title: Identification, solubility enhancement and in vivo testing of a cyanide antidote candidate.
abstract: 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. The maximum solubility of MPTS was found at 90% ethanol of 177.11 ± 12.17 mg/ml. The order of MPTS solubility in different surfactants is Cremophor EL>Cremophor RH40>polysorbate 80>sodium deoxycholate>sodium cholate. The maximum solubility of 40.99 mg/ml was achieved with 20% Cremophor EL. A synergistic solubilizing effect encountered with the combination of 20% Cremophor EL+75% ethanol lead to a 2900-fold increase (compared to water solubility) in solubility. The in vivo efficacy using intramuscular administration was determined on a therapeutic mice model and expressed as a ratio of CN LD50 with and without the test antidote(s) (APR). Intramuscular administration was shown to be effective and the therapeutic antidotal protection by MPTS alone and MPTS+thiosulfate (TS) was significantly higher than the present therapy of TS.
authors.affiliation: Department of Chemistry, Sam Houston State University, Huntsville, TX 77341, USA.
authors.forename: Kristof
authors.initials: K
authors.lastname: Kovacs
authors.forename: Madhuri
authors.initials: M
authors.lastname: Ancha
authors.forename: Mario
authors.initials: M
authors.lastname: Jane
authors.forename: Stephen
authors.initials: S
authors.lastname: Lee
authors.forename: Siva
authors.initials: S
authors.lastname: Angalakurthi
authors.forename: Maelani
authors.initials: M
authors.lastname: Negrito
authors.forename: Senan
authors.initials: S
authors.lastname: Rasheed
authors.forename: Assumpta
authors.initials: A
authors.lastname: Nwaneri
authors.forename: Ilona
authors.initials: I
authors.lastname: Petrikovics
mesh_terms: D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000627:therapeutic use*; D003486:Cyanides / Q000506:poisoning*; D000431:Ethanol / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013440:Sulfides / Q000737:chemistry / Q000627:therapeutic use*; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000931:Antidotes; D003486:Cyanides; D012997:Solvents; D013440:Sulfides; D013501:Surface-Active Agents; D000431:Ethanol; D011092:Polyethylene Glycols; C000515:cremophor EL; D005990:Glycerol