Hydrogen sulfide (H2S) is a lethal gas regarded as a potential chemical threat by the Department of Homeland Security and a "chemical hazard immediately dangerous to life" by the Centers for Disease Control. We have recently developed a paradigm to decrease H2S very rapidly in the blood and tissues of rats based on the use of the crystalline form of low dose of methemoglobin (as a source of ferric Iron) and high dose of Vitamin B12 (as a source of oxidized Cobalt). Both agents are safe (high dose of Vitamin B12 is already FDA approved for cyanide poisoning), can be stored as a kit, in a powder form, and can easily be administered to humans following H2S exposure. The goal of this project is to test the hypothesis that solutions of methemoglobin or Vitamin B12 can be used as antidotes following H2S exposure. The possibility of administering Vitamin B12 in H2S intoxication at a dose 10 times lower than the dose used for cyanide intoxication makes it possible to deliver this agent using intramuscular or intranasal administration. Since we have demonstrated that H2S produces in small animals (rodents) a specific protective response, not found in larger mammals, we intend to conduct our studies in adult sheep. In this proposal, we will determine the ability of these antidotes to lower the concentration of H2S, and its oxidative products, in th blood and the cerebrospinal fluid of adult sheep following infusion of lethal concentrations of H2S. The cerebrospinal fluid will be used as a convenient marker of the exposure of the medullary neurons, exquisitely sensitive to the toxic effects of H2S. At the same time, we will assess the alterations of the respiratory and cardiovascular control systems. H2S intoxication will be generated by intravenous infusion, prepared from a solution of NaHS, a H2S donor, to prevent any risk to the laboratory personnel related to gaseous H2S exposure. H2S infusion will be stopped as soon as an apnea occurs and at this time the end-points proposed in this application will be evaluated in controls and in animals treated with either methemoglobin or Vitamin B12 given one or 20 minutes following the cessation of H2S infusion. Finally, we will determine the blood concentration of Vitamin B12 and the ability of the plasma to oxidize exogenous H2S, following intranasal or intramuscular administration of Vitamin B12. The results of these proposed studies will help determine the proper strategy of use and the respective benefits of these antidotes. Intranasal or intramuscular administration of Vitamin B12 represents an interesting alternative to intravenous infusion that could be implemented by non-professional rescuers to a large number of patients.

Public Health Relevance

Hydrogen sulfide (H2S) is, as defined by the Centers for Disease Control, a chemical hazard immediately dangerous to life, with no proven effective antidote, causing several fatal intoxications every year in the US;as it is easy to produce, this gas is also considered as a threat by the Department of Homeland Security. We have shown that methemoglobin, in a powder form, and Vitamin B12 (hydroxocobalamin) can be injected, after being mixed with saline, to decrease H2S very rapidly in the plasma and various tissues in rodents. This project will determine, in adult sheep, under what conditions these two agents could be used as antidotes in potentially lethal H2S poisoning, and whether intramuscular or intranasal administration of Vitamin B12 could be used to treat subjects intoxicated by hydrogen sulfide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS080788-02
Application #
8551778
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Yeung, David
Project Start
2012-09-28
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$369,113
Indirect Cost
$127,863
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Haouzi, Philippe; Chenuel, Bruno; Sonobe, Takashi et al. (2014) Are H2S-trapping compounds pertinent to the treatment of sulfide poisoning? Clin Toxicol (Phila) 52:566
Haouzi, Philippe; Sonobe, Takashi; Torsell-Tubbs, Nicole et al. (2014) In vivo interactions between cobalt or ferric compounds and the pools of sulphide in the blood during and after H2S poisoning. Toxicol Sci 141:493-504
Haouzi, Philippe; Sonobe, Takashi; Chenuel, Bruno (2014) Oxygen-related chemoreceptor drive to breathe during H?S infusion. Respir Physiol Neurobiol 201:24-30
Klingerman, Candice M; Trushin, Neil; Prokopczyk, Bogdan et al. (2013) H2S concentrations in the arterial blood during H2S administration in relation to its toxicity and effects on breathing. Am J Physiol Regul Integr Comp Physiol 305:R630-8
Haouzi, Philippe; Klingerman, Candice M (2013) Fate of intracellular H2S/HS- and metallo-proteins. Respir Physiol Neurobiol 188:229-30