In vivo protection by amifostine and DRDE-07 against sulphur mustard toxicity.
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.
Kumar
P
P
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Gwalior, India. pharm_tox@yahoo.co.in
Vijayaraghavan
R
R
Kulkarni
A S
AS
Pathak
U
U
Raza
S K
SK
Jaiswal
D K
DK
D000279:Administration, Cutaneous; D000284:Administration, Oral; D004999:Amifostine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D004347:Drug Interactions; D005260:Female; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009151:Mustard Gas / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
C438646:S-2 (2-aminoethylamino)ethylphenylsulfide; D004999:Amifostine; D009151:Mustard Gas