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

Controlled methemoglobin (MHb) formation is one strategy employed to counter cyanide (CN) toxicity. Currently available MHb formers present certain drawbacks and limitations. The purpose of this study was to characterize, in mice, the hematologic effects of the MHb-forming compound p-aminopropiophenone (PAPP), and two structurally-related p-aminophenones, p-aminoheptanoylphenone (PAHP) and p-aminooctanoylphenone (PAOP). Although these three p-aminophenones have been shown previously to be efficacious as pretreatments against CN, a more complete understanding of their hematologic effects is lacking. In addition, because the active form of PAPP has been shown to be its N-hydroxy metabolite, the N-hydroxy metabolites of PAPP, PAHP and PAOP were 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 (NaNO(2)) 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 capacity of the blood, such as, oxygen saturation and oxyhemoglobin decreased. In general, the effects of PAHP and PAOP were longer lasting than those of PAPP and NaNO(2). Furthermore, PAPP and NaNO(2) were equally effective with either route of administration. Conversely, PAHP and PAOP showed larger effects when administered i.p. versus i.m. The animals treated with N-hydroxy metabolites of the p-aminophenones also showed similar changes in the hematological parameters measured. N-hydroxy PAPP was shown to be the most rapidly acting MHb-forming compound examined in this series. It could achieve therapeutic concentrations of MHb within 2 min and thus may be considered as a treatment for CN intoxication. Although additional work is needed, these data provide information that will be useful for the successful development of improved anti-CN MHb formers.

Successful pretreatment/therapy of soman, sarin and VX intoxication.

Chemical pretreatment is effective against a 2 LD50 challenge of soman, sarin or VX or a 5 LD50 challenge of tabun. Chemical pretreatment followed by post challenge therapy should be effective against greater levels of agent. Such tests in guinea pigs are reported here; pretreatment regimens (PRGs) consisted of physostigmine (0.15 mg/kg, im) and an adjunct. The adjuncts [mg/kg, im] used were aprophen [8], atropine (AT)[16], azaprophen (AZA)[5], benactyzine [1.25], benztropine (BT) [4], scopolamine [0.08] and trihexyphenidyl [2]. Pretreatment was given 30 min before, and atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) therapy (T) at one min after, 5 LD50s of agent. Results indicate that, all of the PRG+T regimens, except BT-not tested with T, prevent lethality by soman; trihexyphenidyl and scopolamine (the only adjuncts used therein) regimens each prevent lethality by sarin and VX. Against soman, all PRG+T regimens (vs PRG only) may shorten the median recovery time to 2 hrs or less. Even without therapy, the PRGs containing AT, AZA or BT prevent lethality by 5 LD50s of soman; however, used alone, only the PRG containing AZA reduces the incidence of convulsions at this level of soman.

Protection from lethality and behavioral incapacitation resulting from intoxication by soman (pinacolyl methylphosphonofluoridate) and treatment with atropine sulfate and 2-PAM chloride in the guinea pig, cavia porcellus.

The lethal and incapacitating effects of the toxic organophosphorus (OP) agent, soman were evaluated in guinea pigs. The protective effects of the standard therapies atropine sulfate (ATR) and pralidoxime chloride (2-PAM) in minimizing or reducing soman-produced lethality and incapacitation (evaluated using a modification of the rat conditioned avoidance procedure) were also studied. At 0.75 and 1.5 LD50 soman was extremely toxic and fast-acting; its effects appeared within five minutes, and its lethal effects occurred within the first three hours. Therapeutic combinations of ATR (64 or 128 mg/kg) and 2-PAM (25 or 100 mg/kg) protected animals from the lethality of soman, but not from its incapacitating effects. However, therapeutic treatment with ATR and 2-PAM also produced a behavioral toxicity in its own right, an effect which lasted for at least three hours in the guinea pig. This behavioral toxicity was lessened by reducing ATR dosage from 128 to 64 mg/kg, but 2-PAM dosage did not influence the behavioral toxicity of the treatment combinations within the range of dosages studied.