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In vivo protection by amifostine and DRDE-07 against sulphur mustard toxicity

Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, India; pharm_tox{at}yahoo.co.in

R Vijayaraghavan

A S Kulkarni

Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, India

U Pathak

S K Raza

D K Jaiswal

Division of Synthetic Chemistry, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, India

The study was aimed at investigating the prophylactic efficacy of orally administered amifostine and a newly synthesized compound, S-2(2-amino-ethylamino)ethyl phenyl sulphide (DRDE-07), against dermally applied sulphur mustard (SM) in mice and rats. The LD₅₀ values of amifostine and DRDE-07 were determined following oral and intraperitoneal routes and the LD₅₀ of SM diluted in PEG-300 was determined following dermal route. Amifostine or DRDE-07 (equivalent to their 0.05 LD₅₀, 0.10 LD₅₀ and 0.20 LD₅₀) dissolved in water was fed to mice and rats and, after 30 min, various doses of SM were applied to the hair-clipped area of the skin and were observed for 14 days for mortality. The protection index (PI) was calculated as a ratio of LD₅₀ with treatment to LD₅₀ without treatment. The estimated percutaneous LD₅₀ of SM was found to be 8.1 and 2.4 mg///kg for female mice and male rats, respectively. A dose-related protection was observed with all the three doses of both compounds. Thirty minutes prior, the administration of amifostine in female mice offered a PI of 3.0 at the lowest pretreatment dose (52.5 mg// kg) followed by PI of 6.7 and 9.5 at 105 and 210 mg// /kg pretreatment doses, respectively. DRDE-07 offered better protection against SM in female mice, i.e., a PI of 4.8 at pretreatment dose of 62.5 mg// /kg, a PI of 12.0 at the dose of 124.7 mg///kg and a PI of 27.0 at the dose of 249.4 mg/kg. In male rats, DRDE-07 gave a PI of about 3.0 at all the three pretreatment doses (80, 160 and 320 mg///kg), whilst amifostine offered a PI of 3.1 at the highest pretreatment dose (452 mg///kg). The present study showed that oral administration of both amifostine and DRDE-07 was effective as a prophylactic agent for protecting against SM toxicity, and that DRDE-07 offered better protection.

Key Words: amifostine • chemical warfare agents • DRDE-07 • pretreatment • sulphur mustard

Human & Experimental Toxicology, Vol. 21, No. 7, 371-376 (2002)
DOI: 10.1191/0960327102ht250oa


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