Protection by a transdermal patch system for the prophylaxis against soman poisoning in rhesus monkey

Abstract

A transdermal patch system containing procyclidine, an N‐methyl‐D‐aspartate receptor antagonist possessing anticholinergic action, and physostigmine, a reversible cholinesterase inhibitor, was developed, and its prophylactic efficacy against soman intoxication was investigated. Male rhesus monkeys were shaved on the dorsal area, attached with a matrix‐type patch with various sizes (2 × 2 to 7 × 7 cm) for 24 or 72 hours, and challenged with 2 × LD50 doses (13 μg/kg) of soman. The smallest patch size for the protection against lethality induced by soman intoxication was 3 × 3 cm, resulting in blood procyclidine concentration of 10.8 ng/ml, blood physostigmine concentration of 0.54 ng/ml, which are much lower concentrations than maximum sign‐free doses, and blood cholinesterase inhibition of 42 %. The drug concentrations and enzyme inhibition rate corresponding to a diverging point of survivability were presumably estimated to be around 7 ng/ml for procyclidine, 0.35 ng/ml for physostigmine, and 37 % of enzyme inhibition. Separately, in combination with the patch treatment, the posttreatment consisting of atropine (0.5 mg/kg) plus 1‐[([4‐(aminocarbonyl)pyridinio]methoxy)methyl]‐2‐[(hydroxyimino)methyl]pyridinium (HI‐6, 50 mg/kg) exerted protection against 5 × LD50 challenge of soman, which means the posttreatment remarkablely augmented the efficacy of the patch. Additionally, it was found that brain injuries induced by soman toxicity were effectively prevented by the patch treatment according to histopathological examinations. These results suggest that the patch system could be an effective alternative for diazepam, an anticonvulsant, and the current pyridostigmine pretreatment, and especially in combination with atropine plus HI‐6, could be a choice for quality survival from nerve‐agent poisoning.