a Department of Chemistry , Sam Houston State University , Huntsville , TX , USA and.
b U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground , Aberdeen , MD , USA.
Pharm Dev Technol. 2017 Dec;22(8):958-963. doi: 10.3109/10837450.2015.1125923. Epub 2016 Jan 7.
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 × LD. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 × LD protection, and at the dose of 200 mg/kg, the LD 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 × LD 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.
本研究集中于一种新的潜在氰化物（CN）解毒剂二甲基三硫醚（DMTS）的增溶作用和体内解毒功效测试。各种经 FDA 批准的环糊精（HPβCD、RMβCD、HPγCD）、共溶剂（乙醇、聚乙二醇、丙二醇）、表面活性剂（聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油 RH40、胆酸钠、脱氧胆酸钠、聚山梨醇酯 80）及其组合被应用。基于所测试体系的增溶潜力，选择聚山梨醇酯 80 用于进一步的体内功效研究。由 15%聚山梨醇酯 80 和 50mg/ml DMTS 组成的组合物，应用 DMTS 剂量为 100mg/kg，提供了 3.4×LD 的治疗解毒保护作用。相比之下，目前的硫代硫酸钠（TS）治疗剂量为 100mg/kg 仅提供 1.1×LD 的保护作用，而剂量为 200mg/kg 时，LD 增强了 1.3 倍。当聚山梨醇酯 80 的浓度增加到 20%时（3.2×LD 保护），DMTS 的治疗保护作用没有差异。这些数据表明 DMTS 作为 CN 解毒剂的潜在重要性，包含聚山梨醇酯 80 的配方提供了可注射肌肉内剂型的基础，可作为适合大规模场景的 CN 解毒试剂盒。
