类化合物（氯解磷定、碘解磷定）在给予相当于 LD50 的 25%等毒性剂量的预处理时，在多大程度上能够降低敌百虫诱导的死亡率。将它们的疗效与唯一被 FDA 批准用于此类预防的化合物吡啶斯的明进行比较。通过 Cox 分析来量化疗效，计算死亡率的相对风险（RR），RR=1 表示仅给予敌百虫而未给予任何预防措施的参考组。所有测试的化合物均显著（≤0.05）降低了敌百虫诱导的死亡率。此外，除 K-53 外，所有测试的实验性和确立的肟类化合物的疗效均明显优于 FDA 批准的化合物吡啶斯的明。观察到最好的保护作用的肟类化合物是 K-48（RR=0.20）、K-27（RR=0.23）和碘解磷定（RR=0.21），它们比氯解磷定和吡啶斯的明更有效。第二组疗效较好的预防用化合物包括 K-74（RR=0.26）、K-75（RR=0.35）和氯解磷定（RR=0.37），它们比吡啶斯的明更有效。K-53（RR=0.37）和吡啶斯的明（RR=0.52）的预处理效果最差。我们目前的数据与之前关于其他 OPC 的结果一起表明，实验性肟类化合物 K-27 和 K-48 是非常有前途的预处理化合物。当不希望进入大脑时，已被批准用于临床的奥碘解磷定是最有效的预防性药物。
