Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.
Cyanide toxicity in juvenile pigs and its reversal by a new prodrug, sulfanegen sodium.
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DOI：
10.1213/ane.0b013e31824c4eb5
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发表时间：
2012-05
影响因子：
5.7
通讯作者：
Vince R
中科院分区：
文献类型：
--
作者：
Belani KG;Singh H;Beebe DS;George P;Patterson SE;Nagasawa HT;Vince R
氰化物（CN）毒性是一个严重的临床问题，可发生与硝普钠（SNP），意外吸入烟雾，工业事故和生物恐怖主义。在这项研究中，我们诱导严重的CN毒性独立与SNP或氰化钠（NaCN）在幼年猪模型中，以证明逆转严重CN毒性与一种新的解毒剂，磺胺钠，3-巯基丙酮酸的前药。SNP研究：在11只麻醉、机械通气的幼年猪中进行的初步研究使我们能够确定诱导CN毒性的SNP剂量。监测血CN、血清乳酸和血气。CN毒性定义为发生严重乳酸酸中毒伴血CN水平显著升高。基于该初步研究，八只麻醉的猪接受高剂量SNP（100 mg/hr）IV输注2小时以诱导CN毒性。然后，他们被随机分配接受磺胺酸钠或安慰剂。4头猪在诱导严重CN毒性后每小时接受3次磺胺原钠（2.5 g IV）给药，而4头猪接受安慰剂给药。在四只用丙泊酚加氯胺酮镇静的自发通气猪中进行了一项初步研究，以证明几个小时的血流动力学和代谢稳定性。此后，对6只猪进行类似的镇静，并以推注等分试样给予NaCN，以产生CN毒性，最终导致死亡。跟踪血流动力学和代谢变量，以确定CN毒性峰值。在另一组6头猪中，通过该方法诱导了严重的CN毒性，在毒性峰值时，对动物给予磺胺甲氧嘧啶钠（2.5 g IV），60分钟后对存活动物重复给药。SNP研究：初步研究表明，在接受高剂量SNP的所有猪中，血液CN水平显著增加（p<0.05），伴有严重的乳酸血症（p<0.05）。磺胺原解毒剂的给药导致血液乳酸盐和CN水平的进行性显著降低，存活率为100%（p<0.05），而安慰剂处理的猪恶化，没有存活（p<0.05）。NaCN注射导致CN毒性，伴随着严重的乳酸酸中毒和死亡率在所有的猪。磺胺原钠逆转了这种毒性，并防止了所有用这种解毒剂处理的猪的死亡。CN毒性可以在幼猪模型中用SNP或NaCN成功地诱导。前体药物磺胺原钠可有效逆转SNP或NaCN诱导的CN毒性。
Cyanide (CN) toxicity is a serious clinical problem and can occur with sodium nitroprusside (SNP), accidental smoke inhalation, industrial mishaps and bio-terrorism. In this study we induced severe CN toxicity independently with SNP or sodium cyanide (NaCN) in a juvenile pig model to demonstrate reversal of severe CN toxicity with a new antidote, sulfanegen sodium, a prodrug of 3-mercaptopyruvate. SNP study: A pilot study in eleven anesthetized, mechanically ventilated juvenile pigs allowed us to determine the dose of SNP to induce CN toxicity. Blood CN, serum lactates and blood gases were monitored. CN toxicity was defined as the occurrence of severe lactic acidosis accompanied by significant elevation in blood CN levels. Based on this pilot study, eight anesthetized pigs received a high-dose IV infusion of SNP (100mg/hr) for 2 hours to induce CN toxicity. They were then randomized to receive either sulfanegen sodium or placebo. Four pigs received 3 doses of sulfanegen sodium (2.5g IV) every hour after induction of severe CN toxicity, while 4 pigs received placebo. A pilot study was conducted in four spontaneously ventilating pigs sedated with propofol plus ketamine to demonstrate hemodynamic and metabolic stability for several hours. After this, 6 pigs were similarly sedated and given NaCN in bolus aliquots to produce CN toxicity ultimately resulting in death. Hemodynamics and metabolic variables were followed to define peak CN toxicity. In another group of six pigs, severe CN toxicity was induced by this method, and at peak toxicity, the animals were given sulfanegen sodium (2.5 g IV) followed by a repeat dose 60 minutes later in surviving animals. SNP study: The pilot study demonstrated the occurrence of a significant increase in blood CN levels (p<0.05) accompanied by severe lactic acidemia (p<0.05) in all pigs receiving a high dose of SNP. Administration of the sulfanegen antidote resulted in progressive significant reduction in blood lactate and CN levels with 100% survival (p<0.05), whereas the placebo-treated pigs deteriorated and did not survive (p<0.05). NaCN injection resulted in CN toxicity accompanied by severe lactic acidosis and mortality in all the pigs. Sulfanegen sodium reversed this toxicity and prevented mortality in all the pigs treated with this antidote. CN toxicity can be successfully induced in a juvenile pig model with SNP or NaCN. The prodrug, sulfanegen sodium, is effective in reversing CN toxicity induced by SNP or NaCN.