Crystalline hydroxocobalamin and methemoglobin as a treatment of H2S intoxication

结晶羟钴胺和高铁血红蛋白治疗 H2S 中毒

• 批准号: 8416799
• 负责人: Philippe A Haouzi
• 金额: $ 38.25万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-28 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416799
• 关键词: Accidents; Acute; Address; Adult; Animals; Antidotes; Apnea; Blood; Blood Tests; Breathing; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Cerebrospinal Fluid; Chemicals; Clinical; Cobalt; Cyanides; Dental Pulp; Dose; Environment; Eye; FDA approved; Gases; Goals; Heart Arrest; Hemoglobin; Hospitals; Human; Human Resources; Hydrogen Sulfide; Hydroxocobalamin; Hypotension; In Vitro; Infusion procedures; Injection of therapeutic agent; Intoxication; Intramuscular; Intranasal Administration; Intravenous; Intravenous infusion procedures; Iron; Laboratory Personnel; Life; Lung; Mammals; Mechanical ventilation; Methemoglobin; Neurons; Oils; Paramedical Personnel; Patients; Plants; Plasma; Poisoning; Powder dose form; Rattus; Reporting; Risk; Rodent; Route; Saline; Security; Sheep; Solutions; Source; Suicide; Symptoms; System; Testing; Time; Tissues; Toxic effect; Vitamin B 12; base; hazard; high risk; improved; in vivo; interest; intravenous administration; intravenous injection; metabolic depression; novel; outcome forecast; oxidation; prevent; research study; respiratory; response

DESCRIPTION (provided by applicant): Hydrogen sulfide (H2S) is a lethal gas regarded as a potential chemical threat by the Department of Homeland Security and a "chemical hazard immediately dangerous to life" by the Centers for Disease Control. We have recently developed a paradigm to decrease H2S very rapidly in the blood and tissues of rats based on the use of the crystalline form of low dose of methemoglobin (as a source of ferric Iron) and high dose of Vitamin B12 (as a source of oxidized Cobalt). Both agents are safe (high dose of Vitamin B12 is already FDA approved for cyanide poisoning), can be stored as a kit, in a powder form, and can easily be administered to humans following H2S exposure. The goal of this project is to test the hypothesis that solutions of methemoglobin or Vitamin B12 can be used as antidotes following H2S exposure. The possibility of administering Vitamin B12 in H2S intoxication at a dose 10 times lower than the dose used for cyanide intoxication makes it possible to deliver this agent using intramuscular or intranasal administration. Since we have demonstrated that H2S produces in small animals (rodents) a specific protective response, not found in larger mammals, we intend to conduct our studies in adult sheep. In this proposal, we will determine the ability of these antidotes to lower the concentration of H2S, and its oxidative products, in th blood and the cerebrospinal fluid of adult sheep following infusion of lethal concentrations of H2S. The cerebrospinal fluid will be used as a convenient marker of the exposure of the medullary neurons, exquisitely sensitive to the toxic effects of H2S. At the same time, we will assess the alterations of the respiratory and cardiovascular control systems. H2S intoxication will be generated by intravenous infusion, prepared from a solution of NaHS, a H2S donor, to prevent any risk to the laboratory personnel related to gaseous H2S exposure. H2S infusion will be stopped as soon as an apnea occurs and at this time the end-points proposed in this application will be evaluated in controls and in animals treated with either methemoglobin or Vitamin B12 given one or 20 minutes following the cessation of H2S infusion. Finally, we will determine the blood concentration of Vitamin B12 and the ability of the plasma to oxidize exogenous H2S, following intranasal or intramuscular administration of Vitamin B12. The results of these proposed studies will help determine the proper strategy of use and the respective benefits of these antidotes. Intranasal or intramuscular administration of Vitamin B12 represents an interesting alternative to intravenous infusion that could be implemented by non-professional rescuers to a large number of patients. PUBLIC HEALTH RELEVANCE: Hydrogen sulfide (H2S) is, as defined by the Centers for Disease Control, a chemical hazard immediately dangerous to life, with no proven effective antidote, causing several fatal intoxications every year in the US; as it is easy to produce, this gas is also considered as a threat by the Department of Homeland Security. We have shown that methemoglobin, in a powder form, and Vitamin B12 (hydroxocobalamin) can be injected, after being mixed with saline, to decrease H2S very rapidly in the plasma and various tissues in rodents. This project will determine, in adult sheep, under what conditions these two agents could be used as antidotes in potentially lethal H2S poisoning, and whether intramuscular or intranasal administration of Vitamin B12 could be used to treat subjects intoxicated by hydrogen sulfide.

描述(申请人提供)：硫化氢(H_2S)是一种致命气体，被国土安全部视为潜在的化学威胁，被疾病控制中心视为“直接危及生命的化学危险”。我们最近开发了一种范例，基于使用晶体形式的低剂量高铁血红蛋白(作为铁铁的来源)和高剂量的维生素B12(作为氧化钴的来源)，非常迅速地减少大鼠血液和组织中的硫化氢。这两种制剂都是安全的(大剂量的维生素B12已经被FDA批准用于氰化物中毒)，可以作为药盒储存，以粉末的形式储存，并且在接触硫化氢后很容易给人服用。该项目的目标是验证高铁血红蛋白或维生素B12溶液在接触硫化氢后可用作解毒剂的假设。在硫化氢中毒中给予维生素B12的剂量比氰化物中毒的剂量低10倍，这使得通过肌肉或鼻腔给药来传递这种药物成为可能。由于我们已经证明，在小型动物(啮齿动物)中，硫化氢会产生一种在大型哺乳动物中没有的特定保护性反应，因此我们打算在成年绵羊中进行研究。在这项建议中，我们将确定这些解毒剂在注入致死浓度的硫化氢后，降低成年绵羊血液和脑脊液中硫化氢及其氧化产物浓度的能力。脑脊液将被用作延髓神经元暴露的一个方便的标记，对硫化氢的毒性效应非常敏感。同时，我们将评估呼吸和心血管控制系统的变化。硫化氢中毒将通过静脉输液产生，由硫化氢供体NaHS的溶液制备，以防止与气态硫化氢暴露有关的对实验室人员的任何风险。一旦发生呼吸暂停，硫化氢输注将立即停止，此时，本申请中提出的终点将在对照组和高铁血红蛋白或维生素B12治疗的动物中进行评估，在停止硫化氢输注后1分钟或20分钟。最后，我们将在鼻腔或肌肉注射维生素B12后，测定血液中维生素B12的浓度以及血浆氧化外源性硫化氢的能力。这些拟议研究的结果将有助于确定正确的使用策略和这些解毒剂各自的好处。鼻腔或肌肉注射维生素B12代表了一种有趣的替代静脉输液的方法，非专业救援人员可以对大量患者实施这种方法。 与公共健康相关：根据疾病控制中心的定义，硫化氢(H2S)是一种立即对生命构成危险的化学危险物质，没有经过证实的有效解毒剂，每年在美国造成几起致命中毒事件；由于它很容易产生，国土安全部也将其视为威胁。我们已经证明，粉末状高铁血红蛋白和维生素B12(羟钴胺)与生理盐水混合后，可以非常迅速地降低啮齿动物血浆和各种组织中的硫化氢。该项目将在成年绵羊身上确定这两种药物在什么条件下可以用作潜在致命的硫化氢中毒的解毒剂，以及肌肉或鼻腔注射维生素B12是否可以用于治疗硫化氢中毒的受试者。