title: Pralidoxime and l-lactate effects in vitro on the inhibition of acetylcholinesterase by paraoxon: pralidoxime does not confer superior protection.
abstract: Intoxication with the organophosphorus compound paraoxon (POX), an inhibitor of serine hydrolases, is frequent. Although oximes are the only enzyme reactivators presently available, clinical experience with their use was rather disappointing. Recent work has shown that under certain conditions l-lactate is also able to reduce in vitro the POX inhibition of butyrylcholine- and acetylcholineesterase (BChE and AChE). To assess the practical relevance, if any, of these findings, the protective effects of pralidoxime (PRX) and those of lactate had to be compared in the same in vitro model. Effects of PRX on the inhibition of AChE by POX were assessed in vitro in plasma of 12 (six male and six female) healthy human volunteers. The determinations were repeated using different oxime and different POX concentrations. The AChE activity determinations were performed using the following sampler: sample BL-baseline (or untreated plasma); sample a-after addition of POX to plasma (pl + POX); sample b-after POX and plasma were incubated and then oxime was added (pl + POX/PRX); sample c-after addition of oxime to plasma (pl + PRX); sample d-after oxime and plasma were incubated and then POX was added (pl + PRX/POX); sample e-after oxime and POX were incubated and then added to plasma (PRX + POX/pl). Results were corrected for spurious enzyme 'pseudo-activity' due to interaction between PRX and substrate (acetylthiocholine) in the absence of enzyme. In the micro- and millimolar ranges, PRX is able to protect in vitro AChE from inhibition by POX when added to human plasma prior to POX or when incubated with POX prior to addition to plasma. Adding PRX to plasma after POX has no protective effect. The PRX results were compared statistically with historical lactate data (obtained under identical conditions) using the Wilcoxon matched pairs test, with significance assumed for p = 0.01. No difference between PRX and lactate's protective effect on the AChE inhibition by POX was found in the in vitro model used. We therefore conclude that in vivo testing of lactate as a POX protective agent is warranted.
authors.affiliation: University of Heidelberg at Mannheim, Department of Pharmacology and Toxicology, Maybach Street 14-16, 68169 Mannheim, Germany. petroia@rumms.uni-mannheim.de
authors.forename: G
authors.initials: G
authors.lastname: Petroianu
authors.forename: C
authors.initials: C
authors.lastname: Roth
authors.forename: U
authors.initials: U
authors.lastname: Beha
authors.forename: J
authors.initials: J
authors.lastname: Fisher
authors.forename: W
authors.initials: W
authors.lastname: Bergler
authors.forename: R
authors.initials: R
authors.lastname: Rüfer
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D010261:Paraoxon / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D011220:Pralidoxime Compounds; D019344:Lactic Acid; D000110:Acetylcholinesterase; C028797:pralidoxime; D010261:Paraoxon