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

开发维生素 B12 类似物椰酰胺作为硫化氢解毒剂

基本信息

批准号：
9324373
负责人：
GERRY R BOSS
金额：
$ 92.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324373
关键词：
Agreement Animal Model Animals Antidotes Binding Breathing Carbon Monoxide Cardiovascular system Cells Cobalt Coma Cyanides Data Development Dose Drug Kinetics Exposure to Family suidae Formulation Gases Grant Human Hydrogen Sulfide Hydroxocobalamin Impairment Industrial Accidents Industrialization Industry Infusion procedures Injectable Injury International Intramuscular Intramuscular Injections Intravenous Intravenous infusion procedures Lesion Lung Modeling Monitor Mus Nebulizer Neurologic Neurologic Deficit Neurologic Dysfunctions Nitrites Non-Rodent Model Oryctolagus cuniculus Pathway interactions Persons Petroleum Pharmaceutical Preparations Phase I Clinical Trials Plasma Poisoning Property Rattus Recurrence Research Personnel Route Services Sodium Sodium Nitrite Suicide Sulfides Survivors Symptoms Syringes Testing Therapeutic Time Toxic effect Toxicology Ultrasonics Unconscious State Vitamin B 12 Water Work analog animal rule aqueous cobinamide emergency service responder experimental study exposed human population fly intravenous injection mass casualty meetings neurobehavioral novel therapeutics parenteral administration preference prevent prophylactic public health relevance suicidal weapons of mass destruction

项目摘要

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.

描述（由申请人提供）：硫化氢是一种剧毒气体，无法对其进行处理，许多行业的工人都会接触到硫化氢，尤其是石油工业，其中三分之一的工人接触到的气体足以产生硫化氢。有症状，其中 8% 失去知觉，此外，吸入硫化氢气体是一种常见的自杀方式，这种气体可能被恐怖分子用作大规模杀伤性武器。接触硫化物会导致长期的神经系统异常，即使是短暂的接触也会导致神经功能缺陷。我们发现，维生素 B12 类似物钴酰胺可以使小鼠、兔子和猪免受致命剂量的硫化物的侵害，并减少神经行为损伤和神经病理损伤。硝基可酰胺（Nitrocobinamide），即具有两个与钴原子结合的亚硝酸盐基团的可酰胺，在大鼠体内被硫化物诱导的昏迷后吸收良好。肌内注射通常是治疗重大工业事故或恐怖袭击等大量受害者的首选给药途径，硝基可酰胺非常稳定且可溶于水溶液；可以将其包装在小型预装注射器中，并通过自动注射器快速注射。我们估计，不到 3 毫升的 225 mM 硝基可酰胺溶液就可以将人从致命的危险中拯救出来。该体积也可以使用新开发的高流量超声雾化器吸入给药，吸入给药可用于治疗和预防模式，后者特别适用于经常死于硫化物的急救人员。硫化物在拟议的研究中，我们将确定拯救兔子、猪和小鼠免于致命的硫化物暴露所需的硝基苯酰胺剂量。兔子和猪将接受静脉注射硫化氢钠，并且在单独的实验中，小鼠和小鼠将接受静脉注射硫化氢。兔子将接触硫化氢气体，除了模拟人类接触之外，吸入实验还可以让我们确定雾化硝基可酰胺是否比吸入更有效。注射硝基胆酰胺以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引起的昏迷的神经系统后遗症的硝基胆酰胺剂量，以及昏迷发生后多长时间可以注射硝基胆酰胺并仍然可以预防神经功能障碍。已经确定了肌内注射和吸入给药的硝基联酰胺剂量，我们将进行 FDA 研究人员所需的药代动力学和毒理学研究新然后，我们将与 FDA 举行预 IND 会议并提交 IND 申请，在授权期结束时，我们预计准备好开始 I 期临床试验，并开发出药物。用于治疗硫化物中毒——一种经常致命的疾病，目前尚无治疗方法。