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A Comparison of Potential Azide Antidotes in a Mouse Model
Kristin L Frawley1, Samantha Carpenter Totoni1, Yookyung Bae1
1Department of Environmental and Occupational Health, Graduate School of Public Health , The University of Pittsburgh , 130 DeSoto Street , Pittsburgh , Pennsylvania 15219 , United States.
Chemical Research in Toxicology
|January 11, 2020
Summary
Cobalt compounds show promise in treating azide toxicity by reducing recovery time in mice. Warming and sodium nitrite also aided recovery and mitigated temperature drops caused by azide poisoning.
Area of Science:
- Toxicology
- Biochemistry
- Pharmacology
Background:
- Cyanide antidotes, specifically cobalt-containing macrocyclic compounds, have demonstrated efficacy.
- Sublethal azide toxicity presents a significant challenge in toxicological research.
- Understanding the mechanisms of azide toxicity is crucial for developing effective treatments.
Purpose of the Study:
- To evaluate three cobalt-containing macrocyclic compounds for their effectiveness in ameliorating sublethal azide toxicity in mice.
- To determine the lowest effective doses of hydroxocobalamin, a cobalt porphyrin, and a cobalt-Schiff base macrocycle as azide antidotes.
- To investigate the physiological effects of azide toxicity, including behavioral changes and body temperature reduction, and the impact of potential treatments.
Main Methods:
- Comparative evaluation of three cobalt-containing macrocyclic compounds in juvenile Swiss-Webster mice.
- Administration of sodium azide (27 mg/kg) followed by behavioral assessments (pole climbing test) and tail temperature measurements.
- Electron paramagnetic resonance (EPR) spectroscopy to detect nitrosylhemoglobin and methemoglobin azide adducts in mouse blood.
- Use of 15N sodium azide to confirm the origin of nitrosylhemoglobin.
Main Results:
- Two of the three cobalt compounds significantly reduced recovery time in azide-intoxicated mice.
- Azide administration caused a decrease in tail temperature (approximately 3 °C), which was reversed by warming.
- Sodium nitrite treatment (24 mg/kg) accelerated recovery and prevented azide-induced hypothermia.
- EPR studies detected nitrosylhemoglobin (10-20 μM) and methemoglobin azide adducts (up to ~300 μM) in mouse blood following azide exposure.
Conclusions:
- Hydroxocobalamin, cobalt porphyrin, and cobalt-Schiff base macrocycles show potential as antidotes for azide toxicity.
- Azide toxicity is associated with hypothermia and the formation of nitrosylhemoglobin and methemoglobin azide adducts.
- Therapeutic interventions including warming, sodium nitrite, and specific cobalt compounds can mitigate the effects of azide toxicity.
