Evaluation of the toxicity, pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys

Abstract

Cyclohexylmethylphosphonofluoridate (CMPF) is an organophosphate cholinesterase inhibitor with military significance. The purpose of these studies was 1) to determine the acute toxicity of CMPF in the male rhesus monkey, 2) to evaluate the efficacy of pyridostigmine (PYR) pretreatment plus atropine and oxime (2-PAM or H16) treatment, and 3) to evaluate the pathological consequences of acute poisoning. An i.m. LD50 of CMPF was estimated using an up-and-down dose selection procedure and 12 animals. The 48-h and 7-day LD50 was 46.6 micrograms/kg, i.m. In the protection experiments, pyridostigmine (0.3-0.7 mg/kg/24 h) was administered by surgically implanted osmotic minipumps for 3-12 days resulting in 21-65% inhibition of erythrocyte acetylcholinesterase activity. Animals were challenged with 5 x L50 CMPF (233 micrograms/kg) and treated with atropine (0.4 mg/kg) and either 2-PAM (25.7 mg/kg) or HI6 (37.8 mg/kg) at the onset of signs or 1 min after challenge. Osmotic pumps were removed within 30 min after agent challenge. Pyridostigmine, atropine, and either 2-PAM or H16 were completely effective against CMPF, saving ten of ten animals in each group. In comparison, three of five animals challenged with 5 x LD50 of soman and treated with atropine and 2-PAM survived 7 days. The primary histologic lesions in the acute toxicity group were neuronal degeneration/necrosis and spinal cord hemorrhage. The CMPF treated groups (total of 20 animals) had minimal nervous system changes with no significant lesion difference resulting from the different oxime therapies. The primary non-neural lesions were degenerative cardiomyopathy and skeletal muscle degeneration which occasionally progressed to necrosis and mineralization.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed Neurologic and Behavioral Effects of Subtoxic Doses of Cholinesterase Inhibitors

“…The mechanism of this protection seems to be the preoccupation by the carbamate of ChE reactive sites, which become unavailable to the OP ChE inhibitor, with subsequent restoration of enzymatic activity due to the reversible decarbamylation of ChE. This phenomenon is the basis for the use of PB as a prophylactic of nerve agent intoxication (Dirnhuber et al, 1979;Leadbeater et al, 1985;Kluwe et al, 1987;Keeler et al, 1991;Koplovitz et al, 1992). The therapeutic target for this application of PB has been to maintain inhibition of plasma butyrylcholinesterase (BuChE) between 20 and 40%.…”

Effectivity of New Acetylcholinesterase Reactivators in Treatment of Cyclosarin Poisoning in Mice and Rats

“…On the other hand, equimolar dosing of oximes is useful when in vitro and in vivo results should be compared. Although cyclosarin is an extremely strong inhibitor of human AChE and butyrylcholinesterase (EC 3.1.1.8) and has obviously an even higher potency than the nerve agent soman 9 , in vivo, cyclosarin is less toxic than soman in several species, including non-human primates 10 , indicating different toxicokinetic behaviour. It was already shown that intoxications with cyclosarin are rather resistant to convential oxime therapy 9 .…”

Interactions of Subsymptomatic Doses of Sarin with Pyridostigmine - Neurochemical, Behavioral, and Physiological Effects

“…The mechanism of this protection appears to be the pre-occupation by the carbamate of ChE reactive sites, which become unavailable to the OP ChE inhibitor, with subsequent restoration of enzymatic activity due to the reversible decarbamylation of ChE. This phenomenon is the basis for the use of PB as a prophylactic of nerve agent intoxication Leadbeater et al, 1985;Koplovitz et al, 1992;. The therapeutic target for this apphcation of PB has been to maintain inhibition of plasma butyrylcholinesterase (BuChE) between 20% to 40%.…”

“…The carbamate ChE inhibitor pyridostigmine bromide (PB) has been fielded as a prophylactic treatment against OP ChE inhibitors by the US Armed Forces and used in the Persian Gulf War ; (Leadbeater et al, 1985); (Koplovitz et al, 1992); ; . Although acute intoxication with OP ChE inhibitors and the protective effect of PB on this phenomenon have been extensively studied in animals ; (Sidell, 1974); , the potential long term harmful effects of low level (subsymptomatic) exposure to OP ChE inhibitors, alone or in combination with PB have received little attention.…”

“…Caibamate cholinesterase inhibitors provide additional protection, when used as pretreatment, from exposure to soman and tabun than that afforded by atropine and oxime alone (Leadbeater et al 1985) (Koplovitz et al, 1992) . On the basis of these findings, the quaternary cholmesterase inhibitor pyridostigmine bromide (PB) was adopted by USA and NATO armies as wartime pretreatment adjunct for nerve agent exposure.…”