The effect of amifostine, a cytoprotective agent, on paraquat toxicity in mice.
BACKGROUND
Paraquat (PQ) is a highly poisonous herbicide with a variety of toxic effects, most notably pulmonary fibrosis. In alveolar epithelial cells, it is converted to a PQ radical and subsequently generates other reactive species resulting in lipid peroxidation and cell destruction. Amifostine is a thiophosphate prodrug approved by the FDA for the prevention of toxicities associated with cisplatin and therapeutic radiation. When amifostine is converted to an active metabolite (WR-1065), it functions as an oxygen and DNA radical scavenger that has been shown to protect against lipoperoxidation. The aim of this study was to determine whether amifostine improves survival or lung injury resulting from PQ toxicity.


METHODS
Swiss mice (n = 23 per group) were given an approximate LD75 dose of PQ intraperitoneal (60 mg/kg). Thirty minutes prior to PQ injection, group 1 was pretreated with 200 mg/kg of amifostine subcutaneously (s.c.). Subsequent doses of amifostine at 75 mg/kg were administered 4 hours after PQ injection, and injections continued every 8 hours for a total of 6 doses (cumulative dose: 575 mg/kg). Four hours after PQ injection, group 2 received 200 mg/kg of amifostine subcutaneously. Subsequent doses of amifostine at 75 mg/kg were administered every 8 hours (cumulative dose: 575 mg/kg). Four hours after PQ injection, group 3 received 100 mg/kg of amifostine subcutaneously. Subsequent doses of amifostine at 30 mg/kg were administered every 8 hours (cumulative dose: 250 mg/kg). Group 4 received equivolume injections of sterile 0.9% saline s.c. at the same time intervals. We removed lungs from all mice for histologic analysis and injury scoring.


RESULTS
The number of surviving mice in groups 1, 2, 3, and 4 were 17, 18, 17, and 17 respectively. The Kaplan-Meier with log rank analysis showed no differences in survival. Lung injury scores did not differ between treatment groups and the control group for either dead or surviving mice.


CONCLUSIONS
Amifostine does not appear to improve survival or lung injury due to PQ toxicity at the doses administered.
Wills
Brandon K
BK
Toxikon Consortium, Chicago, IL, USA. bkwills@gmail.com
Aks
Steven
S
Maloney
Gerry E
GE
Rhee
James
J
Brand
Rhonda
R
Sekosan
Marin
M
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010269:Paraquat / Q000633:toxicity*
D004999:Amifostine; D010269:Paraquat