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

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 ( = 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.

Antidotal efficacies of the cyanide antidote candidate dimethyl trisulfide alone and in combination with cobinamide derivatives.

Formulation optimization and antidotal combination therapy are the two important tools to enhance the antidotal protection of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The focus of this study is to demonstrate how the formulation with polysorbate 80 (Poly80), an excipient used in pharmaceutical technology, and the combinations with other CN antidotes having different mechanisms of action enhance the antidotal efficacy of the unformulated (neat) DMTS. The LD for CN was determined by the statistical Dixon up-and-down method on mice.

Methemoglobin Forming Effect of Dimethyl Trisulfide in Mice.

Dimethyl trisulfide (DMTS) is a natural organic trisulfide that has been patented as a promising antidotal candidate against cyanide (CN). The primary mode of action of DMTS is as a sulfur donor that enables the conversion of CN to thiocyanate. Recently, it was discovered that DMTS is capable of oxidizing hemoglobin (Hb) to methemoglobin (MetHb) in vitro.

Development of magnetic carbon nanotubes for dispersive micro solid phase extraction of the cyanide metabolite, 2-aminothiazoline-4-carboxylic acid, in biological samples.

2-aminothiazoline-4-carboxylic acid (ATCA) is a minor metabolite of cyanide and is suggested to be a promising biomarker for cyanide exposure due to its specificity to cyanide metabolism and its excellent short- and long-term stability during storage. In this study, magnetic carbon nanotubes, including magnetic multi-walled carbon nanotubes (Mag-MWCNT) and magnetic single-walled carbon nanotubes (Mag-SWCNT) were synthesized as a novel sorbent for dispersive micro solid phase extraction (d-μSPE) to extract ATCA from biological matrices. ATCA spiked deionized water samples with the addition of the isotopic internal standard (ATCA - C, N) were subjected to Mag-CNT/d-μSPE to confirm extraction efficiency of this new technique.

Correction to: Monitoring Dose Response of Cyanide Antidote Dimethyl Trisulfide in Rabbits Using Diffuse Optical Spectroscopy.

The online version of the original article can be found at.

Monitoring Dose Response of Cyanide Antidote Dimethyl Trisulfide in Rabbits Using Diffuse Optical Spectroscopy.

Introduction: Cyanide (CN) poisoning is a serious chemical threat from accidental or intentional exposures. Current CN exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Dimethyl trisulfide (DMTS) is capable of reacting with CN to form the less toxic thiocyanate with high efficiency, even without the sulfurtransferase rhodanese.

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

Background: Dimethyl 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.

From the Cover: In Vitro and In Vivo Blood-Brain Barrier Penetration Studies with the Novel Cyanide Antidote Candidate Dimethyl Trisulfide in Mice.

Recent in vitro and in vivo studies highlight the strong potential of dimethyl trisulfide (DMTS) as an antidote for cyanide (CN) intoxication. Due to its high oxygen demand, the brain is one of the main target organs of CN. The blood-brain barrier (BBB) regulates the uptake of molecules into the brain.

Reaction of Dimethyl Trisulfide with Hemoglobin.

Dimethyl trisulfide (DMTS) is a promising antidotal candidate for cyanide intoxication. DMTS acts as a sulfur donor in the conversion of cyanide to the less-toxic thiocyanate. The alternate reaction pathways of DMTS in the blood are not well understood.

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

The antidotal potency of dimethyl trisulfide (DMTS) against cyanide poisoning was discovered and investigated in our previous studies. Based on our results it has better efficacy than the Cyanokit and the Nithiodote therapies that are presently used against cyanide intoxication in the US. Because of their absence in the literature, the goal of this work was to develop analytical methods for determining DMTS from blood and brain that could be employed in future pharmacokinetic studies.

Intravascular Residence Time Determination for the Cyanide Antidote Dimethyl Trisulfide in Rat by Using Liquid-Liquid Extraction Coupled with High Performance Liquid Chromatography.

These studies represent the first report on the intravascular residence time determinations for the cyanide antidote dimethyl trisulfide (DMTS) in a rat model by using high performance liquid chromatography coupled with ultraviolet absorption spectroscopy (HPLC-UV). The newly developed sample preparation included liquid-liquid extraction by cyclohexanone. The calibration curves showed a linear response for DMTS concentrations between 0.

Determination of dimethyl trisulfide in rabbit blood using stir bar sorptive extraction gas chromatography-mass spectrometry.

Cyanide poisoning by accidental or intentional exposure poses a severe health risk. The current Food and Drug Administration approved antidotes for cyanide poisoning can be effective, but each suffers from specific major limitations concerning large effective dosage, delayed onset of action, or dependence on enzymes generally confined to specific organs. Dimethyl trisulfide (DMTS), a sulfur donor that detoxifies cyanide by converting it into thiocyanate (a relatively nontoxic cyanide metabolite), is a promising next generation cyanide antidote.

A Lipid Base Formulation for Intramuscular Administration of a Novel Sulfur Donor for Cyanide Antagonism.

This study represents a new formulation of the novel Cyanide (CN) antidote, Dimethyl trisulfide (DMTS), for intramuscular administration. This is a naturally occurring organosulfur molecule with the capability of reacting with CN more efficiently than the present sulfur donor type CN therapy of Thiosulfate (TS). Two types of micelles (PEG2000-DSPE and PEG2000-DSPE/TPGS) were prepared and tested for their ability to encapsulate the liquid, highly lipophilic and volatile drug, DMTS.

Dimethyl trisulfide: A novel cyanide countermeasure.

In the present studies, the in vitro and in vivo efficacies of a novel cyanide countermeasure, dimethyl trisulfide (DMTS), were evaluated. DMTS is a sulfur-based molecule found in garlic, onion, broccoli, and similar plants. DMTS was studied for effectiveness as a sulfur donor-type cyanide countermeasure.

