Intertek Health Sciences, Inc., Pharmaceuticals & Healthcare, Mississauga, ON, Canada.
Southern Research, Birmingham, AL, United States of America.
Toxicol Appl Pharmacol. 2021 Oct 15;429:115702. doi: 10.1016/j.taap.2021.115702. Epub 2021 Aug 28.
Intramuscular (IM) injection of nitrite (1-10 mg/kg) confers survival benefit and protects against lung injury after exposure to chlorine gas in preclinical models. Herein, we evaluated safety/toxicity parameters after single, and repeated (once daily for 7 days) IM injection of nitrite in male and female Sprague Dawley rats and Beagle dogs. The repeat dose studies were performed in compliance with the Federal Drug Administration's (FDA) Good Laboratory Practices Code of Federal Regulations (21 CFR Part 58). Parameters evaluated consisted of survival, clinical observations, body weights, clinical pathology, plasma drug levels, methemoglobin and macroscopic and microscopic pathology. In rats and dogs, single doses of ≥100 mg/kg and 60 mg/kg resulted in death and moribundity, while repeated administration of ≤30 or ≤ 10 mg/kg/day, respectively, was well tolerated. Therefore, the maximum tolerated dose following repeated administration in rats and dogs were determined to be 30 mg/kg/day and 10 mg/kg/day, respectively. Effects at doses below the maximum tolerated dose (MTD) were limited to emesis (in dogs only) and methemoglobinemia (in both species) with clinical signs (e.g. blue discoloration of lips) being dose-dependent, transient and reversible. These signs were not considered adverse, therefore the No Observed Adverse Effect Level (NOAEL) for both rats and dogs was 10 mg/kg/day in males (highest dose tested for dogs), and 3 mg/kg/day in females. Toxicokinetic assessment of plasma nitrite showed no difference between male and females, with C occurring between 5 mins and 0.5 h (rats) or 0.25 h (dogs). In summary, IM nitrite was well tolerated in rats and dogs at doses previously shown to confer protection against chlorine gas toxicity.
肌内（IM）注射亚硝酸盐（1-10mg/kg）可在临床前模型中提供生存益处并预防氯气暴露后的肺损伤。在此，我们评估了雄性和雌性 Sprague Dawley 大鼠和比格犬单次和重复（每天一次，连续 7 天）肌内注射亚硝酸盐后的安全性/毒性参数。重复剂量研究符合美国食品和药物管理局（FDA）的良好实验室规范法规（21 CFR 第 58 部分）。评估的参数包括生存、临床观察、体重、临床病理学、血浆药物水平、高铁血红蛋白以及宏观和微观病理学。在大鼠和犬中，≥100mg/kg 和 60mg/kg 的单剂量导致死亡和濒死，而分别重复给予≤30 或≤10mg/kg/天则可耐受良好。因此，在大鼠和犬中，重复给药后的最大耐受剂量（MTD）分别确定为 30mg/kg/天和 10mg/kg/天。低于最大耐受剂量（MTD）的剂量的作用仅限于呕吐（仅在犬中）和高铁血红蛋白血症（在两种物种中），其临床症状（例如嘴唇发蓝）呈剂量依赖性、短暂和可逆。这些症状不被认为是不利的，因此大鼠和犬的未观察到不良效应水平（NOAEL）分别为雄性 10mg/kg/天（犬的最高测试剂量）和雌性 3mg/kg/天。血浆亚硝酸盐的毒代动力学评估显示，雄性和雌性之间没有差异，C 发生在 5 分钟至 0.5 小时之间（大鼠）或 0.25 小时（犬）。总之，在先前显示可预防氯气毒性的剂量下，肌内亚硝酸盐在大鼠和犬中耐受良好。
