Development of the Vitamin B12 Analog cobinamide as a Hydrogen Sulfide Antidote

 描述（由申请人提供）：硫化氢是一种剧毒气体，无法进行处理。许多行业的工人都暴露在硫化氢中，尤其是石油行业，三分之一的工人暴露在足够的气体中，出现症状，其中8%的工人失去意识。此外，吸入硫化氢气体是一种常见的自杀方式，这种气体可能被恐怖分子用作大规模杀伤性武器。硫化物暴露的幸存者可以发展长期的神经系统异常，即使是一个短暂的暴露导致神经功能缺损。我们已经发现，维生素B12类似物cobinamide拯救小鼠，兔子和猪从致命剂量的硫化物，并减少神经行为障碍和神经病理学病变的硫化物诱导的昏迷大鼠。硝基烟酰胺，即，具有与钴原子结合的两个亚硝酸根基团的可宾酰胺在肌内注射后被很好地吸收，肌内注射通常是治疗大量受害者（如在重大工业事故或恐怖袭击中）的优选给药途径。硝代烟酰胺在水溶液中非常稳定且可溶;这些性质，沿着其高度效力，将允许其包装在小型预充式注射器中并通过自动注射器快速给药。我们估计，少于3毫升的225 mM的硝基烟酰胺溶液将拯救一个人从致命的硫化物暴露。该体积也可以使用新开发的高流量超声雾化器通过吸入给药。吸入给药既可用于治疗，也可用于预防，后者特别适用于第一反应者，他们经常死于硫化物 气体在拟议的研究中，我们将确定从致命的硫化物暴露中拯救兔子、猪和小鼠所需的硝代烟酰胺剂量。兔子和猪将接受静脉注射硫化氢钠，在单独的实验中，小鼠和兔子将暴露于硫化氢气体。除了模拟人体暴露外，吸入实验还将使我们能够确定雾化的硝基烟酰胺是否比注射的硝基烟酰胺更有效地保护肺部免受吸入硫化氢气体的影响。我们还将确定预防硫化物诱导昏迷的神经系统后遗症的硝氨酰胺剂量，以及在昏迷发作后多久可以给予硝氨酰胺并仍然预防神经功能障碍。一旦我们确定了肌内注射和吸入给药的硝氨酰胺剂量，我们将进行FDA研究者新药（IND）申请所需的药代动力学和毒理学研究。然后，我们将与FDA举行IND前会议，并提交IND申请。到资助期结束时，我们预计将准备好开始第一阶段临床试验，并开发出一种治疗硫化物中毒的药物，硫化物中毒是一种目前没有治疗方法的常见致命疾病。

 DESCRIPTION (provided by applicant): Hydrogen sulfide is an extremely toxic gas for which no treatment is available. Workers in a variety of industries are exposed to hydrogen sulfide most notably the petroleum industry, where one-third of workers are exposed to sufficient gas to have symptoms, with 8% having suffered loss of consciousness. Moreover, inhalation of hydrogen sulfide gas is a common mode of suicide and the gas could be used by terrorists as a weapon of mass destruction. Survivors of sulfide exposure can develop long-term neurological abnormalities, with even one brief exposure leading to neurological deficits. We have found that the vitamin B12 analog cobinamide rescues mice, rabbits, and pigs from lethal doses of sulfide, and reduces the neurobehavioral impairment and neuropathological lesions from sulfide-induced coma in rats. Nitrocobinamide, i.e., cobinamide with two nitrite groups bound to the cobalt atom, is well absorbed after intramuscular injection, which is generally the preferred administration route for treating a large number of victims as in a major industrial accident or a terrorist attack. Nitrocobinamide is both very stable and soluble in aqueous solutions; these properties, along with its high degree of potency, would allow it to be packaged in a small pre-filled syringe and be administered quickly via an autoinjector. We estimate that less than 3 ml of a 225 mM nitrocobinamide solution would rescue a human from a lethal sulfide exposure. This volume could also be administered by inhalation using newly-developed, high-flow ultrasonic nebulizers. Inhalational delivery could be used both in a therapeutic and prophylactic mode, with the latter being particularly applicable to first responders, who frequently succumb to the sulfide gas. In the proposed studies, we will define the nitrocobinamide dose required to rescue rabbits, pigs, and mice from lethal sulfide exposures. The rabbits and pigs will receive an infusion of intravenous sodium hydrogen sulfide, and, in separate experiments, the mice and rabbits will be exposed to hydrogen sulfide gas. In addition to simulating human exposure, the inhalation experiments will allow us to determine if nebulized nitrocobinamide is more effective than injected nitrocobinamide at protecting the lungs from inhaled hydrogen sulfide gas. We will also define the nitrocobinamide dose to prevent the neurological sequelae of sulfide-induced coma, and how long after the onset of coma nitrocobinamide can be administered and still prevent neurological dysfunction. Once we have determined the nitrocobinamide dose for both intramuscular injection and inhalational delivery, we will conduct the pharmacokinetic and toxicology studies necessary for an FDA Investigators New Drug (IND) application. We will then have a pre-IND meeting with the FDA and submit an IND application. By the end of the grant period, we expect to be ready to start Phase I Clinical Trials, and to have developed a drug for treating sulfide poisoning-a frequently lethal condition for which no treatment currently exists.