title: A novel paradigm for assessing efficacies of potential antidotes against neurotoxins in mice.
abstract: Historically, antidotal potencies of cyanide antagonists were measured as increases in the experimental LD(50) for cyanide elicited by the antidotes. This required the use of high doses of cyanide following pre-treatment with the putative antidote. Since IACUC guidelines at our institutions strongly discourage LD(50) determinations: we developed a new test paradigm that allowed for maximal survival of cyanide-treated animals with greatly reduced numbers of animals. Symptoms of cyanide toxicity include disruption of neuromuscular coordination, i.e., the righting reflex. Therefore, to establish a dose-response curve, the times required for recovery of this righting reflex with increasing doses of cyanide were measured. A cyanide dose that disrupted this righting reflex for approximately 1h with minimal deaths was then selected. Using this paradigm, the current cyanide antidotes, viz., nitrite plus thiosulfate and hydroxocobalamin, as well as some potential cyanide antidotes that we developed, were evaluated pre- and post-cyanide. This allowed, for the first time, the assessment of the post-cyanide effectiveness of the current antidotes against cyanide poisoning in a live animal. In addition, some prototype compounds were found to exhibit antidotal efficacy not only when injected i.p. following cyanide, but also when administered orally 30 min before cyanide. Pre-cyanide oral efficacy suggests that such compounds have the potential of being administered prophylactically before exposure to cyanide. This new test paradigm was found to be a powerful tool for assessing the efficacies of some novel antidotes against cyanide and should be equally applicable for evaluating putative antidotes for other neurotoxins.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, MN, United States. cranksdl@umn.edu
authors.forename: Daune L
authors.initials: DL
authors.lastname: Crankshaw
authors.forename: David J W
authors.initials: DJ
authors.lastname: Goon
authors.forename: Jacquie E
authors.initials: JE
authors.lastname: Briggs
authors.forename: David
authors.initials: D
authors.lastname: DeLong
authors.forename: Michael
authors.initials: M
authors.lastname: Kuskowski
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Herbert T
authors.initials: HT
authors.lastname: Nagasawa
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006879:Hydroxocobalamin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000506:poisoning*; D012018:Reflex / Q000187:drug effects; D012966:Sodium Cyanide / Q000506:poisoning*; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000627:therapeutic use; D013885:Thiosulfates / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000931:Antidotes; D009498:Neurotoxins; D013885:Thiosulfates; C017717:sodium thiosulfate; D012977:Sodium Nitrite; D012966:Sodium Cyanide; D006879:Hydroxocobalamin