Effects of acute administration of the Phenothiazinium Chromophore Methylene blue during life threatening cyanide intoxication

项目总结/摘要 氰化物是一种毒性很强的线粒体毒物，广泛应用于各种工业生产中。是 存在于许多合成材料中，并且可以在房屋火灾期间以气体形式释放。由于CN可以 它很容易制成武器，被认为是对平民的严重威胁。急性CN的治疗 中毒依赖于（1）特定解毒剂，以降低血液和组织中氯化萘的浓度， (2)对症治疗，在暴露的早期阶段至关重要，包括积极的治疗， 和循环支持，类似于治疗任何与心肺抑制相关的疾病。 我们最近发现吩噻嗪生色团亚甲基蓝（MB）， 抵消各种线粒体毒物（硫化氢和天青B）的毒性，也可以对抗CN- 导致急性循环衰竭。MB的作用机制及其有效性限度，如下 氯化萘中毒，仍有待确定。 我们建议的目的是首先验证我们的初步观察结果， 在大鼠CN中毒诱导昏迷和心力衰竭期间和之后使用MB的兴趣。我们 将确定MB单独使用时是否可改善CN中毒的即刻和长期结局 更重要的是作为已批准用于治疗CN中毒的解毒剂的佐剂。 其次，我们将探索MB的潜在作用机制，使用分离的收缩心肌细胞 用CN麻醉这些研究将与Joseph Cheung博士的团队合作进行， 天普大学。 由于MB已被用于治疗人类高铁血红蛋白血症（1 - 2 mg/kg iv）数十年，我们的研究表明， 目标是重新定位亚甲蓝，一种已经在世界卫生组织基本药物清单上的药物，作为一种治疗方法 CN中毒

PROJECT SUMMARY/ABSTRACT Cyanide, a very toxic mitochondrial poison, has a wide spread usage in various industrial activities. It is present in many synthetic materials and can be released in gaseous form during a house fire. Since CN can be easily weaponized, it is considered as a serious threat for the civilian population. The treatment of acute CN intoxication relies on (1) specific antidotes, to decrease the concentration of CN in the blood and tissues, and (2) symptomatic treatments, essential at the early stage of exposure, consisting in an aggressive ventilatory and circulatory support, akin to the treatment of any conditions associated with cardio-respiratory depression. We have recently found that the phenothiazinium chromophore methylene blue (MB), which can counteract the toxicity of various mitochondrial poisons (hydrogen sulfide and Azure B), can also oppose CN- induced acute circulatory failure. The mechanisms of action of MB as well as the limits of its efficacy, following CN intoxication, remain to be determined. The objective of our proposal is first to validate our preliminary observations and to determine the interest of the use of MB during and following CN intoxication induced coma and cardiac failure in the rat. We will determine if MB can improve the immediate and long-term outcome of CN intoxication when used alone and more importantly as an adjuvant of antidotes already approved for the treatment of CN intoxication. Second, we will explore the potential mechanisms of action of MB, using isolated contracting cardiomyocytes intoxicated with CN. These studies will be performed in collaboration with the group of Dr. Joseph Cheung, Temple University. Since MB has been used for decades for treating methemoglobinemia (1-2 mg/kg iv) in humans, our goal is to reposition methylene blue, a drug already on the WHO's list of essential medications, as a treatment of CN intoxication.