Efficacy of Cobinamide for Treatment of Hydrogen Sulfide-induced Neurotoxicity

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Hydrogen sulfide (H2S), the gas with a "rotten egg" smell, is a colorless highly neurotoxic gas. It is an environmental pollutant and an occupational hazard in several industries including the oil and gas industry, intensive animal farming operations, sewer and wastewater treatment plants, pulp and paper, and gas storage facilities, among others. There is also a significant concern about the use H2S as a weapon of mass destruction, particularly in confined spaces such as underground transit facilities. Catastrophic industrial accidents are also a concern. Hydrogen sulfide has the potential to cause mass civilian casualties under these circumstances. Symptoms in acutely exposed individuals include seizures, respiratory distress, and death. Lingering neurological sequelae include neurobehavioral and cognitive deficits, hearing impairment, and permanent vegetative states, among others. Currently, recommended treatment for H2S poisoning includes intravenous injections of nitrites, and the administration of hyperbaric oxygen. However, none of these treatment modalities is suitable for field treatment of mass casualties. Besides, the efficacy of nitrites is both debatable and associated with major side effects such as hypotension. Treatment of mass victims of H2S poisoning in the field requires medications that can be given by intramuscular (IM) injections, similar to the EpiPen(R) or ComboPen(R). Cobinamide is a novel drug and our preliminary investigations have shown that it is efficacious for treatment of H2S-induced neurotoxicity in the C57 Black mouse animal model. Cobinamide has a significant advantage over current therapies in that it is stable and can be given IM. The objective of the proposed study is to investigate the efficacy of cobinamide as an antidote to H2S poisoning. The proposed study has two Specific Aims. In Specific Aim #1 we will fully characterize our mouse model of H2S-induced neurotoxicity. In Specific Aim #2 we will conduct a series of experiments to evaluate the efficacy of cobinamide to prevent and treat H2S-induced neurotoxicity. Results of this study will be used for development of competitive grant applications for future support under the NIH CounterAct and other relevant funding programs.