The acute toxicity of organophosphorus (OP) compounds in mammals is due to their irreversible inhibition of
acetylcholinesterase (AChE) in the nervous system, which leads to increased synaptic
acetylcholine levels. The protective actions of intravenously (i.v.) administered
pyridostigmine,
physostigmine,
eptastigmine, and an
organophosphate hydrolase,
phosphotriesterase, in acute
sarin intoxication were studied in mice. The acute intragastric (i.g.) toxicity (LD50) of
sarin with and without the pretreatments was tested by the up-and-down method. The mice received
pyridostigmine (0.06 mg/kg
body weight),
physostigmine (0.09 mg/kg
body weight), the
physostigmine derivative
eptastigmine (0.90 mg/kg
body weight) or
phosphotriesterase (104 U/g, 10.7 microg/g
body weight) 10 min prior to the i.g. administration of
sarin.
Physostigmine was also administered with
phosphotriesterase.
Phosphotriesterase was the most effective
antidote in
sarin intoxication. The LD50 value for
sarin increased 3.4-fold in mice receiving
phosphotriesterase.
Physostigmine was the most effective
carbamate in
sarin exposure. The protective ratios of
physostigmine and
pyridostigmine were 1.5- and 1.2-1.3-fold, respectively.
Eptastigmine did not give any protection against
sarin toxicity. Both the
phosphotriesterase and
physostigmine treatments protected the brain AChE activities measured 24 h after
sarin exposure. In
phosphotriesterase and
physostigmine-treated mice, a 4- and 2-fold higher
sarin dose, respectively, was needed to cause a 50% inhibition of brain AChE activity. Moreover, the combination of
phosphotriesterase-
physostigmine increased the LD50 value for
sarin 4.3-fold. The animals pretreated with
phosphotriesterase-ephysostigmine tolerated four times the lethal dose in control animals, furthermore their survival time was 2-3 h in comparison to 20 min in controls. In conclusion,
phosphotriesterase and
physostigmine were the most effective treatments against
sarin intoxication. However,
eptastigmine did not provide any protection against
sarin toxicity.