Method development for detecting the novel cyanide antidote dimethyl trisulfide from blood and brain, and its interaction with blood

Kiss, Lóránd; Holmes, Secondra; Chou, Ching-En; Dong, Xinmei; Ross, James; Brown, D. H.; Mendenhall, Brooke; Coronado, Valerie; Silva, Deepthika De; Rockwood, Gary A.; Petrikovics, Ilona; Thompson, David E.

doi:10.1016/j.jchromb.2017.01.010

Cited by 14 publications

(17 citation statements)

References 15 publications

(19 reference statements)

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“…This wavelength selection was consistent with prior HPLC–UV investigations of DMTS. 19 , 20 The HPLC chromatogram of the F3-formulated DMTS with dimethyl disulfide (DMDS) internal standard (IS) is shown in Figure 2 . DMTS and DMDS were eluted at 8.1 and 6.0 min, respectively.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Long-Term Storage Stability of the Cyanide Antidote: Dimethyl Trisulfide and Degradation Product Identification

Warnakula

Ebrahimpour

et al. 2020

ACS Omega

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This study reports the long-term storage stability of a formulation of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The F3-formulated DMTS was stored in glass ampules at 4, 22, and 37 °C. Over a period of one year, nine ampules ( n = 3 at each temperature) were analyzed by high-performance liquid chromatography (HPLC)–UV/vis at daily time intervals in the first week, weekly time intervals in the first month, and monthly thereafter for a period of one year to determine the DMTS content. No measurable loss of DMTS was found at 4 and 22 °C, and good stability was noted up to five months for samples stored at 37 °C. At 37 °C, a 10% (M/M) decrease of DMTS was discovered at the sixth month and only 30% (M/M) of DMTS remained by the end of the study; discoloration of the formulation and the growth of new peaks in the HPLC chromatogram were also observed. To identify the unknown peaks at 37 °C, controlled oxidation studies were performed on DMTS using two strong oxidizing agents: meta -chloroperoxybenzoic acid ( m CPBA) and hydrogen peroxide (H 2 O 2 ). Dimethyl tetrasulfide and dimethyl pentasulfide were observed as products using both of the oxidizing agents. Dimethyl disulfide was also observed as a product of degradation, which was further oxidized to S -methyl methanethiosulfonate only when m CPBA was used. HPLC–UV/vis and gas chromatography–mass spectrometry/solid phase microextraction analysis revealed good agreement between the degradation products of the stability study at 37 °C and those of disproportionation reactions. Furthermore, at 4 and 22 °C, chromatograms were remarkably stable over the one-year study period, indicating that the F3-formulated DMTS shows excellent long-term storage stability at T ≤ 22 °C.

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Section: Resultsmentioning

confidence: 99%

Evaluation of the Long-Term Storage Stability of the Cyanide Antidote: Dimethyl Trisulfide and Degradation Product Identification

Warnakula

Ebrahimpour

et al. 2020

ACS Omega

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“…This has fueled efforts to develop novel cyanide countermeasures suitable for rapid administration, such as intramuscular injection. Three antidotes in preclinical development include dimethyl trisulfide (110)(111)(112)(113)(114), cobinamide (115)(116)(117)(118), and sulfanegen (119)(120)(121)(122)(123). Animal models have included the Nagasawa sublethal mouse (119), the Boss lethal mouse (115), the Brenner sublethal rabbit (116,120), and lethal models developed by Borron and colleagues (121,124,125).…”

Section: American Thoracic Society Documentsmentioning

confidence: 99%

“…Dimethyl trisulfide is a natural product that converts cyanide to thiocyanate. It has been successfully administered as an intramuscular formulation in murine and rabbit models (110)(111)(112)(113)(114). Cobinamide is a biosynthetic precursor to hydroxocobalamin.…”

Section: American Thoracic Society Documentsmentioning

confidence: 99%

An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness

Summerhill¹,

Hoyle²,

Jordt³

et al. 2017

Annals ATS

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This report is based on the proceedings from the Inhalational Lung Injury Workshop jointly sponsored by the American Thoracic Society (ATS) and the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program on May 21, 2013, in Philadelphia, Pennsylvania. The CounterACT program facilitates research leading to the development of new and improved medical countermeasures for chemical threat agents. The workshop was initiated by the Terrorism and Inhalational Disasters Section of the Environmental, Occupational, and Population Health Assembly of the ATS. Participants included both domestic and international experts in the field, as well as representatives from U.S. governmental funding agencies. The meeting objectives were to (1) provide a forum to review the evidence supporting current standard medical therapies, (2) present updates on our understanding of the epidemiology and underlying pathophysiology of inhalational lung injuries, (3) discuss innovative investigative approaches to further delineating mechanisms of lung injury and identifying new specific therapeutic targets, (4) present promising novel medical countermeasures, (5) facilitate collaborative research efforts, and (6) identify challenges and future directions in the ongoing development, manufacture, and distribution of effective and specific medical countermeasures. Specific inhalational toxins discussed included irritants/pulmonary toxicants (chlorine gas, bromine, and phosgene), vesicants (sulfur mustard), chemical asphyxiants (cyanide), particulates (World Trade Center dust), and respirable nerve agents.

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“…Analytical methods were developed for DMTS detection from formulations, blood, and brain [ 15 , 16 ]. Methods such as these enabled us to follow the storage stability of DMTS in a 15% Poly80 formulation over 29 weeks [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Sealing Effects on the Storage Stability of the Cyanide Antidotal Candidate, Dimethyl Trisulfide

et al. 2017

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BackgroundDimethyl trisulfide (DMTS) is a highly lipid-soluble cyanide (CN) antidote candidate molecule. In prior studies with various US FDA-approved co-solvents, surfactants, and their combinations, aqueous solutions containing 15% polysorbate 80 (Poly80) were found to effectively solubilize DMTS in formulations for intramuscular administration. However, DMTS formulated in 15% aqueous Poly80 solutions showed gradual losses over time when stored in vials with septum-based seals.ObjectiveThe present study tested whether storing DMTS formulations in hermetically sealed glass ampules could mitigate storage losses.MethodsSamples consisted of 1-mL aliquots of a 50 mg/ml stock solution of DMTS in 15% aqueous Poly80. The control samples were stored using a vial-within-a-vial system—the inner and outer vials were sealed respectively, with a snap cap, and with a crimped septum. The hermetically sealed test samples were stored in fire-sealed glass ampules. The DMTS content was measured by HPLC–UV analysis at specific time points over a 100-day period.ResultsWhile the control samples exhibited systematic DMTS losses, no DMTS losses were observed from the test samples stored in hermetically sealed glass ampules over the 100-day testing period.ConclusionDMTS formulated in 15% aqueous Poly80 solution has excellent stability when stored in fire-sealed glass ampules and thus has the potential to be effectively stored as an intramuscular CN countermeasure for mass casualty scenarios.

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Method development for detecting the novel cyanide antidote dimethyl trisulfide from blood and brain, and its interaction with blood

Cited by 14 publications

References 15 publications

Evaluation of the Long-Term Storage Stability of the Cyanide Antidote: Dimethyl Trisulfide and Degradation Product Identification

Evaluation of the Long-Term Storage Stability of the Cyanide Antidote: Dimethyl Trisulfide and Degradation Product Identification

An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness

Sealing Effects on the Storage Stability of the Cyanide Antidotal Candidate, Dimethyl Trisulfide

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