Cobinamide is effective for treatment of hydrogen sulfide–induced neurological sequelae in a mouse model

Abstract

Hydrogen sulfide (H2S) is a highly neurotoxic gas. Acute exposure can lead to neurological sequelae among survivors. A drug for treating neurological sequelae in survivors of acute H2S intoxication is needed. Using a novel mouse model we evaluated the efficacy of cobinamide (Cob) for this purpose. There were two objectives: (1) to determine the dose–response efficacy of Cob and (2) to determine the effective therapeutic time window of Cob. To explore objective 1, mice were injected intramuscularly with Cob at 0, 50 or 100 mg/kg at 2 min after H2S exposure. For objective 2, mice were injected intramuscularly with 100 mg/kg Cob at 2, 15, and 30 min after H2S exposure. For both objectives, mice were exposed to 765 ppm of H2S gas. Cob significantly reduced H2S-induced lethality in a dose-dependent manner (P < 0.05). Cob-treated mice exhibited significantly fewer seizures and knockdowns compared with the H2S-exposed group. Cob also reversed H2S-induced weight loss, behavioral deficits, neurochemical changes, cytochrome c oxidase enzyme inhibition, and neurodegeneration in a dose- and time-dependent manner (P < 0.01). Overall, these findings show that Cob increases survival and is neuroprotective in a mouse model of H2S-induced neurological sequelae.

Intramuscular aminotetrazole cobinamide as a treatment for inhaled hydrogen sulfide poisoning in a large swine model

“…13 Cobinamide reacts quickly with H 2 S to form a stable complex (SSH 2 -). [21][22][23][24] In a large swine model of high-dose, inhaled H 2 S gas, we found that intramuscular aminotetrazole cobinamide rescued all animals when administered at the very end of sulfide exposure. Admittedly, this is not the same as being treated in a hospital sometime after sulfide exposure, but if the antidote were available in the field, it could be administered at the same time as removal of victims from the H 2 S source.…”

“…Cobinamide was found to improve survival and offer neuroprotection in mice when administered after H 2 S exposure. 21 Brenner et al and Ng et al showed that intramuscular administration of cobinamide improves survival in sulfide-poisoned rabbits and pigs, respectively, but in both cases, the animals were injected with intravenous NaHS. 23,26 In this study, exposure to H 2 S occurred via the inhaled route, which is the most common route of exposure.…”

“…It is particularly important to have a drug that can be administered after sulfide exposure since in many animal studies, treatment is given before sulfide exposure 13 . Cobinamide reacts quickly with H 2 S to form a stable complex (SSH 2 – ) 21–24 …”

“…H 2 S reacts rapidly with cobinamide to form a stable complex (SSH 2 − ), thereby neutralizing the sulfide. [21][22][23][24] Cobinamide is considerably more water-soluble than hydroxocobalamin, enabling the administration of higher concentrations in smaller volumes. 22,25,26 However, aquohydroxocobinamide, which forms on dissolving cobinamide in water, is not well absorbed after intramuscular injection, because it binds to macromolecules in the extracellular matrix (ECM).…”

“…1). H 2 S reacts rapidly with cobinamide to form a stable complex (SSH 2 − ), thereby neutralizing the sulfide 21–24 . Cobinamide is considerably more water‐soluble than hydroxocobalamin, enabling the administration of higher concentrations in smaller volumes 22,25,26 .…”