Methylene blue as an antidote against hydrogen sulfide intoxication

亚甲蓝作为硫化氢中毒的解毒剂

基本信息

批准号：
9144894
负责人：
Philippe A Haouzi
金额：
$ 80.38万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144894
关键词：
Acute Affect Affinity Animal Model Animals Antidotes Applications Grants Binding Proteins Blood Brain Brain Ischemia Breathing Calcium Cardiac Cardiac Myocytes Cardiogenic Shock Cardiotoxicity Cells Cessation of life Chemicals Cobalt Cognitive deficits Coma Contracts Cysteine Cytochromes Data Depressed mood Development Dissociation Dose Electrons Emergency Situation Exposure to Farming environment Ferric Compounds Gases Goals Grant Heart Human Hydrogen Sulfide Incidence Industry Injection of therapeutic agent Institutes Intoxication Ion Channel Ion Channel Protein Laboratories Life Mammals Mechanics Mental Depression Methemoglobinemia Methods Methylene blue Mitochondria Modeling Muscle Neuraxis Neurologic Neurological outcome Neurological status Neurons Outcome Oxidases Oxidative Stress Pattern Pharmaceutical Preparations Phase Play Population Potassium Channel Production Property Proteins Publishing Rattus Reactive Oxygen Species Recovery Research Risk Rodent Role Sheep Slice Suicide Sulfides Testing Time Toxic effect United States National Institutes of Health Universities activity marker animal rule base chemical threat cognitive function disulfide bond effective therapy hazard hemodynamics improved in vivo mortality motor deficit neurotoxicity patch clamp prevent protective effect relating to nervous system respiratory response voltage

项目摘要

PROJECT SUMMARY/ABSTRACT Hydrogen sulfide (H2S) remains a chemical hazard in the gas and farming industry. It is easy to manufacture from common chemicals and thus represents a potential threat for the civilian population. It is also employed as a method of suicide, for which incidence has recently increased in the US. H2S exerts its toxicity through its high affinity with various metallo-proteins (cytochrome C oxidase) and its interactions with the cysteine residues of proteins. The latter has been recently shown to alter ion channels in cardiomyocytes and neurons. Indeed, during severe H2S intoxication, a reduction in cardiac contractility, associated with a coma, develops within minutes or even seconds leading to death by complete electro- mechanical dissociation of the heart. If the level of intoxication is milder, a rapid and spontaneous recovery of the coma occurs as soon as the exposure stops. However, in many instances, a cardiogenic shock will persist along with a risk of developing debilitating motor or cognitive deficits. One of the major challenges impeding our effort to offer an effective treatment against H2S intoxication after exposure is that the pool of free/soluble H2S almost immediately disappears from the body, preventing agents trapping free H2S (cobalt or ferric compounds) to play their protective role. We found that methylene blue (MB) appears to overcome this challenge: MB drastically decreases the immediate mortality of H2S intoxication-induced cardiogenic shock and improves the long-term neurological outcome. MB appears to counteract the consequences of H2S intoxication related to the persistent pool of protein-bound H2S. The objective of our proposal is twofold. First, we intend to extend our previous findings on the efficacy of MB against H2S intoxication in two animal models (a large mammal -sheep- and unsedated rats), an essential prerequisite under the Animal Rule, in conditions (inhaled H2S) more faithful to human intoxication. The effects of MB on the short and long term outcomes will be established at two different doses administered up to 30 minutes after the end of intoxication. Second, we will continue to explore the mechanisms of action of MB using isolated contracting cardiomyocytes (studies performed by the group of Dr. Joseph Cheung, Temple University), and cortical neurons from acute brain slices in rats (studies performed by the group of Dr. Brady Maher, Lieber Institute for Brain Development, Johns Hopkins University). Since MB has been used for decades for treating methemoglobinemia (1-2 mg/kg iv) in humans, our ultimate goal is to reposition methylene blue, a drug already on the WHO's list of essential medications, as a key treatment of H2S intoxication.

项目概要/摘要硫化氢 (H2S) 仍然是天然气和农业中的化学危害。这很容易由普通化学品制造，因此对平民构成潜在威胁。这也是被用作自杀的一种方法，最近美国的自杀率有所增加。 H2S 通过与各种金属蛋白（细胞色素 C 氧化酶）的高亲和力发挥毒性，它与蛋白质的半胱氨酸残基的相互作用。后者最近被证明可以改变离子通道在心肌细胞和神经元中。事实上，在严重的 H2S 中毒期间，心肌收缩力下降，与昏迷相关，在几分钟甚至几秒钟内发生，导致完全电击死亡心脏的机械分离。如果中毒程度较轻，中毒症状会迅速自发恢复一旦曝光停止，彗差就会发生。然而，在许多情况下，心源性休克会持续存在以及出现运动或认知缺陷的风险。阻碍的主要挑战之一我们为暴露后 H2S 中毒提供有效的治疗方法所做的努力是，游离/可溶性的池 H2S 几乎立即从体内消失，防止介质捕获游离 H2S（钴或铁）化合物）发挥其保护作用。我们发现亚甲蓝 (MB) 似乎克服了这一挑战：MB 显着降低了减少 H2S 中毒引起的心源性休克的立即死亡率，并改善长期神经功能结果。 MB 似乎可以抵消与持久池相关的 H2S 中毒后果蛋白质结合的 H2S。我们提案的目标是双重的。首先，我们打算扩展我们之前关于功效的发现 MB 在两种动物模型（大型哺乳动物 - 绵羊 - 和未镇静的大鼠）中对抗 H2S 中毒，动物规则下的基本先决条件，在更接近人类中毒的条件（吸入 H2S）下。 MB 对短期和长期结果的影响将在两种不同的给药剂量下确定中毒结束后最多 30 分钟。二是继续探索作用机制。使用分离的收缩心肌细胞进行 MB（由 Temple Joseph Cheung 博士小组进行的研究）大学）和大鼠急性脑切片的皮层神经元（布雷迪博士小组进行的研究 Maher（约翰·霍普金斯大学利伯大脑发育研究所）。由于 MB 已用于治疗人类高铁血红蛋白血症（1-2 mg/kg iv）数十年，我们的最终目标是将亚甲蓝（一种已列入世界卫生组织基本药物清单的药物）重新定位为 H2S中毒的关键治疗。