Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity

Citation
R. Vijayaraghavan et al., Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity, TOXICOLOGY, 163(2-3), 2001, pp. 83-91
Citations number
27
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGY
ISSN journal
0300-483X → ACNP
Volume
163
Issue
2-3
Year of publication
2001
Pages
83 - 91
Database
ISI
SICI code
0300-483X(20010621)163:2-3<83:PEOAAI>2.0.ZU;2-E
Abstract
The successful implication of the chemical weapons convention stimulated re search with a new vigour on the destruction of the stockpiled sulphur musta rd (SM). A prophylactic agent for SM will be very useful for personnel enga ged 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 reg imen has evolved for SM. Amifostine an organophosphorothioate, originally d eveloped as a radioprotector, and its analogues were evaluated as a prophyl actic agent for SM. Three analogues by varying the chain length and substit ution at the sulphur atom were synthesised and coded as DRDE-06. DRDE-07 an d DRDE-08. LD50 of amifostine and its analogues were estimated through intr aperitoneal (i.p.) route. For the protection studies. amifostine and its an alogues were administered i.p, in mice. 30 min before dermal (percutaneous) application of SM. The dose of the prophylactic agent was 0.2 LD50, (i.p.) and that of SM was 152 mg/kg (undiluted) equal to 19-fold LD50 of SM. Amif ostine and one of its analogues, DRDE-07 gave significant protection. Furth er studies were carried out using amifostine and DRDE-07, and both of them significantly protected mice against SM (155 mg:kp. in PEG 300, equal to 19 LD50) when they were administered i.p. either 30 min before or simultaneou sly. LD50 of amifostine and DRDE-07 were also estimated through the oral ro ute (1049 or 1248 mg/kg. respectively). Prophylactically administered amifo stine and DRDE-07 (0.2 LD50, p.o.) significantly protected the mice against dermally applied SM (155 mg/kg. in PEG 300, equal to 19 LD50). The protect ion offered by DRDE-07 was better than that of amifostine by the oral route . DRDE-07 (0.2 LD50. 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 LD50, p.o.). Further studies are in progress on the various pharmacologic al and toxicological properties of DRDE-07. (C) 2001 Elsevier Science Irela nd Ltd. All rights reserved.