Modification of cyanide toxicodynamics: mechanistic based antidote development.
Cyanide's actions are complex and cannot be attributed solely to inhibition of oxygen utilization. Recent mechanistic studies show that cyanide inhibits multiple enzymes and alters several vital intracellular processes to produce the intoxication syndrome. By understanding the intracellular targets and the mechanisms underlying the toxicity, it is proposed that more effective antidotal regimens can be achieved. A mechanistic based, multi-step in vitro model was developed for screening potential cyanide antidotes. A series of compounds was screened for their ability to reverse the effect of cyanide on six neurochemical markers in the PC12 cell line (neuronal cell model). Each compound was assigned a composite score based on the six assays; several compounds were identified which then exhibited efficacy in animal testing. Additional mechanistic based studies show that antioxidants and nitric oxide generators have promise as anti-cyanide agents. It is concluded that mechanistic based antidote design can be used to identify new compounds for testing in animal models.
Isom
G E
GE
Department of Pharmacology and Toxicology, Purdue University, West Lafayette, IN 47906, USA.
Borowitz
J L
JL
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D003486:Cyanides / Q000633:toxicity*; D006801:Humans; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D017382:Reactive Oxygen Species / Q000633:toxicity
D000931:Antidotes; D003486:Cyanides; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D007548:Isosorbide Dinitrate