The protective action of 1,2,3,4-tetrahydro-9-aminoacridine (THA) against acute
diisopropylfluorophosphate (
DFP) intoxication was evaluated in mice by measuring the effects of the pretreatment of the animals with various doses of the
drug on the
DFP LD50. In the same experiments, the action of
physostigmine and
pyridostigmine were compared. THA at the doses 2.5, 5 and 7.5 mg/kg injected subcutaneously 15 min before
DFP caused a dose-dependent increase in the
DFP LD50, resulting in protection ratios equal to 3, 3.1 and 4.4, respectively, in the absence of
atropine and 4.5, 8.6 and 14.5, respectively, in the absence of
atropine and 4.5, 8.6 and 14.5, respectively, in the presence of
atropine sulfate (17.4 mg/kg)
therapy. Under the same experimental conditions, the protective ratios of 0.1 mg/kg
physostigmine and
pyridostigmine were 2.2 and 1.3, respectively, without
atropine and 11.0 and 12.2, respectively, with
atropine. The effectiveness of THA antidotal effect was inversely correlated to the time between pretreatment and
DFP administration, being maximal when THA was injected 15 min before
poisoning. In separate experiments, the time-course of
acetylcholinesterase (AChE; EC 3.1.1.7) activity recovery was evaluated in the whole brain and diaphragm tissues of mice pretreated with THA (5 mg/kg) and
physostigmine (0.1 mg/kg) 15 min before
poisoning with
DFP (8 mg/kg).
At 10 min after
DFP administration residual AChE activity in the brain averaged 4, 25 and 15% of that in controls in the animals pretreated with
atropine alone,
atropine plus THA or
atropine plus
physostigmine, respectively. At 24 h after
poisoning, brain AChE activity averaged 34 and 47% of that in controls in the mice protected by THA and
physostigmine, respectively. As for the diaphragm, AChE activity in THA-pretreated animals was 29% of controls 10 min after
poisoning versus 8 and 23% in unprotected and
physostigmine-pretreated animals, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)