Continuous Administration of Low Dose Rates of Physostigmine and Hyoscine to Guinea-pigs Prevents the Toxicity and Reduces the Incapacitation Produced by Soman Poisoning

Abstract— A regime was developed, using mini-osmotic pumps, for the continuous subcutaneous administration of low doses of physostigmine (12.1, 9.7, 4.85 and 2.43 μgh^?1), in combination with hyoscine (1.94 or 0.39 μg h^?1), to guinea-pigs for up to 13 days. Physostigmine, in combination with hyoscine, inhibited plasma Cholinesterase, and red blood cell and brain acetylcholinesterase, in a concentration-dependent manner, did not affect the normal growth rate of guinea-pigs, and produced no obvious signs of poisoning. A dose rate of 4.85 μg h^?1 physostigmine and 1.94 μg h^?1 hyoscine was required to inhibit red cell acetylcholinesterase by 30% and brain acetylcholinesterase by 5–15%, with an accompanying plasma hyoscine concentration of 700–850 pg mL^?1. There was an apparent decline in red cell acetylcholinesterase activity during the 13 days. Hyoscine levels were higher in the cholinergic-rich areas of the brain than in the plasma. Continuous pretreatment (1 or 6 days) with physostigmine (4.84 μg h^?1) and hyoscine (1.94 μg h^?1) provided complete protection against the lethal effects, and minimized the incapacitation and weight loss produced by soman at a dose equivalent to the LD99 value. Following soman challenge, guinea-pigs exhibited early signs of soman poisoning, but generally these signs of poisoning were minimal by 1–2 h. Extending the pretreatment time to 13 days protected 75% of the guinea-pigs against the lethal effects of soman poisoning. Red cell acetylcholinesterase activity, 24 h after soman poisoning, was higher following continuous pretreatment with physostigmine and hyoscine than after acute treatment with atropine.