The relationship between oxime-induced reactivation of carbamylated acetylcholinesterase and antidotal efficacy against carbamate intoxication.
The efficacy of the oximes pyridinium-2-aldoxime methochloride (2-PAM) and 1-[[[(4-aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydro xyimino) methyl]pyridinium dichloride (HI-6), in combination with atropine (At), against lethality by either carbaryl (CA) or physostigmine (Phy) was investigated in rats. The protection by At, 8 mg/kg, iv, against CA intoxication was reduced by 2-PAM (22 mg/kg, iv) and HI-6 (50 mg/kg, iv) from a protective ratio (PR) of 6.6 to 3.5 and 2.3, respectively. However, in Phy-intoxicated rats, the administration, iv, of At alone, At + 2-PAM, or At + HI-6 at 1 min following Phy provided good protection and resulted in PRs of 7.2, 8.8, and 23.3, respectively. In experiments on decarbamylation of inhibited acetylcholinesterase (AChE), HI-6 and 2-PAM accelerated (p less than 0.05) the decarbamylation of Phy-inhibited AChE in vitro, and HI-6 decreased (p less than 0.05) the inhibition of whole blood AChE in Phy-intoxicated rats. These findings show that the protection was increased substantially by the use of either 2-PAM or HI-6 against Phy-induced lethality, whereas the use of oximes against carbaryl poisoning was contraindicated. Furthermore, even though CA and Phy are both N-methyl carbamates, the data indicate that there is no adverse interaction between 2-PAM or HI-6 and Phy.
Harris
L W
LW
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425.
Talbot
B G
BG
Lennox
W J
WJ
Anderson
D R
DR
D000110:Acetylcholinesterase / Q000097:blood*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology*; D012721:Carbaryl / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000097:blood; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004347:Drug Interactions; D004912:Erythrocytes / Q000201:enzymology*; D007928:Lethal Dose 50; D008297:Male; D010091:Oximes; D010830:Physostigmine / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D001285:Atropine; D010830:Physostigmine; D000110:Acetylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime; D012721:Carbaryl