Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal
effects of organophosphorus compounds (OPCs). The usefulness of pyridostigmine, the only compound approved by the
Food and Drug Administration (FDA) for such pretreatment, has been questioned. In search for more efficacious
alternatives, we have examined in vivo the efficacy of a group of ten compounds with known anti-AChE activity
(pyridostigmine, metoclopramide, tiapride, ranitidine, physostigmine, tacrine, amiloride, methylene blue, 7-
methoxytacrine and K-27) to reduce mortality induced by the OPC methyl-paraoxon. AChE inhibitors were given
intraperitoneally in equitoxic dosage (25% of LD01) 30 min before OPC exposure. Protection was quantified in rats by
determining the relative risk of death (RR) by Cox analysis, with RR=1 for animals given only methyl-paraoxon, but no
Only physostigmine (RR=0.39), K-27 (RR=0.40) and tacrine (RR=0.48) significantly (p≤ 0.05) reduced methylparaoxon-
induced mortality, when given prophylactically. Pretreatment with pyridostigmine, ranitidine, tiapride,
amiloride, metoclopramide and methylene blue did not significantly protect against the lethal effects of methyl-paraoxon.
7-methoxytacrine (7-MEOTA) significantly (p≤ 0.05) increased the relative risk of methyl-paraoxon-induced death
(RR=1.31). These results indicate that pretreatment with pyridostigmine cannot be considered a broad-spectrum approach
against OPC exposure. K-27 may be a suitable alternative if passage into the brain is contraindicated.