Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity.
The successful implication of the chemical weapons convention stimulated research with a new vigour on the destruction of the stockpiled sulphur mustard (SM). A prophylactic agent for SM will be very useful for personnel engaged in the destruction of SM and during inspections by the Organisation for the Prohibition of Chemical Weapons. Due to simple method of preparation, SM can be used clandestinely during war or by terrorist groups. Inspite of research over several decades no satisfactory prophylactic or treatment regimen has evolved for SM. Amifostine an organophosphorothioate, originally developed as a radioprotector, and its analogues were evaluated as a prophylactic agent for SM. Three analogues by varying the chain length and substitution at the sulphur atom were synthesised and coded as DRDE-06, DRDE-07 and DRDE-08. LD(50) of amifostine and its analogues were estimated through intraperitoneal (i.p.) route. For the protection studies, amifostine and its analogues were administered i.p. in mice, 30 min before dermal (percutaneous) application of SM. The dose of the prophylactic agent was 0.2 LD(50) (i.p.) and that of SM was 152 mg/kg (undiluted) equal to 19-fold LD(50) of SM. Amifostine and one of its analogues, DRDE-07 gave significant protection. Further studies were carried out using amifostine and DRDE-07, and both of them significantly protected mice against SM (155 mg/kg, in PEG 300, equal to 19 LD(50)) when they were administered i.p. either 30 min before or simultaneously. LD(50) of amifostine and DRDE-07 were also estimated through the oral route (1049 or 1248 mg/kg, respectively). Prophylactically administered amifostine and DRDE-07 (0.2 LD(50), p.o.) significantly protected the mice against dermally applied SM (155 mg/kg, in PEG 300, equal to 19 LD(50)). The protection offered by DRDE-07 was better than that of amifostine by the oral route. DRDE-07 (0.2 LD(50), p.o.) also protected significantly with respect to the decrease in body weight and the depletion of GSH induced by SM. DNA damage induced by SM was also significantly reduced by amifostine and DRDE-07 (0.2 LD(50), p.o.). Further studies are in progress on the various pharmacological and toxicological properties of DRDE-07.
Vijayaraghavan
R
R
Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India. drde@sancharnet.in
Kumar
P
P
Joshi
U
U
Raza
S K
SK
Lakshmana Rao
P V
PV
Malhotra
R C
RC
Jaiswal
D K
DK
D000284:Administration, Oral; D004999:Amifostine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D053938:DNA Fragmentation; D003879:Dermatologic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005260:Female; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008466:Mechlorethamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D013997:Time Factors
D003879:Dermatologic Agents; D008466:Mechlorethamine; D004999:Amifostine