Sodium Tetrathionate as a Cyanide Antidote

氰化物是一种快速起作用的毒药，因此，解毒剂必须迅速使用。用于治疗肿块 战场上的伤亡--可能在重大工业事故或恐怖袭击后发生--可能是最好的 治疗方式是使用预注满的注射器或自动注射器肌肉注射。四硫代钠 (Na2S4O6)被认为是一种有效的氰化物解毒剂已经有一段时间了。它可以中和两种氰化物 分子与氰化物直接反应生成硫氰酸盐和硫代硫酸盐，然后通过罗丹宁- 硫代硫酸盐与氰化物的依赖反应，也生成硫氰酸盐。尽管四硫酸根不稳定 在水溶液中，我们设计了一种方法来稳定四硫酸盐溶液，方法是添加低浓度的 二甲基亚砜；这将允许四硫酸钠在注射时预先装入注射器 制造业。我们发现，四硫代硫酸钠可以使兔子、猪和小鼠免于致命的氰化物。 中毒，现在建议在严谨的随机盲法研究中确定人的剂量。 和猪；因为氰化物解毒剂将通过“动物规则路径”获得FDA批准，人类 解毒剂的剂量是在动物实验中确定的。我们还建议确定四硫酸钠是否 在怀孕、新生儿、幼年和老年动物中有效，由于小鼠数量众多，因此使用小鼠进行这些研究 所需动物的数量。提议的项目为期三年，在去年，我们计划有一个FDA IND预备会。为此，我们将进行FDA要求的研究，包括确定 四硫酸钠在两种动物--大鼠和狗--体内的药代动力学和安全性，并测试 四硫酸盐会导致基因突变。我们将确定有能力大规模合成钠的公司 四硫酸盐、注射器和自动注射器制造商，以及填充和涂装合同组织。对于 动物规则路径，FDA要求关键的动物研究使用准确的设备 最终投放市场，并在开始I期临床之前在设备中启动稳定性测试 研究；虽然关键的动物研究和第一阶段研究将在完成 建议工作时，此时需要安排好注塑装置，使之顺畅、不间断 未来的工作。我们将为未来的人为因素研究开发用户需求文档，目标 适用于FDA提交的产品简介，以及详细的产品开发计划。除了Pre- IND会议在去年，我们计划召开一次BARDA技术观察会议，并提交一份BARDA White 纸。后者将使我们能够在项目完成后过渡到BARDA资助。

Cyanide is a rapidly acting poison, and, thus, antidotes must be administered quickly. For treating mass casualties in the field—as could occur after a major industrial accident or a terrorist attack—probably the best mode of treatment is intramuscular injection using a pre-filled syringe or autoinjector. Sodium tetrathionate (Na2S4O6) has been known for some time to be an effective cyanide antidote. It can neutralize two cyanide molecules by a direct reaction with cyanide generating thiocyanate and thiosulfate, and then by a rhodanese- dependent reaction of thiosulfate with cyanide, also generating thiocyanate. Although tetrathionate is unstable in aqueous solutions, we devised a method to stabilize tetrathionate solutions by adding low concentrations of dimethyl sulfoxide; this would allow sodium tetrathionate to be pre-loaded into syringes at the time of manufacturing. We have found that sodium tetrathionate rescues rabbits, pigs, and mice from lethal cyanide poisoning, and now propose to determine the human dose in rigorous, randomized, blinded studies in rabbits and pigs; because cyanide antidotes will be approved by the FDA via the “Animal Rule Pathway,” human doses of antidote are established in animal studies. We also propose to determine if sodium tetrathionate is effective in pregnant, neonatal, juvenile, and old animals, using mice for these studies due to the large number of animals required. The proposed project is for three years, and, during the last year, we plan to have a FDA pre-IND meeting. To that end, we will conduct FDA-required studies, including determining the pharmacokinetic and safety profile of sodium tetrathionate in two animal species—rats and dogs, and testing if tetrathionate causes genetic mutations. We will identify companies capable of large-scale synthesis of sodium tetrathionate, syringe and auto-injector manufacturers, and fill-and-finish contract organizations. For the Animal Rule Pathway, the FDA requires that the pivotal animal studies be done using the exact device that will ultimately be marketed and that stability testing be initiated in the device prior to starting Phase I clinical studies; although the pivotal animal studies and Phase I studies would be done after completion of the proposed work, we need to arrange for the injection devices at this time to allow for smooth and uninterrupted future work. We will develop a User Requirements Document for a future human factors study, a Target Product Profile suitable for FDA submission, and a detailed Product Development Plan. In addition to a pre- IND meeting during the last year, we plan to have a BARDA Tech Watch meeting, and submit a BARDA White Paper. The latter will position us to transition to BARDA funding after project completion.