Protection efficacy of continuous prophylactic administration of physostigmine and scopolamine against sarininduced toxicity was evaluated previously in guinea pigs. The present study in large animals used Beagle dogs, that serve as an animal model with cholinergic sensitivity similar to that of humans. Pretreatment with physostigmine salicylate and scopolamine hydrochloride at dose rates of 2.5 and 1 ยตg kg -1 h -1 , respectively, was administered via Alzet mini-osmotic pumps. At the time of exposure, the physostigmine salicylate concentration in plasma was 0.7 ng ml -1 and the scopolamine hydrochloride concentration was ca. 0.2 ng ml -1 , both of which are levels known to be well tolerated in humans. Whole-blood cholinesterase inhibition was 15-20%. This regimen conferred full protection against 2.5 ร LD 50 i.v. of sarin. Albeit the high-dose exposure, cholinergic toxicity symptoms were mild with no convulsions. About 11-14 min following poisoning the treated animals started to walk and 15-20 min following exposure full recovery was observed and the dogs behaved normally. With higher dose rates of physostigmine salicylate and scopolamine hydrochloride, at plasma concentrations of 2.1 and 0.6 ng ml -1 , respectively, treated dogs regained normal posture 6-10 min after exposure. Copyright ๏ 2001 John Wiley & Sons, Ltd.
Methods
Scopolamine hydrochloride and physostigmine salicylate were purchased from Sigma Chemical Co. Ltd, UK. An Alzet mini-osmotic pump (model 2001, Palo Alto, CA, USA) were used for drug delivery over 48 h. Beagle dogs (12-14 kg; male) were acquired from Marshal, USA. Rompun solution (2%) was used for anaesthesia (Bayer,