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±12.17mg/ml. The order of MPTS solubility in different surfactants is Cremophor EL>Cremophor RH40>polysorbate 80>sodium deoxycholate>sodium cholate. The maximum solubility of 40.99mg/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.
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