Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review.

Organophosphorus compounds (OPCs), inhibitors of acetylcholinesterase (AChE), are useful agents as pesticides, but also represent a serious health hazard. Standard therapy with atropine and established oxime‐type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. Better therapeutic results are obtained, when reversible AChE inhibitors are administered before OPC exposure. This review summarizes the history of such a pretreatment approach and sums up a set of experiments undertaken in search of compounds that are efficacious when given before a broad range of OPCs. The prophylactic efficacy of 10 known AChE inhibitors, either already used clinically for different indications (physostigmine, pyridostigmine, ranitidine, tiapride, tacrine, amiloride, metoclopramide, methylene blue) or developed for possible therapeutic use in the future (7‐methoxytacrine, K‐27) was compared, when administered before exposure to six chemically diverse OPCs in the same experimental setting: ethyl‐paraoxon, methyl‐paraoxon, diisopropylfluorophosphate, terbufos sulfone, azinphos‐methyl and dicrotophos. The experimental oxime K‐27 was the most efficacious compound, affording best protection, when administered before terbufos sulfone, azinphos‐methyl and dicrotophos, second best before ethyl‐ and methyl‐paraoxon exposure and third best before diisopropylfluorophosphate administration. This ranking was similar to that of physostigmine, which was superior to the Food and Drug Administration‐approved pretreatment for soman with pyridostigmine. Tiapride, amiloride, metoclopramide, methylene blue and 7‐methoxytacrine did not achieve protection. No correlation was observed between the IC50 of the reversible AChE inhibitors and their protective efficacy. These studies indicate that K‐27 can be considered a very promising broad‐spectrum prophylactic agent in case of imminent organophosphate exposure, which may be related to its AChE reactivating activity rather than its AChE inhibition. Organophosphorus inhibitors of acetylcholinesterase (OPCs) represent a serious health hazard. Standard oxime therapy is unsatisfactory. Reversible cholinesterase inhibitors administered before OPC exposure achieve better results. This review describes the history of such a pretreatment approach and summarizes experiments undertaken in search of compounds that are efficacious when given before a broad range of OPCs. These studies indicate that the experimental oxime K‐27 is a very promising broad‐spectrum prophylactic agent, which may be related to its AChE reactivating capacity. [ABSTRACT FROM AUTHOR]