title: Intoxications with anticholinesterases: effect of different combinations of antidotes on the dynamics of acetylcholine in mouse brain.
abstract: Intoxications with organophosphorus compounds are normally treated with a mixture of atropine and an enzyme regenerating oxime. The addition of diazepam to the conventional drug therapy is reported to greatly improve the antidotal effect. The implication of the cholinergic system in such intoxications prompted us to study the effect of different combinations of antidotes on the acetylcholine (ACh) synthesizing system in mouse brain in vivo. The antidotes studied in this paper are diazepam, HI-6 and 1-hyoscyamine, the active enantiomer of atropine. Diazepam decreases the synthesis rate of ACh both when administered separately and in combination with 1-hyoscyamine and HI-6. This is in contrast to 1-hyoscyamine which, in addition to blocking muscarinic receptors, also increases the release and rate of synthesis of ACh, which probably is an unfavourable effect of the antidote. This might at least partly explain the advantage of combining 1-hyoscyamine and an oxime with diazepam in intoxications with anticholinesterases. Mice administered soman (0.75 x LD50), after pretreatment with the three-drug combination of antidotes, show no cholinergic symptoms despite a 50% increase in endogenous ACh. The rate of synthesis of ACh in these mice is in the same range as in animals administered diazepam alone. Mice administered the same dose of soman with no antidotal pretreatment suffer from severe tremor and salivation, and have a strongly reduced synthesis rate of ACh.
authors.affiliation: Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Nordgren
authors.forename: B
authors.initials: B
authors.lastname: Karlén
authors.forename: M
authors.initials: M
authors.lastname: Kimland
authors.forename: L
authors.initials: L
authors.lastname: Palmér
authors.forename: B
authors.initials: B
authors.lastname: Holmstedt
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D010091:Oximes; D011041:Poisoning / Q000188:drug therapy; D011726:Pyridinium Compounds / Q000494:pharmacology; D012999:Soman / Q000506:poisoning
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; C022870:asoxime chloride; D000109:Acetylcholine; D003975:Diazepam