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Abstract
<p class="first" id="d7412585e107">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 × LD50 protection, and at the dose
of 200 mg/kg, the LD50 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 × LD50 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.
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