Organophosphorus nerve agents (NA) inhibit acetylcholinesterase (AChE) which results in the over-stimulation of both the central and peripheral nervous systems, creating a toxic syndrome that can be lethal if left untreated (Cannard, 2006). It is standard practice to treat Sarin (GB) intoxication with an oxime, an antimuscarinic such as atropine and an anticonvulsant. Three common oximes are available: HI-6, Pralidoxime (2-PAM) and Obidoxime (Obi), all possess a nucleophile that can break the NA-AChE covalent bond. However, each oxime's efficacy profile against various agents is different (Thiermann and Worek, 2018). In an effort to broaden therapeutic efficacy against a range of possible NA's, consideration should be given to the use of two oximes in combination. Using a guinea pig model, the first arm of this study was to determine the pharmacokinetics (PK) of HI-6 DMS, 2-PAM chloride and Obi chloride (at autoinjector equivalent doses) following intramuscular (i.m.) co-administration along with atropine to replicate either a single isometrically scaled dose (referred to in this study as a single autoinjector equivalent) of 2-PAM (and equimolar doses of Obi and HI-6) or double doses (referred to in this study as two autoinjector equivalents). The second arm of the study evaluated the efficacy of Obi and 2-PAM individually at a single or double autoinjector dose and also in combination against GB exposure. Pharmacokinetic profiles of each oxime were evaluated for both arms of the study and no significant change in parameters reported. Improved cholinesterase reactivation was observed in a dose dependent manner with combined therapy showing similar reactivation to individual oximes alone at a two autoinjector equivalent dose. Seizure activity was reduced when combined oxime therapy was administered. This improvement was also reflected in the Racine seizure index score assigned at the end of the experimental period. To the best of our knowledge, this study is the first to evaluate and compare the pharmacokinetics of three oximes and the combination of two oximes (2-PAM and Obi) administered in naïve animals or those exposed to GB. Combined oxime therapy (Obi and 2-PAM) resulted in improved seizure control, increased cholinesterase reactivation peripherally and centrally and improved behavioral signs (Racine score. This study provides evidence that combination of oximes is effective and does not result in adverse events and that the pharmacokinetics of each oxime are not affected when administered in combination.

中文翻译：

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三种肟在豚鼠模型中的药代动力学比较和肟联合治疗的疗效

有机磷神经毒剂 (NA) 会抑制乙酰胆碱酯酶 (AChE)，这会导致中枢和外周神经系统过度刺激，从而产生一种毒性综合征，如果不及时治疗可能会致命（Cannard，2006 年）。标准做法是用肟、抗毒蕈碱药如阿托品和抗惊厥药治疗沙林 (GB) 中毒。可以使用三种常见的肟：HI-6、解磷定 (2-PAM) 和 Obidoxime (Obi)，它们都具有可以破坏 NA-AChE 共价键的亲核试剂。然而，每种肟对各种药剂的功效是不同的（Thiermann 和 Worek，2018 年）。为了扩大针对一系列可能的 NA 的治疗效果，应考虑联合使用两种肟。使用豚鼠模型，本研究的第一组是确定 HI-6 DMS、2-PAM 氯化物和 Obi 氯化物（以自动注射器等效剂量）与阿托品肌肉内 (im) 共同给药后的药代动力学 (PK) 2-PAM（以及等摩尔剂量的 Obi 和 HI-6）或双倍剂量（在本研究中称为两个自​​动注射器等价物）的缩放剂量（在本研究中称为单次自动注射器等价物）。该研究的第二组分别评估了 Obi 和 2-PAM 在单次或双次自动注射器剂量下以及联合使用对 GB 暴露的疗效。对研究的两个组评估了每种肟的药代动力学特征，并且没有报告参数的显着变化。以剂量依赖性方式观察到胆碱酯酶再激活的改善，联合治疗显示出与单独使用两个自动注射器等效剂量的单个肟类似的再激活。联合肟治疗时癫痫发作活动减少。这种改善也反映在实验期结束时分配的 Racine 癫痫指数评分中。据我们所知，这项研究是第一个评估和比较三种肟和两种肟组合（2-PAM 和 Obi）在幼稚动物或暴露于 GB 的动物中的药代动力学的研究。联合肟疗法（Obi 和 2-PAM）可改善癫痫发作控制，增加外周和中枢胆碱酯酶的再激活，并改善行为体征（Racine 评分。