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

Hendry‐Hofer, Tara B.; Witeof, Alyssa E.; Lippner, Dennean S.; Ng, Patrick; Mahon, Sari B.; Brenner, Matthew; Rockwood, Gary A.; Bebarta, Vikhyat S.

doi:10.1080/15563650.2018.1511800

Cited by 12 publications

(6 citation statements)

References 18 publications

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“…In addition to the mouse study that provided the dose selection of the current experiment, 14 DMTS has successfully been used in a swine model of acute cyanide toxicity. 32 In this model, swine were anaesthetized and then given a continuous infusion of KCN. Five minutes after the onset of apnoea, either 82.5 mg/kg DMTS or saline control was given IM and subjects were observed for another 90 minute.…”

Section: Discussionmentioning

confidence: 99%

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Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Rice

Rauscher

Wilkins

et al. 2019

Basic Clin Pharma Tox

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Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional‐poisoning hazard. Effective antidotes to cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective cyanide antidote that can be administered intramuscularly in pre‐hospital and/or mass‐casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25‐200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25‐100 mg/kg) increased survival after oral cyanide poisoning, and the lower DMTS doses (6.25‐25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50‐200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24‐72 hour. Thus, DMTS shows promise as an intramuscularly administered cyanide antidote useful for prompt pre‐hospital or mass‐casualty emergency medical treatment.

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Section: Discussionmentioning

confidence: 99%

“…In addition to the mouse study that provided the dose selection of the current experiment, DMTS has successfully been used in a swine model of acute cyanide toxicity . In this model, swine were anaesthetized and then given a continuous infusion of KCN.…”

Section: Discussionmentioning

confidence: 99%

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Rice

Rauscher

Wilkins

et al. 2019

Basic Clin Pharma Tox

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“…Additional studies should be performed to evaluate sodium tetrathionate completely as a countermeasure for cyanide toxicity. Finally, as oral cyanide is a rising threat, evaluation of tetrathionate for oral cyanide ingestion would be important as a higher dose of cyanide with different pharmacokinetics generally occurs with oral ingestion than inhaled or intravenous cyanide [29,30].…”

Section: Discussionmentioning

confidence: 99%

Intramuscular sodium tetrathionate as an antidote in a clinically relevant swine model of acute cyanide toxicity

Hendry‐Hofer

Witeof

et al. 2019

Clinical Toxicology

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Background-Cyanide is a metabolic poison used in multiple industries and is a high threat chemical agent. Current antidotes require intravenous administration, limiting their usefulness in a mass casualty scenario. Sodium tetrathionate reacts directly with cyanide yielding thiosulfate and the non-toxic compound thiocyanate. Thiosulfate in turn neutralizes a second molecule of cyanide, thus, per mole, sodium tetrathionate neutralizes two moles of cyanide. Historical studies examined its efficacy as a cyanide antidote, but it has not been evaluated in a clinically relevant, large animal model, nor has it previously been administered by intramuscular injection.Objective-The objective of this study is to evaluate the efficacy of intramuscular sodium tetrathionate on survival and clinical outcomes in a large, swine model of severe cyanide toxicity.Methods-Anesthetized swine were instrumented for continuous monitoring of hemodynamics, then acclimated and breathing spontaneously prior to potassium cyanide infusion (0.17 mg/kg/ min). At 6-minutes post apnea (no breaths for 20 seconds), the cyanide infusion was terminated, and animals treated with sodium tetrathionate (~18 mg/kg) or normal saline control. Clinical parameters and laboratory values were evaluated at various time points until death, or termination of the experiment (90 minutes post treatment).

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“…Several agents such as sulfur-transferases, cobinamide, and dimethyl trisulfide (DMTS) are currently under development [18,[44][45][46][47][48][49][50][51]. Sodium nitrite and sodium thiosulfate administered intramuscularly at low doses can be effective, but the current FDA-approved formulation is not packaged to be used this way [51].…”

Section: Antidote Developmentmentioning

confidence: 99%

A Review on Ingested Cyanide: Risks, Clinical Presentation, Diagnostics, and Treatment Challenges

Hendry‐Hofer

Witeof

et al. 2018

J. Med. Toxicol.

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Cyanide, a metabolic poison, is a rising chemial threat and ingestion is the most common route of exposure. Terrorist organizations have threatened to attack the USA and international food and water supplies. The toxicokinetics and toxicodynamics of oral cyanide are unique, resulting in high-dose exposures, severe symptoms, and slower onset of symptoms. There are no FDAapproved therapies tested for oral cyanide ingestions and no approved intramuscular or oral therapies, which would be valuable in mass casualty settings. The aim of this review is to evaluate the risks of oral cyanide and its unique toxicokinetics, as well as address the lack of available rapid diagnostics and treatments for mass casualty events. We will also review current strategies for developing new therapies. A review of the literature using the PRISMA checklist detected 7284 articles, screened 1091, and included 59 articles or other reports. Articles referenced in this review were specific to risk, clinical presentation, diagnostics, current treatments, and developing therapies. Current diagnostics of cyanide exposure can take hours or days, which can delay treatment. Moreover, current therapies for cyanide poisoning are administered intravenously and are not specifically tested for oral exposures, which can result in higher cyanide doses and unique toxicodynamics. New therapies developed for oral cyanide exposures that are easily delivered, safe, and can be administered quickly by first responders in a mass casualty event are needed. Current research is aimed at identifying an antidote that is safe, effective, easy to administer, and has a rapid onset of action.

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

Cited by 12 publications

References 18 publications

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Intramuscular sodium tetrathionate as an antidote in a clinically relevant swine model of acute cyanide toxicity

A Review on Ingested Cyanide: Risks, Clinical Presentation, Diagnostics, and Treatment Challenges

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