Protection against diisopropylfluorophosphate intoxication by pyridostigmine and physostigmine in combination with atropine and mecamylamine

Abstract

Atropine (A), mecamylamine (M), pyridostigmine (Py) and physostigmine (Ph) are pretreatment components of Mix I (A=0.79, M=0.79, Py=0.056 mg/kg) and Mix II (A=0.79, M=0.79, Ph=0.026 mg/kg). They have been successfully used in antagonizing Soman intoxication in experimental animals. Rats were pretreated with either Mix I or Mix II and subsequently exposed to diisopropylfluorophosphate (DFP). Pretreatment with Mix I or Mix II (i.m.) 30 min before DFP (i.v.) protected rats from the lethal effects of DFP. The protective ratios were 2.8 (Mix I) and 6.9 (Mix II). Changes in brain levels of acetylcholine (ACh) were measured to help understand the basis for effectiveness of these pretreatments. In the absence of DFP, pretreatments had no significant (P>0.05) effect on bound or free ACh. Pretreatment did not prevent the DFP-induced rise in bound and free ACh nor the agentinduced physical incapacitation at 30 min post exposure. At 2 h after DFP exposure, rats pretreated with Mix II, but not Mix I, showed significant recovery from signs of physical incapacitation. At 30 min after the administration of 3.3 mg/kg of DFP (i.v.), the levels of free and bound ACh in rats given Mix I or Mix II pretreatment increased above control levels by 705% and 116% and 120% and 43%, respectively. By 2 h after DFP, cerebral ACh levels had changed to 437% and 91% with Mix I pretreatment and 26% and 50% with Mix II pretreatment. These data suggest a correlation between DFP-induced increases in the levels of cerebral ACh, possibly free, and physical incapacitation. The reversal of DFP-induced physical debilitation as well as enhanced protection against lethality by Mix II appears to be related to the central actions of physostigmine.