Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication

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 protec tive actions of intravenously (i.v.) administered pyridostigmine, physostig mine, eptastigmine, and an organophosphate hydrolase, phosphotriesterase, i n 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 bod y weight), physostigmine (0.09 mg/kg body weight), the physostigmine deriva tive eptastigmine (0.90 mg/kg body weight) or phosphotriesterase (104 U/g, 10.7 mu g/g body weight) 10 min prior to the i.g. administration of sarin. Physostigmine was also administered with phosphotriesterase. Phosphotrieste rase was the most effective antidote in sarin intoxication. The LD50 value for sarin increased 3.4-fold in mice receiving phosphotriesterase. Physosti gmine was the most effective carbamate in sarin exposure. The protective ra tios of physostigmine and pyridostigmine were 1.5- and 1.2-1.3-fold, respec tively. Eptastigmine did not give any protection against sarin toxicity. Bo th the phosphotriesterase and physostigmine treatments protected the brain AChE activities measured 24 h after sarin exposure. In phosphotriesterase a nd physostigmine-treated mice, a 4- and 2-fold higher sarin dose, respectiv ely, was needed to cause a 50% inhibition of brain AChE activity. Moreover, the combination of phosphotriesterase-physostigmine increased the LD50 val ue for sarin 4.3-fold. The animals pretreated with phosphotriesterase-ephys ostigmine tolerated four times the lethal dose in control animals, furtherm ore their survival time was 2-3 h in comparison to 20 min in controls. In c onclusion. phosphotriesterase and physostigmine were the most effective tre atments against sarin intoxication. However, eptastigmine did not provide a ny protection against sarin toxicity. (C) 1999 Elsevier Science Ireland Ltd . All rights reserved.