Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity

Garrett, Kimberly K; Frawley, Kristin L.; Totoni, Samantha; Bae, Yookyung; Peterson, Jim; Pearce, Linda L.

doi:10.1021/acs.chemrestox.9b00095

Cited by 4 publications

(4 citation statements)

References 45 publications

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“…Pole Testing. A modified protocol (Garrett et al, 2019) was used to study the recovery of mice following intoxication with sodium azide. Each trial consisted of placing a mouse $20 cm from one end of the pole (60 cm in length × 1 cm in diameter) held horizontally $15 cm above a foam pad on the bench.…”

Section: Methodsmentioning

confidence: 99%

“…From a mechanistic perspective, cobalamin is approved for use as a decorporating agent, that is, scavenging cyanide from tissue by binding it in a nontoxic form suitable for excretion. The molecule is excreted in the urine when present in amounts exceeding the binding capacity of the plasma; however, most is secreted into the gastrointestinal tract in bile and then reabsorbed, with only $10% net excretion daily (Fukuwatari et al, 2009;Doets et al, 2013)-note that if it were not for the long elimination time (half-life of several days or hundreds of days for the liver), some cobalamin (vitamin B 12 ) nutritional replacement/supplementation therapies might not work. Thus, although cobalamin may be a reasonable cyanide scavenger, trapping the ligand in a nontoxic coordination complex, it may, in fact, also prolong cyanide's systemic residence time by preventing its rhodanese-dependent conversion to more rapidly excretable thiocyanate.…”

Section: Introductionmentioning

confidence: 99%

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A Potential Antidote for Both Azide and Cyanide Poisonings

Pearce,

Garrett,

Bae

et al. 2024

J Pharmacol Exp Ther

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There do not appear to be any established therapeutics for treating azide poisoning at this time, and presently available antidotes to cyanide poisoning are far from ideal, being particularly impractical for use if multiple victims present. The cobalt (II/III) complex of the Schiff-base ligand trans-[14]-diene (5,7,7,12,14,4,8,) is shown to act as an effective antidote to both azide and cyanide toxicity in mice. Groups of animals challenged with an LD 40 dose of NaCN (100 mmol/kg i.p.) exhibited significantly faster recovery from knockdown and fewer (zero) deaths if given CoN 4 [14] (50 mmol/kg i.p.) 2 minutes after the toxicant. Groups of animals challenged with an essentially lethal dose of NaCN (1.5 x LD 50 5 150 mmol/kg i.p.) all survived if given the CoN 4 [14] (75 mmol/kg i.p.) 5 minutes before the toxicant dose. These data represent improved antidotal capability over the Food and Drug Administration-approved cobalt-based cyanide antidote hydroxocobalamin. Recovery of animals challenged sublethally with NaN 3 (415 mmol/kg i.p.) was assessed employing a modified pole-climbing test. Mice given the CoN 4 [14] antidote (70 mg/kg i.p.) 5 minutes after the toxicant dose recovered twice as fast as the controls given no antidote. The interactions of cyanide and azide with CoN 4 [14] in vitro (buffered aqueous solutions) have been further investigated by a combination of spectroscopic approaches. The Co(II) form of the complex is able to bind two CN À anions while only binding a single N 3 À , providing a reasonable explanation for the difference between their therapeutic abilities. SIGNIFICANCE STATEMENTThe Schiff-base complex CoN 4 [14] is shown to be an effective antidote to cyanide in mice, with improved therapeutic capabilities compared to the Food and Drug Administration-approved cobalt-containing hydroxocobalamin. CoN 4 [14] is also antidotal in mice toward azide poisoning, for which there is seemingly no approved therapy currently available. The activity toward cyanide involves a "redox-switching" mechanism that could be a common, but largely unrecognized, feature of all cobalt-based cyanide antidotes in use and under development.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Potential Antidote for Both Azide and Cyanide Poisonings

Pearce,

Garrett,

Bae

et al. 2024

J Pharmacol Exp Ther

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“…The neuromuscular recovery of mice following intoxication with NaN 3 is slow, and multiple stages can readily be observed. A basic pole test was clearly inadequate for present purposes, and so, a modified experimental paradigm was developed . Individual trials were started by placing the mouse at one end of a pole (60 cm in length × 1 cm in diameter) held in a horizontal position ∼15 cm above a foam pad on the bench.…”

Section: Methodsmentioning

confidence: 99%

“…A basic pole test 18 was clearly inadequate for present purposes, and so, a modified experimental paradigm was developed. 19 Individual trials were started by placing the mouse at one end of a pole (60 cm in length × 1 cm in diameter) held in a horizontal position ∼15 cm above a foam pad on the bench. Subsequently, the pole was slowly raised through a 90°angle to become perpendicular to the laboratory bench.…”

Section: T H Imentioning

confidence: 99%

A Comparison of Potential Azide Antidotes in a Mouse Model

Frawley

Totoni

Bae

et al. 2020

Chem. Res. Toxicol.

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Three cobalt-containing macrocyclic compounds previously shown to antagonize cyanide toxicity have been comparatively evaluated for the amelioration of sublethal azide toxicity in juvenile (7−8 weeks) Swiss-Webster mice. The lowest effective doses were determined for hydroxocobalamin, a cobalt porphyrin, and a cobalt-Schiff base macrocycle by giving the antidotes 5 min prior to the toxicant, 27 mg (415 μmol) /kg sodium azide. Both male and female mice were evaluated for their response to the toxicant as well as the antidotes, and no significant differences were noted once weight differences were taken into account. Two of the three compounds significantly decreased the recovery time of azide-intoxicated mice at 10 min after the administration of sodium azide, as determined by a behavioral test (pole climbing). Additionally, azide was determined to cause a several degree drop (∼3 °C) in measured tail temperature, and warming the mice led to a more rapid recovery. The mice were also shown to recover more rapidly when given sodium nitrite, 24 mg (350 μmol)/kg, 5 min after the toxicant; this treatment also suppressed the azide-induced tail temperature decrease. Electron paramagnetic resonance (EPR) measurements of mouse blood treated with sodium azide demonstrated the presence of nitrosylhemoglobin at levels of 10−20 μM which persisted for ∼300 min. The presence of the methemoglobin azide adduct was also detected by EPR at a maximum level of ∼300 μM, but these signals disappeared around 200 min after the administration of azide. The treatment of mice with 15 N sodium azide proved that the nitrosylhemoglobin was a product of the administered azide by the appearance of a two-line hyperfine (due to the 15 N) in the EPR spectrum of mouse blood.■ EXPERIMENTAL SECTION Chemicals. Gases were purchased from Matheson, and all nongaseous reagents (ACS grade or better), including Na 15 N 3 (98%

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