Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication.
Intramuscular administration of glyoxylate rescues swine from lethal cyanide poisoning and ameliorates the biochemical sequalae of cyanide intoxication.
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肌内注射乙醛酸盐可以使猪免于致命的氰化物中毒，并改善氰化物中毒的生化后遗症。
DOI：
10.1093/toxsci/kfac116
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发表时间：
2023-01-31
期刊：
影响因子：
--
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中科院分区：
文献类型：
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氰化物是一种快速作用的毒药，由于其在制造业中的广泛应用，很容易获得。它是一种高威胁化学剂，除了是恐怖分子制剂外，还构成职业接触的风险。FDA批准的氰化物解毒剂必须通过静脉注射，由于获得静脉注射所需的时间和技能，这在大规模伤亡情况下是不切实际的。乙醛酸是一种内源性代谢物，可结合氰化物并逆转氰化物诱导的氧化还原失衡，而不依赖于螯合作用。尚未报告FDA批准的临床前动物模型中的疗效和生化机制研究。因此，在氰化物中毒的猪模型中，我们评价了肌内注射乙醛酸盐对临床、代谢和生化终点的疗效。对动物进行连续血流动力学监测，并输注氰化钾。氰化物诱导的呼吸暂停后，肌肉注射生理盐水对照或乙醛酸盐。在整个研究过程中，采集了系列血液样本用于药代动力学、代谢产物和生化研究，此外，还测量了生命体征、血流动力学参数和实验室值。乙醛酸盐处理动物的存活率为83%，而盐水处理对照动物的存活率为12%（p < .01）。乙醛酸治疗改善了生理参数，包括脉搏血氧饱和度，动脉氧合，呼吸和pH值。此外，柠檬酸循环代谢产物的水平恢复到基线水平的研究结束。此外，乙醛酸对氧化还原平衡产生了明显的影响，与氰化物螯合对策相比。在我们的临床前猪致死性氰化物中毒模型中，肌肉注射内源性代谢产物乙醛酸改善了存活率和临床结局，并改善了氰化物的生化效应。
Cyanide—a fast-acting poison—is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being a terrorist agent. FDA-approved cyanide antidotes must be given intravenously, which is not practical in a mass casualty setting due to the time and skill required to obtain intravenous access. Glyoxylate is an endogenous metabolite that binds cyanide and reverses cyanide-induced redox imbalances independent of chelation. Efficacy and biochemical mechanistic studies in an FDA-approved preclinical animal model have not been reported. Therefore, in a swine model of cyanide poisoning, we evaluated the efficacy of intramuscular glyoxylate on clinical, metabolic, and biochemical endpoints. Animals were instrumented for continuous hemodynamic monitoring and infused with potassium cyanide. Following cyanide-induced apnea, saline control or glyoxylate was administered intramuscularly. Throughout the study, serial blood samples were collected for pharmacokinetic, metabolite, and biochemical studies, in addition, vital signs, hemodynamic parameters, and laboratory values were measured. Survival in glyoxylate-treated animals was 83% compared with 12% in saline-treated control animals (p < .01). Glyoxylate treatment improved physiological parameters including pulse oximetry, arterial oxygenation, respiration, and pH. In addition, levels of citric acid cycle metabolites returned to baseline levels by the end of the study. Moreover, glyoxylate exerted distinct effects on redox balance as compared with a cyanide-chelating countermeasure. In our preclinical swine model of lethal cyanide poisoning, intramuscular administration of the endogenous metabolite glyoxylate improved survival and clinical outcomes, and ameliorated the biochemical effects of cyanide.
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DOI：
10.1152/ajpgi.00331.2011
发表时间：
2012-03-01
影响因子：
4.5
作者：
Jiang, Juquan;Johnson, Lynnette C.;Lowther, W. Todd
通讯作者：
Lowther, W. Todd
影响因子：
3.3
作者：
Hendry-Hofer, Tara B.;Severance, Carter C.;Bebarta, Vikhyat S.
通讯作者：
Bebarta, Vikhyat S.
DOI：
10.1111/j.1463-1326.2010.01266.x
发表时间：
2010-10
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Jones DP;Go YM
通讯作者：
Go YM
影响因子：
6.2
作者：
Bebarta VS;Brittain M;Chan A;Garrett N;Yoon D;Burney T;Mukai D;Babin M;Pilz RB;Mahon SB;Brenner M;Boss GR
通讯作者：
Boss GR
影响因子：
8
作者：
Kimberly, W. Taylor;O'Sullivan, John F.;Gerszten, Robert E.
通讯作者：
Gerszten, Robert E.