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

Abstract

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. A composition comprising 15% polysorbate 80 and 50 mg/ml DMTS with the applied DMTS dose of 100 mg/kg provided a therapeutic antidotal protection of 3.4 × LD. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 × LD protection, and at the dose of 200 mg/kg, the LD was enhanced by 1.3 times. No difference in the therapeutic protection by DMTS was detected when the concentration of polysorbate 80 was increased to 20% (3.2 × LD protection). These data demonstrate the potential importance of DMTS as a CN countermeasure, and the formulation comprising polysorbate 80 provides the base of an injectable intramuscular dosage form that can later serve as a CN antidotal kit suitable for mass scenario.

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

“…The physiological safety issues observed here were not observed in the mouse model, 14 though they were evident in a previous formulation. 20 In prior work using the current formulation, mice showed, at worst, minor limping that rapidly recovered. To our knowledge, the severity of toxicity observed in the current experiment has not been observed elsewhere using DMTS.…”

“…With this formulation, a DMTS dose of 100 mg/mL provided an APR of 3.4 against KCN. The 200 mg/kg DMTS dose was more effective (4.1 APR) but caused some muscle damage, and the authors suggested 100 mg/kg as the optimal antidotal dose . This formulation was also later found to be stable for at least 100 days when stored in fire‐sealed glass ampules, making it a potential candidate to be stockpiled for use in a mass‐casualty incident .…”

“…The 200 mg/kg DMTS dose was more effective (4.1 APR) but caused some muscle damage, and the authors suggested 100 mg/kg as the optimal antidotal dose. 20 This formulation was also later found to be stable for at least 100 days when stored in fire-sealed glass ampules, making it a potential candidate to be stockpiled for use in a mass-casualty incident. 21 A more recent formulation of DMTS has been developed with a concentration of 440 mg/mL when dissolved in a surfactant mixture of 25% Span-80 and 75% Tween-80 (by weight).…”

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

“…An 80 mg/mL heparin solution was prepared by dissolving 2.00 g of sodium heparin in 25 mL of distilled water. A DMTS stock solution (Poly80-DMTS) at a concentration of 50 mg/mL was prepared by dissolving DMTS in 15% Poly80 aqueous solution described by Kovacs et al [21] and Petrikovics and Kovacs [12]. …”

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

“…Recently the antifungal [5] and larvicidal [6] activities of DMTS have been reported. DMTS has also been shown to have promising properties as a cyanide antidote [7][8][9].…”