Stability Characterization of a Polysorbate 80-Dimethyl Trisulfide Formulation, a Cyanide Antidote Candidate.

Novel cyanide countermeasures are needed for cases of a mass-exposure cyanide emergency. A lead candidate compound is dimethyl trisulfide (DMTS), which acts as a sulfur donor for rhodanese, thereby assisting the conversion of cyanide into thiocyanate. DMTS is a safe compound for consumption and, in a 15% polysorbate 80 (DMTS-PS80) formulation, has demonstrated good efficacy against cyanide poisoning in several animal models.

Parenteral dosage form development and testing of dimethyl trisulfide, as an antidote candidate to combat cyanide intoxication.

This study focused on the solubility enhancement and the in vivo antidotal efficacy testing of a new potential cyanide (CN) countermeasure, dimethyl trisulfide (DMTS). Various FDA approved cyclodextrins (HPβCD, RMβCD, HPγCD), cosolvents (ethanol, polyethylene glycols, propylene glycol), surfactants (cremophor EL, cremophor RH 40, sodium cholate, sodium deoxycholate, polysorbate 80) and their combinations were applied. Based on the solubility enhancing potential of the tested systems, polysorbate 80 was chosen for further in vivo efficacy studies.

Simultaneous determination of 3-mercaptopyruvate and cobinamide in plasma by liquid chromatography-tandem mass spectrometry.

The current suite of Food and Drug Administration (FDA) approved antidotes (i.e., sodium nitrite, sodium thiosulfate, and hydroxocobalamin) are effective for treating cyanide poisoning, but individually, each antidote has major limitations (e.

Past, present and future of cyanide antagonism research: From the early remedies to the current therapies.

This paper reviews milestones in antidotal therapies for cyanide (CN) spanning early remedies, current antidotal systems and research towards next generation therapies. CN has been a part of plant defense mechanisms for millions of years. It became industrially important in the nineteenth century with the advent of CN assisted gold mining and the use of CN as a pest control agent.

Optimization of liposomal encapsulation for ceftazidime for developing a potential eye drop formulation.

Ceftazidime is a broad spectrum third generation cephalosporin antibiotic which is effective mainly against Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter and Enterobacteriaceae, the pathogens which most often cause ophthalmological infections. Unlike other commonly used beta lactam antibiotics, ceftazidime is resistant to several types of beta lactamases (e.g.

Cyanide toxicokinetics: the behavior of cyanide, thiocyanate and 2-amino-2-thiazoline-4-carboxylic acid in multiple animal models.

Cyanide causes toxic effects by inhibiting cytochrome c oxidase, resulting in cellular hypoxia and cytotoxic anoxia, and can eventually lead to death. Cyanide exposure can be verified by direct analysis of cyanide concentrations or analyzing its metabolites, including thiocyanate (SCN(-)) and 2-amino-2-thiazoline-4-carboxylic acid (ATCA) in blood. To determine the behavior of these markers following cyanide exposure, a toxicokinetics study was performed in three animal models: (i) rats (250-300 g), (ii) rabbits (3.

Liposomes for topical use: a physico-chemical comparison of vesicles prepared from egg or soy lecithin.

Developments in nanotechnology and in the formulation of liposomal systems provide the opportunity for cosmetic dermatology to design novel delivery systems. Determination of their physico-chemical parameters has importance when developing a nano-delivery system. The present study highlights some technological aspects/characteristics of liposomes formulated from egg or soy lecithins for topical use.

Identification, solubility enhancement and in vivo testing of a cyanide antidote candidate.

Present studies focused on the in vitro testing, the solubility enhancement and the in vivo testing of methyl propyl trisulfide (MPTS), a newly identified sulfur donor to treat cyanide (CN) intoxication. To enhance the solubility of the lipophilic MPTS, various FDA approved co-solvents, surfactants and their combinations were applied. The order of MPTS solubility in the given co-solvents was found to be the following: ethanol >> PEG 200 ≈ PEG400 ≈ PEG300 > PG.

Confidence limit calculation for antidotal potency ratio derived from lethal dose 50.

Aim: To describe confidence interval calculation for antidotal potency ratios using bootstrap method.

Methods: We can easily adapt the nonparametric bootstrap method which was invented by Efron to construct confidence intervals in such situations like this. The bootstrap method is a resampling method in which the bootstrap samples are obtained by resampling from the original sample.

LC-MS/MS analysis of 2-aminothiazoline-4-carboxylic acid as a forensic biomarker for cyanide poisoning.

Aim: To demonstrate the potential of using 2-aminothiazoline-4-carboxylic acid (ATCA) as a novel biomarker/forensic biomarker for cyanide poisoning.

Methods: A sensitive method was developed and employed for the identification and quantification of ATCA in biological samples, where the sample extraction and clean up were achieved by solid phase extraction (SPE). After optimization of SPE procedures, ATCA was analyzed by high performance liquid chromatography-tandem mass spectrometry.

Simultaneous determination of cyanide and thiocyanate in plasma by chemical ionization gas chromatography mass-spectrometry (CI-GC-MS).

An analytical method utilizing chemical ionization gas chromatography-mass spectrometry was developed for the simultaneous determination of cyanide and thiocyanate in plasma. Sample preparation for this analysis required essentially one-step by combining the reaction of cyanide and thiocyanate with pentafluorobenzyl bromide and simultaneous extraction of the product into ethyl acetate facilitated by a phase-transfer catalyst, tetrabutylammonium sulfate. The limits of detection for cyanide and thiocyanate were 1 μM and 50 nM, respectively.