# Cyanide/Azide Detoxification by New Cobalt Complexes and NO Donors

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $453,373

## Abstract

Drawing on past experience of gaseous HCN poisoning through smoke inhalation, it is clear that
many treatable individuals (mass casualties) will present at triage more than 30 min after
exposure still exhibiting signs of acute cyanide toxicity. Compounds that lower the circulating
level of free cyanide in the bloodstream have been shown to be effective antidotes to cyanide
poisoning in such cases. Cobalamin and a sodium nitrite/thiosulfate combination are currently
the only FDA-approved cyanide antidotes for emergency and clinic use, but they are far from ideal
and cobalamin is expensive. There are some other potential cyanides antidotes in reasonably
advanced stages of development, but none are without serious issues, particularly in relation to
mass-casualty applications. Cobinamide, the biological precursor of cobalamin, is significantly
toxic, α-ketoglutarate requires extremely high doses for efficacy, while the active sulfur-
containing compounds like sulfanegens have stability problems. Hypothesizing that many
compounds in which cobalt(II/III) is surrounded by a square-planar arrangement of nitrogen-
donors with two labile ligands in the axial positions might be good candidate antidotes for cyanide
poisoning, we have now shown that several inexpensive complexes of cobalt(II/III) having this
necessary surrounding ligand geometry are, indeed, impressively antidotal and appear to be non-
toxic at the levels required to be efficacious in treating cyanide intoxication. At least some of these
are also antidotal toward azide intoxication. During an earlier project (U01 NS063732: 9/08-
6/11) we demonstrated that sodium nitrite (and other NO donors) reverse cyanide inhibition of
cytochrome c oxidase via a mechanism involving displacement of cyanide bound at the active site
by NO – independent of methemoglobin formation. Consequently, we now propose a
combination of (i) NO donor to reverse inhibition of oxidative phosphorylation by
cyanide and (ii) easily synthesized cobalt-based decorporating agents to bind the
released cyanide in non-toxic forms for excretion. The antidotes will are inexpensive,
some stable enough for stockpiling under ambient conditions and suitable for self-administration,
or with the help untrained assistants. We have the following Specific Aims: Aim 1. Show that
some easily prepared cobalt complexes are candidate cyanide antidotes with scavenging
properties better than those of hydroxocobalamin and at least comparable to those of cobinamide.
Aim 2. Show that the combined therapy (new cobalt complexes + NO donor) is better than either
alone in cases of acute cyanide poisoning. Aim 3. Demonstrate in mice that the new
decorporating agents scavenge cyanide in the bloodstream and are then excreted in the urine (or
feces) with toxicant bound. Aim 4. Show that the proposed combined therapy does not lead to
undesirable long-term sequelae in mice.

## Key facts

- **NIH application ID:** 9998023
- **Project number:** 5U01NS109793-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** LINDA L PEARCE
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,373
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998023

## Citation

> US National Institutes of Health, RePORTER application 9998023, Cyanide/Azide Detoxification by New Cobalt Complexes and NO Donors (5U01NS109793-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9998023. Licensed CC0.

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