The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model.
OBJECTIVE
Hydrogen sulfide (H2S) is a highly toxic gas for which no effective antidotes exist. It acts, at least in part, by binding to cytochrome c oxidase, causing cellular asphyxiation and anoxia. We investigated the effects of three different ligand forms of cobinamide, a vitamin B12 analog, to reverse sulfide (NaHS) toxicity.


METHODS
New Zealand white rabbits received a continuous intravenous (IV) infusion of NaHS (3 mg/min) until expiration or a maximum 270 mg dose. Animals received six different treatments, administered at the time when they developed signs of severe toxicity: Group 1-saline (placebo group, N = 9); Group 2--IV hydroxocobalamin (N = 7); Group 3--IV aquohydroxocobinamide (N = 6); Group 4--IV sulfitocobinamide (N = 6); Group 5--intramuscular (IM) sulfitocobinamide (N = 6); and Group 6-IM dinitrocobinamide (N = 8). Blood was sampled intermittently, and systemic blood pressure and deoxygenated and oxygenated hemoglobin were measured continuously in peripheral muscle and over the brain region; the latter were measured by diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS).


RESULTS
Compared with the saline controls, all cobinamide derivatives significantly increased survival time and the amount of NaHS that was tolerated. Aquohydroxocobinamide was most effective (261.5 ± 2.4 mg NaHS tolerated vs. 93.8 ± 6.2 mg in controls, p < 0.0001). Dinitrocobinamide was more effective than sulfitocobinamide. Hydroxocobalamin was not significantly more effective than the saline control.


CONCLUSIONS
Cobinamide is an effective agent for inhibiting lethal sulfide exposure in this rabbit model. Further studies are needed to determine the optimal dose and form of cobinamide and route of administration.
Beckman Laser Institute, University of California , Irvine, CA , USA.
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Brenner
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Benavides
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Mahon
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Lee
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Yoon
D
D
Mukai
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Viseroi
A
A
Chan
J
J
Jiang
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N
Narula
S M
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Azer
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Alexander
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Boss
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003038:Cobamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000008:administration & dosage / Q000506:poisoning*; D006879:Hydroxocobalamin / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D011817:Rabbits; D019265:Spectroscopy, Near-Infrared; D013440:Sulfides / Q000506:poisoning*; D015996:Survival Rate
D000931:Antidotes; D003038:Cobamides; D006454:Hemoglobins; D013440:Sulfides; C017142:cobinamide; C025451:sodium bisulfide; D006879:Hydroxocobalamin; D006862:Hydrogen Sulfide
CNS/Psychological; Heart; Lung; Muscle