Evaluation of the toxicity, pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys.
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)
Koplovitz
I
I
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Gresham
V C
VC
Dochterman
L W
LW
Kaminskis
A
A
Stewart
J R
JR
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000506:poisoning / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000506:poisoning / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008297:Male; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology
D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D001285:Atropine; D000110:Acetylcholinesterase; C022870:asoxime chloride; D011729:Pyridostigmine Bromide; C028797:pralidoxime; C053914:cyclohexyl methylphosphonofluoridate