Comparison of hematologic consequences and efficacy of p-aminophenones in mice

Controlled methemoglobin (MHb) formation is one strategy employed to counte r cyanide (CN) toxicity. Currently available MHb formers present certain dr awbacks and limitations. The purpose of this study was to characterize, in mice, the hematologic effects of the MHb-forming compound p-aminopropiophen one (PAPP), and two structurally-related p-aminophenones, p-amino-heptanoyl phenone (PAHP) and p-aminooctanoylphenone (PAOP). Although these three p-am inophenones have been shown previously to be efficacious as pretreatments a gainst CN, a more complete understanding of their hematologic effects is la cking. In addition, because the active form of PAPP has been shown to be it s N-hydroxy metabolite, the N-hydroxy metabolites of PAPP, PAHP and PAOP we re also tested. Using a hemoximeter, blood samples obtained -2 to + 180 min relative to intramuscular (i.m.) or intraperitoneal (i.p.) drug injections were evaluated. Sodium nitrite (NaNO2) and the appropriate solvents served as the positive and negative controls, respectively. Dose-, time-, route-, and compound-related effects were observed. MHb and sulfhemoglobin levels increased, whereas levels of those parameters related to oxygen-carrying ca pacity of the blood, such as, oxygen saturation and oxyhemoglobin decreased . In general, the effects of PAHP and PAOP were longer lasting than those o f PAPP and NaNO2. Furthermore, PAPP and NaNO2 were equally effective with e ither route of administration. Conversely, PAHP and PAOP showed larger effe cts when administered i.p. versus i.m. The animals treated with N-hydroxy m etabolites of the p-aminophenones also showed similar changes in the hemato logical parameters measured. N-hydroxy PAPP was shown to be the most rapidl y acting MHb-forming compound examined in this series. It could achieve the rapeutic concentrations of MHb within 2 min and thus may be considered as a treatment for CN intoxication. Although additional work is needed, these d ata provide information that will be useful for the successful development of improved anti-CN MHb formers. (C) 1999 Published by Elsevier Science B.V . All rights reserved.