title: 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 × LD50. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 × LD50protection, and at the dose of 200 mg/kg, the LD50was 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 × LD50protection). 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.
authors.affiliation: a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
authors.forename: Kristof
authors.initials: K
authors.lastname: Kovacs
authors.affiliation: a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Duke
authors.affiliation: a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
authors.forename: Marla
authors.initials: M
authors.lastname: Shifflet
authors.affiliation: a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
authors.forename: Brittany
authors.initials: B
authors.lastname: Winner
authors.affiliation: a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Lee
authors.affiliation: b U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground , Aberdeen , MD , USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rockwood
authors.affiliation: a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
authors.forename: Ilona
authors.initials: I
authors.lastname: Petrikovics
mesh_terms: D000818:Animals; D000931:Antidotes / Q000737:chemistry* / Q000494:pharmacology*; D003486:Cyanides / Q000506:poisoning*; D008297:Male; D051379:Mice; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000931:Antidotes; D003486:Cyanides; D013440:Sulfides; C054170:dimethyl trisulfide
keywords: Cyanide antagonism; solubility enhancement; sulfur donor