Assessment of false transmitters as treatments for nerve agent poisoning.

Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.

Assessment of the therapeutic and anticonvulsive efficacy of a drug combination consisting of trihexyphenidyle and HI-6 in soman-poisoned rats.

1. The influence of two anticholinergic drugs (atropine, trihexyphenidyle) on the effectiveness of antidotal treatment to eliminate soman-induced lethal effects and convulsions was studied in rats. 2. The oxime HI-6 when combined with centrally acting anticholinergic drug trihexyphenidyle seems to be more efficacious in the elimination of acute toxic effects of soman than its combination with atropine. 3. The findings support the hypothesis that the choice of the anticholinergic drug is important for the effectiveness of antidotal mixture in the case of antidotal treatment of soman-induced acute poisoning.

Assessment of motor performance decrement following soman poisoning in mice.

A simple motor performance test, the inverted screen test, was used to assess the incapacitating effects of soman in mice and to evaluate the effectiveness of carbamate pretreatment and/or treatment with atropine plus 2-PAM on soman-induced debilitation. The test requires minimal equipment and personnel training, and can be done rapidly on untrained animals. Mice were placed individually on wire mesh screens which were horizontally mounted on a metal rod. The rod was rotated 180 degrees so that the mice were oriented upside down on the bottom of the screen. The animals were observed for their ability to climb to the top of the screen within one minute. Mice exhibited significant disruption of performance on the screen test 24 hours after soman doses of 0.71 LD50 or more. Treatment with atropine and 2-PAM i.m. 10 sec post-soman (1.1 x LD50) did not improve screen test performance when measured at 24 hours. Pretreatment with pyridostigmine or physostigmine in combination with post-soman therapy with atropine and 2-PAM significantly improved screen test performance as early as 2 hours after soman. The results suggest that the inverted screen test may be useful as a first-line assessment of the efficacy of pretreatment and treatment compounds against nerve agent-induced incapacitation.