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

 描述(申请人提供)：硫化氢是一种剧毒气体，无法处理。各种行业的工人都暴露在硫化氢中，其中石油行业最突出，三分之一的工人暴露在足以出现症状的气体中，8%的工人失去了知觉。此外，吸入硫化氢气体是一种常见的自杀方式，这种气体可能会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能会发展成长期的神经异常，即使是一次短暂的暴露也会导致神经缺陷。我们发现维生素B12类似物椰子酰胺可以使小鼠、兔和猪从致死剂量的硫化物中解救出来，并减轻硫化物诱导的大鼠昏迷所致的神经行为障碍和神经病理损害。硝基钴酰胺，即钴原子上有两个亚硝酸基的钴酰胺，在肌肉注射后被很好地吸收，这通常是治疗重大工业事故或恐怖袭击中大量受害者的首选给药途径。硝基可比胺在水溶液中非常稳定和易溶；这些特性，加上其高度的效力，将使其能够被包装在一个小的预注满的注射器中，并通过自动注射器快速给药。我们估计，不到3毫升的225毫升硝基可比胺溶液就能将人从致命的硫化物暴露中解救出来。这一体积也可以通过使用新开发的高流量超声波雾化器进行吸入。吸入分娩既可用于治疗，也可用于预防，后者尤其适用于经常死于硫化物的急救人员。 汽油。在拟议的研究中，我们将确定将兔子、猪和小鼠从致命的硫化物暴露中拯救出来所需的硝基可比胺剂量。兔子和猪将接受静脉注射硫化氢，在不同的实验中，小鼠和兔子将暴露在硫化氢气体中。除了模拟人体暴露，吸入实验将使我们能够确定雾化吸入硝基可比胺是否比注射硝基可比胺更有效地保护肺部免受吸入的硫化氢气体的影响。我们还将确定预防硫化物诱导的昏迷的神经后遗症的硝基可比胺剂量，以及昏迷发生后多长时间可以给予硝基可比胺并仍可预防神经功能障碍。一旦我们确定了肌肉注射和吸入给药的硝基可比胺剂量，我们将进行FDA调查人员新药(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。到授权期结束时，我们预计将准备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--一种目前尚无治疗方法的经常致命的疾病。

 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.