Effect of carboxylesterase inhibition on carbamate protection against soman toxicity.
The ability of the carbamates pyridostigmine and physostigmine to protect against the lethal effects of soman, an extremely toxic anticholinesterase agent, was measured in rats, guinea pigs and rabbits. Pharmacologically equivalent doses of these carbamates that inhibited 70% of the blood acetylcholinesterase in each species were injected i.m. 25 min before s.c. injection with soman. Pretreatment with either carbamate, in combination with 17.4 mg/kg of atropine, produced protection against soman toxicity in all species. When protection was expressed as the ratio between the soman LD50 values in carbamate-protected animals and control animals, this protective ratio varied 3-fold between species (2.1-6.1 for pyridostigmine; 2.2-6.6 for physostigmine). When protection was expressed as the difference in the soman LD50 values between carbamate-protected animals and control animals, this protective difference was consistent among species (126 +/- 19 micrograms/kg). Species variation in protective ratios was observed largely because the control LD50 values defining soman toxicity in unprotected animals varied among species (20 micrograms/kg in rabbits, 28 micrograms/kg in guinea pigs and 126 micrograms/kg in rats). The species variation of the soman LD50 values in control animals was eliminated by pretreating animals with cresylbenzodioxaphosphorin oxide, which reduced the species variation in soman detoxification. The LD50 values for soman in cresylbenzodioxaphosphorin oxide-treated animals (9.8-15.6 micrograms/kg) did not differ significantly between species. Similarly, protective ratios for carbamates against soman in cresylbenzodioxaphosphorin oxide-treated animals were also clustered in a narrow range (8.5-11.4 for pyridostigmine; 9.0-13.4 for physostigmine) that did not differ significantly, regardless of species or carbamate.(ABSTRACT TRUNCATED AT 250 WORDS)
United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.
D M
DM
Maxwell
K M
KM
Brecht
D E
DE
Lenz
B L
BL
O'Neill
D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology*; D011729:Pyridostigmine Bromide / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000633:toxicity*
D009943:Organophosphorus Compounds; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D012999:Soman; D010830:Physostigmine; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide