title: A Lipid Base Formulation for Intramuscular Administration of a Novel Sulfur Donor for Cyanide Antagonism.
abstract: 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. The micellar encapsulation for DMTS does not only eliminate the possible muscle necrosis at the injection sites, but the rate of evaporation within the micelles is suppressed, that can provide a level of stability for the formulation. The method of micelle preparation was optimized and it was demonstrated that the PEG2000-DSPE preparation can dissolve up to 2.0 mg/ml of the antidote candidate. Keeping the injection volume minimized this could provide a maximum DMTS dose of 12.5 mg/kg. However, even this low dose of DMTS showed a remarkable in vivo therapeutic efficacy (2 X LD50 protection) in a mice model when injected intramuscularly. These in vitro and in vivo findings proved the efficacy of DMTS in combating CN intoxication, and the presented work gives valuable insight to micelle preparation and sets the bases for a more advanced future formulation of DMTS.
authors.forename: Kristof
authors.initials: K
authors.lastname: Kovacs
authors.forename: Prashanth K
authors.initials: PK
authors.lastname: Jayanna
authors.forename: Anna
authors.initials: A
authors.lastname: Duke
authors.forename: Brittany
authors.initials: B
authors.lastname: Winner
authors.forename: Melaeni
authors.initials: M
authors.lastname: Negrito
authors.forename: Siva
authors.initials: S
authors.lastname: Angalakurthi
authors.forename: Jorn C C
authors.initials: JC
authors.lastname: Yu
authors.forename: Petra
authors.initials: P
authors.lastname: Füredi
authors.forename: Krisztina
authors.initials: K
authors.lastname: Ludányi
authors.forename: Peter
authors.initials: P
authors.lastname: Sipos
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rockwood
authors.affiliation: Department of Chemistry, Faculty of College of Science, Sam Houston State University, P.O. Box: 2117, Huntsville, TX USA. ixp004@shsu.edu.
authors.forename: Ilona
authors.initials: I
authors.lastname: Petrikovics
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D003486:Cyanides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D008823:Micelles; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D012995:Solubility; D013440:Sulfides / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D014810:Vitamin E / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000931:Antidotes; D003486:Cyanides; D004337:Drug Carriers; D008823:Micelles; D010714:Phosphatidylethanolamines; D013440:Sulfides; D014810:Vitamin E; C054170:dimethyl trisulfide; D011092:Polyethylene Glycols; C014225:tocophersolan