Prophylactic Efficacy of Amifostine, DRDE-07, and their Analogues against Percutaneously Administered Nitrogen Mustards and Sulphur Mustard

Nitrogen mustards (HN-1, HN-2 and HN-3) and sulphur mustard are alkylating and blister-inducing chemical warfare agents. This study was aimed at investigating the prophylactic efficacy of amifostine, DRDE-07, and their analogues and some recommended antidotes against dermally-applied nitrogen mustards and sulphur mustard in preventing their systemic toxicity in mice. The antidotes were administered as single oral dose, 30 min prior to the mustard agent application. For DRDE-07, 0.2 LD50 (249 mg/kg) was used and for other analogues, equimolar dose of DRDE-07 was used. For amifostine, N-acetyl cysteine, melatonin and sodium thiosulphate, oral dose was 185 mg/kg, 250 mg/kg, 250 mg/kg, and 1000 mg/kg respectively. The animals were observed for mortality for 14 days. The protection index (PI) was calculated as a ratio of LD50 with treatment to LD50 without treatment. The protection of the antidotes was also determined by intraperitoneal route and half of the oral dose of the antidotes was given. The estimated percutaneous LD50 of HN-1, HN-2, HN-3 and sulphur mustard was 11.9 mg/kg, 20.0 mg/kg, 7.1 mg/kg and 7.1 mg/kg, respectively. Compounds that showed marginal protection against HN-1 were DRDE-10 and melatonin with a PI of 1.4. Compounds that showed marginal protection against HN-2 were amifostine, DRDE-07, DRDE-09, DRDE-30, DRDE-35 and melatonin with a PI of 1.4. Compounds that showed marginal protection against HN-3 were amifostine, DRDE-30, DRDE-35, sodium thiosulphate and melatonin with a PI of 1.7. In the case of sulphur mustard, DRDE-07, DRDE-10, DRDE-21, DRDE-30, and DRDE-35 gave a good protection with a PI of more than 5.0. Amifostine and sodium thiosulphate gave a PI of 4.5 and 4.0, respectively, while DRDE-09, N-acetyl cysteine and melatonin gave less protection against sulphur mustard. Intraperitoneally administered amifostine, DRDE-30, sodium thiosulphate and melatonin gave marginal protection against HN-2 with a PI of 1.2, while intraperitoneally administered amifostine, DRDE-07, DRDE-09, DRDE-10, DRDE-30, DRDE-35 and melatonin gave excellent protection against percutaneously administered sulphur mustard with a PI of more than 5.0. The present study shows, that oral and intraperitoneal administration of amifostine, DRDE-07 and their analogues are effective as prophylactic agents for sulphur mustard systemic toxicity, but not against nitrogen mustards.Defence Science Journal, 2009, 59(5), pp.512-516, DOI:http://dx.doi.org/10.14429/dsj.59.155