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

University Of California, San Diego, La Jolla CA

Investigators

Linked publications & trials

Abstract

? 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.