The vitamin B12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model

Abstract

Background and purpose 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.

High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide-poisoning-induced cardiac depression in sheep

“…Five grams of Hydroxocobalamin, corresponding to 10 6 times the recommended daily intake, can drop the concentration of soluble H 2 S to almost zero during infusion of moderate to severe levels of H 2 S infusion (4). This observation supports the view that Hydroxocobalamin or other Vitamin B12 analogues (11), could exert a protective effect against H 2 S toxicity since not only can they diffuse within cells (12) via non-transcobalamin mechanisms (13–15), but they also oppose the effects of Nitric oxide (16–19), recently shown to potentiate the effects of H 2 S (20, 21). Finally, intravenous infusion of large dose of Hydroxocobalamin is already FDA approved for the treatment of cyanide poisoning (22, 23).…”

Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions

“…We previously found that aquohydroxocobinamide is poorly absorbed after IM injection in animals [17], but that both sulfitocobinamide and dinitrocobinamide are well absorbed after IM injection [20]. Aquohydroxocobinamide has two free ligand binding sites, and could be retarded in absorption due to binding to a muscle component more than sulfito- or dinitrocobinamide where the ligand sites are occupied with sulfite and nitrite groups, respectively.…”

Are H2S-trapping compounds pertinent to the treatment of sulfide poisoning?

“…(1) on the effects of the Vitamin B12 analog cobinamide on H 2 S toxicity. In this study, the effects of various vitamin B12 analogs were compared using, as the main outcome, the duration of NaHS infusion that can be maintained after administering the antidote until death occurred – or up to a maximum of 270 mg.…”