Further Study of the Mechanisms of Toxic Action of TVOPA

Abstract : The investigation is a study and evaluation of toxic effects of the NF compound designated TVOPA emphasizing in vivo and in vitro degradation of the compound and its action at the cellular level. Study of the pharmacologic activity was made in rats, dogs, and cynamolgus monkeys. To some degree, effects were species specific. A very low rate of TVOPA hydrolysis in aqueous solutions was determined in earlier experiments. The assumption that degradation in biological media would not differ significantly from in vitro buffered media was incorrect. Using various blood fractions, experiments account for the majority of fluoride and cyanide ion metabolites from TVOPA within two hours; however, ionic blood levels were not sufficiently elevated to explain all signs of toxicity. Studies of inhibition of cytochrome c oxidase activity further confirmed that cyanide ions contribute to TVOPA action, but KCN and NaF mixtures were not equal to TVOPA and procedures known to protect against cyanide toxicity were unsuccessful against TVOPA. This investigation supports earlier contentions that TVOPA or early organic degradation products have direct toxic action. Inorganic degradation products influence the delayed effects of TVOPA, but are not responsible for death at high doses.