As a result of the solubility studies, compositions that were able to solubilize significant amounts of MPTS were developed. A composition SRT1720 in vitro comprising 10% Cremophor
EL, 50% ethanol and 50 mg/ml MPTS was chosen for the animal studies. The in vivo efficacy studies were performed with MPTS alone (dose = 100 mg/kg and 200 mg/kg) and TS alone (dose = 100 mg/kg and 200 mg/kg) and their combination with the doses of 200 mg/kg for each. Therapeutic antidotal potency ratios (APRs) of the drugs and their combinations are shown in Table 6. The following were used for the calculation of the antidote potency ratio (APR) and the relative antidote potency ratio (RAPR): APR = LD50 of CN with the antidote(s)/LD50 of CN without antidote(s) (control); relative antidotal potency ratio (RAPR) = APR(1)/APR(2). The antidotal efficacy tests demonstrated the superior effect of MPTS over TS (Exp. 1 vs. Exp. 3; and Exp. 2 vs. Exp. 4). The positive dose effects are also demonstrated: MPTS alone provided a selleck chemical 1.2 LD50 protection when the dose was 100 mg/kg, while the double dose (200 mg/kg) provided an enhanced protection with the APR of 1.67 (RAPR = 1.39). TS alone provided only a slight protection with the APR of 1.1 when the dose was 100 mg/kg, and when the dose was
doubled (200 mg/kg), the APR was enhanced to 1.25 (RAPR = 1.13). Employing the same dose of 200 mg/kg for both components of the combination with MPTS and TS (Exp. 5), the antidotal protection was significantly enhanced to 3.66× LD50. The enhancement by TS was 2.19× compared to MPTS alone. The enhancement by MPTS was 2.92× compared to TS alone. The tests not only showed that MPTS is effective in combating cyanide intoxication but it also revealed that the newly identified molecule is more effective than the currently used TS. Furthermore,
it was also shown that intramuscular administration is an effective way of applying the antidote as absorption of the molecule from the muscle was fast enough to counteract the toxic effects of cyanide. The identification of a possible Cediranib (AZD2171) antidote (MPTS) for CN intoxication and its solubilization for the therapeutic antidotal studies using a lethal animal model were addressed in this study. Based on in vitro CN to SCN conversion testing of potential sulfur donors it was concluded that MPTS is a potentially effective molecule because its in vitro efficacy was superior to that of TS, the SD component in one of the currently approved antidote kits. Following the identification of the SD it was seen that it is a highly lipophilic molecule with low water solubility, thus its solubilization was initiated.