Translational Antidote Research: A Bedside to Bench Tale

Abstract

Although antidote development should proceed in an orderly fashion from observation, to experimental and safety studies, to clinical trials, this sequence is not always precisely followed. The development of fomepizole as an antidote for toxic alcohol and glycol poisoning is an example of how this may not be the case. Interest in the development of fomepizole was spurred in the 1960s. Shortly thereafter studies characterized by administration to humans commenced. The potential value of fomepizole as an antidote for methanol poisoning was highlighted by primate experiments. Simultaneously, the utility of fomepizole was shown in an experimental model of ethylene glycol poisoning. Further studies on humans showed effectiveness of fomepizole in the treatment of disulfiram-alcohol reactions and ethylene glycol poisoning. In addition, in primate experiments, the safety of fomepizole was established as the subjects tolerated serum fomepizole concentrations over 150 times higher than therapeutic target levels. Subsequent studies have validated the efficacy of fomepizole in the treatment of ethylene glycol and methanol poisonings. Fomepizole has been found to be associated with fewer complications than the alternative alcohol dehydrogenase inhibitor, ethanol. In serious cases of methanol toxicity, fomepizole has been shown to improve survival compared to that obtained with ethanol.