尽管1997年批准了禁止化学武器的国际公约,但涉及此类武器的冲突和恐怖袭击的威胁仍然存在。其中,有机磷神经毒剂(OPs)抑制胆碱酯酶(ChE)引起胆碱能综合征。因此,这些酶的重新激活对于保护中毒的人至关重要。然而,这些重新激活的分子,主要命名为肟,具有主要缺点,对某些OPs的功效有限,如果以不足的剂量给药,则具有不可忽视的ChE抑制剂潜力,他们应该减轻的效果。因此,这个项目专注于评估治疗效果,在老鼠身上,达到NOAEL剂量,不引起任何可观察到的毒性作用的肟的最大剂量。HI-6DMS的NOAEL剂量,参考肟,JDS364HCl,候选人重新激活者,使用双腔体积描记术进行评估,以呼吸通气损害为毒性标准。时程建模参数和药效学谱,反映了肟与循环ChE之间的相互作用,评估其NOAEL和更高剂量的治疗。最后,OPs中毒的治疗潜力是通过保护指数评估确定的.对于JDS364。HCl,NOAEL剂量对应于诱导最显著治疗效果而不引起ChE活性异常的最小剂量。相比之下,对于HI-6DMS,在高于其NOAEL的剂量下观察到其治疗益处,导致呼吸功能改变。这些改变不能与ChE抑制直接相关,并且对存活没有不利影响。它们可能归因于HI-6DMS对非酶胆碱能靶标的刺激。因此,NOAEL似乎是评估肟疗效的最佳剂量,特别是当它可以与由ChE抑制有效导致的呼吸改变有关时。
Despite the international convention on the prohibition of chemical weapons ratified in 1997, the threat of conflicts and terrorist attacks involving such weapons still exists. Among these, organophosphorus-nerve agents (OPs) inhibit cholinesterases (ChE) causing cholinergic syndrome. The reactivation of these enzymes is therefore essential to protect the poisoned people. However, these reactivating molecules, mainly named oximes, have major drawbacks with limited efficacy against some OPs and a non-negligible ChE inhibitor potential if administered at an inadequate dose, an effect that they are precisely supposed to mitigate. As a result, this project focused on assessing therapeutic efficacy, in mice, up to the NOAEL dose, the maximum dose of
oxime that does not induce any observable toxic effect. NOAEL doses of HI-6 DMS, a reference
oxime, and JDS364. HCl, a candidate reactivator, were assessed using dual-chamber plethysmography, with respiratory ventilation impairment as a toxicity criterion. Time-course modeling parameters and pharmacodynamic profiles, reflecting the interaction between the
oxime and circulating ChE, were evaluated for treatments at their NOAEL and higher doses. Finally, the therapeutic potential against OPs poisoning was determined through the assessment of protective indices. For JDS364. HCl, the NOAEL dose corresponds to the smallest dose inducing the most significant therapeutic effect without causing any abnormality in ChE activity. In contrast, for HI-6 DMS, its therapeutic benefit was observed at doses higher than its NOAEL, leading to alterations in respiratory function. These alterations could not be directly correlated with ChE inhibition and had no adverse effects on survival. They are potentially attributed to the stimulation of non-enzymatic cholinergic targets by HI-6 DMS. Thus, the NOAEL appears to be an optimal dose for evaluating the efficacy of oximes, particularly when it can be linked to respiratory alterations effectively resulting from ChE inhibition.