A Comparison of Potential Azide Antidotes in a Mouse Model

Abstract

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%

Preclinical reserpine models recapitulating motor and non-motor features of Parkinson’s disease: Roles of epigenetic upregulation of alpha-synuclein and autophagy impairment

“…The pole (1 cm diameter and 60 cm in length) was used to test the climbing ability of mice ( Frawley et al, 2020 ). The mice were placed on the thicker end of a pole to ensure that their heads were facing downwards, while their tails were facing upwards.…”

Potential therapies for sodium azide intoxication; a case report and review of the literature

“…Cobalt containing antidotes, including hydroxocobalamin, have shown some potential beneficial results in mice exposed to sublethal sodium azide concentrations. 32 The effectiveness in humans still needs to be determined.…”

An Appraisal of Antidotes’ Effectiveness: Evidence of the Use of Phyto-Antidotes and Biotechnological Advancements

“…Also, ethotoin, a dose-dependent ricin toxin inhibitor, has been shown to reduce the mortality rate in mice models injected via the intranasal and intra-peritoneal routes with lethal doses of ricin, thus showing potential for the reversal of food intoxications and/or bioterror circumstances linked to ricin [79]. More recently, cobalt-containing macrocyclic (CCM) antidotes with established efficacy against cyanide toxicity were also found to attenuate sublethal azide toxicity in male and female Swiss-Webster mice [80]. The lowest effective doses of the CCM antidotes remarkably shortened the recovery time of the azide-poisoned mice as elucidated in a pole climbing experimental model [80].…”

“…More recently, cobalt-containing macrocyclic (CCM) antidotes with established efficacy against cyanide toxicity were also found to attenuate sublethal azide toxicity in male and female Swiss-Webster mice [80]. The lowest effective doses of the CCM antidotes remarkably shortened the recovery time of the azide-poisoned mice as elucidated in a pole climbing experimental model [80]. A list of selected studies lending credence to the use and effectiveness of common antidotes in both in vivo and in vitro experimental models is presented in Table 2.…”