Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion

Abstract

Objective: Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large gastrointestinal cyanide reservoirs. Since humans cannot be exposed to cyanide experimentally, we studied oral cyanide poisoning in rabbits, testing oral sodium thiosulfate with and without gastric alkalization. Setting: University research laboratory.Subjects: New Zealand white rabbits.Interventions: Seven animal groups studied; Groups 1-5 received high dose oral NaCN (50 mg, >LD100) and were treated immediately with oral (via nasogastric tube): 1) saline, 2) glycine, 3) sodium thiosulfate or 4) sodium thiosulfate and glycine, or 5) after 2 min with intramuscular injection of sodium nitrite and sodium thiosulfate plus oral sodium thiosulfate and glycine. Groups 6-7 received moderate dose oral NaCN (25 mg, LD70) and delayed intramuscular 6) saline or 7) sodium nitrite-sodium thiosulfate. Measurements and Main Results:All animals in the high dose NaCN group receiving oral saline or glycine died very rapidly, with a trend towards delayed death in glycine-treated animals; saline versus glycine-treated animals died at 10.3+3.9 and 14.6+5.9 min, respectively (p=0.13). In contrast, all sodium thiosulfate-treated high dose cyanide animals survived (p<0.01), with more rapid recovery in animals receiving both thiosulfate and glycine, compared to thiosulfate alone (p<0.03). Delayed intramuscular treatment alone in the moderate cyanide dose animals increased survival over control animals from 30% to 71%. Delayed treatment in high dose cyanide animals was not as effective as immediate treatment, but did increase survival time and rescued 29% of animals (p<0.01 versus cyanide alone). Conclusions:Oral sodium thiosulfate with gastric alkalization rescued animals from lethal doses of ingested cyanide. The combination of oral glycine and sodium thiosulfate may have potential for treating high dose acute cyanide ingestion and merits further investigation. The combination of systemic and oral therapy may provide further options.

Characterization of a Swine (Sus scrofa) Model of Oral Potassium Cyanide Intoxication

“…[2][3][4]14,[24][25] Future studies should evaluate promising countermeasures in our swine model-similar to what has been done for intravenous KCN models-in experiments that reflect clinically relevant scenarios. 3,4,7,8 Our study has limitations. This study was a pilot study, and the sample size was small.…”

“…In particular, the authors used continuous-wave near-infrared tissue spectroscopy system to monitor for toxicity in real-time and found that a combination of oral glycine and sodium thiosulfate may be useful for treating high-dose acute cyanide ingestion. 7 The authors highlighted the difference between the metabolic rates of rabbits and humans as a limitation of using rabbits for these types of studies. Of the 2 species, rabbits have a higher metabolic rate, and this difference has implications regarding the toxicokinetics of oral poisonings, time window for antidote administration, and response to potential oral antidotes.…”

“…Rabbits and swine complement each other well in terms of drug development and assessment of physiologic and biochemical variables. [1][2][3][4]7 The FDA Animal Rule likely will require 2 animal models (including at least one large animal species) for testing the efficacy of oral cyanide countermeasures. 10 The selection of swine as a model of cyanide toxicity is appropriate for several reasons.…”

Intramuscular dimethyl trisulfide: efficacy in a large swine model of acute severe cyanide toxicity

“…However, our model does allow for invasive assessment of clinically relevant parameters. While most cases of cyanide toxicity result from ingestion or inhalation, we chose intravenous administration of potassium cyanide in an effort to induce reproducible, predictable, controlled, and rapid toxicity [2,3,12,17,18,20]. Intravenous administration minimizes the risk to research staff compared to the inhaled route.…”

Hazardous Chemical Emergencies and Poisonings

“…80 Robust research is under way to develop antidotes that have higher potency or that may be given intramuscularly or orally in the case of mass casualties (e.g., cobinamide, a hydroxocobalamin congener; sulfanegan, a sulfate donor; intramuscular nitrite and thiosulfate; and oral glycine or thiosulfate). 72,81,82 Hydrogen sulfide also binds to methemoglobin and cobalt compounds, and patients may benefit from the prompt administration of nitrite (without thiosulfate) or hydroxocobalamin. 58 In addition, cobinamide was shown to have antidotal efficacy on the toxic effects of hydrogen sulfide in a study in animals.…”