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Pretreatment for acute exposure to diisopropylfluorophosphate: in vivo efficacy of various acetylcholinesterase inhibitors
Author(s) -
Lorke Dietrich E.,
Hasan Mohamed Y.,
Nurulain Syed M.,
Shafiullah Mohamed,
Kuča Kamil,
Petroianu Georg A.
Publication year - 2011
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1589
Subject(s) - tacrine , pharmacology , pyridostigmine , acetylcholinesterase , in vivo , chemistry , antidote , cholinesterase , physostigmine , aché , pyridostigmine bromide , medicine , toxicity , acetylcholine , biochemistry , enzyme , biology , myasthenia gravis , microbiology and biotechnology , organic chemistry
Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors before exposure to organophosphorus compounds (OPCs) can reduce OPC‐induced mortality. Pyridostigmine is the only FDA‐approved substance for such use. The AChE‐inhibitory activity of known AChE inhibitors was quantified in vitro and their in vivo mortality‐reducing efficacy was compared, when given prophylactically before the exposure to the OPC diisopropylfluorophosphate (DFP). The IC 50 was measured in vitro for the known AChE inhibitors pyridostigmine, physostigmine, ranitidine, tiapride, tacrine, 7‐methoxytacrine, amiloride, metoclopramide, methylene blue and the experimental oxime K‐27. Their in vivo efficacy, when given as pretreatment, to protect rats from DFP‐induced mortality was quantified by determining the relative risk of death (RR) by Cox analysis, with RR = 1 for animals given only DFP, but no pretreatment. Physostigmine was the strongest in vitro AChE‐inhibitor (IC 50 = 0.012 µ m ), followed by 7‐methoxytacrine, tacrine, pyridostigmine and methylene blue. Ranitidine (IC 50 = 2.5 µ m ), metoclopramide and amiloride were in the mid‐range. Tiapride (IC 50 = 256 µ m ) and K‐27 (IC 50 = 414 µ m ) only weakly inhibited RBC AChE activity. Best in vivo protection from DFP‐induced mortality was achieved when physostigmine (RR = 0.02) or tacrine (RR = 0.05) was given before DFP exposure, which was significantly superior to the pretreatment with all other tested compounds, except K‐27 (RR = 0.18). The mortality‐reducing effect of pyridostigmine, ranitidine and 7‐methoxytacrine was inferior, but still significant. Tiapride, methylene blue, metoclopramide and amiloride did not significantly improve DFP‐induced mortality. K‐27 may be a more efficacious alternative to pyridostigmine, when passage into the brain precludes administration of physostigmine or tacrine. Copyright © 2010 John Wiley & Sons, Ltd.