Use of amifostine, a novel cytoprotective, in alpha-amanitin poisoning.
BACKGROUND
Mortality from ingestions of the mushroom Amanita phalloides remains as high as 20-40% with many surviving patients requiring liver transplantation. A variety of treatments for Amanita ingestion have been evaluated, yet other than supportive measures, no effective therapy has been identified. In addition, an antidote for Amanita toxicity may not be practical due to delayed patient presentation. The drug amifostine was proposed to potentially improve survival from alpha-amanitin toxicity by conferring cytoprotective effects on hepatocytes at risk for cell death. Amifostine is used as a radio--and chemo-protective agent. It protects against lipoperoxidation, interferes with the cross-linking of DNA, and may act by other mechanisms yet to be identified, making it attractive for potentially attenuating ongoing hepatic necrosis. It has not previously been studied in a toxicologic model.


OBJECTIVE
To determine whether amifostine is an effective postexposure therapy for alpha-amanitin, the primary lethal toxin in Amanita phalloides.


METHODS
Swiss mice (n = 30 in all groups) were given an approximate LD75 dose of intraperitoneal (i.p.) alpha-amanitin. Amifostine was administered i.p. 6 h after poisoning in three cumulative dosing groups: 250 mg/kg; 500 mg/kg; and 1600 mg/kg. Controls received equal volumes of i.p. sterile 0.9% saline. Mice were monitored and time of death recorded. At day 7, survival was assumed and the remaining mice were euthanized. Qualitative histologic comparisons of hepatic and renal toxicity were performed.


RESULTS
At day 7, only 10% of the control mice survived. Survival in the amifostine 250, 500, and 1600 mg/kg groups was 20%, 20%, and 3%, respectively. No statistically significant differences were detected in Kaplan-Meier survival between the control group and those receiving 250 or 500 mg/kg; however, there was a statistically significant decrease in survival for the group receiving 1600 mg/kg (p = 0.0002).


CONCLUSIONS
No survival benefit was seen with cumulative doses between 250 and 500 mg/kg; however, higher doses may result in subsequent toxicity and decreased survival.
Wills
Brandon K
BK
Emergency Medicine Residency Program, Akron General Medical Center, Akron, Ohio, USA. bkwills@gmail.com
Haller
Nairmeen Awad
NA
Peter
David
D
White
Lynn J
LJ
D000546:Amanitins / Q000506:poisoning*; D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects; D007668:Kidney / Q000473:pathology; D007928:Lethal Dose 50; D008099:Liver / Q000473:pathology; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000506:poisoning*; D016019:Survival Analysis
D000546:Amanitins; D016166:Free Radical Scavengers; D019384:Nucleic Acid Synthesis Inhibitors; D004999:Amifostine