title: Kinetic prerequisites of oximes as effective reactivators of organophosphate-inhibited acetylcholinesterase: a theoretical approach.
abstract: The standard treatment of poisoning by organophosphorus compounds (OP) includes the reversible muscarine receptor antagonist atropine and oximes for the reactivation of OP-inhibited acetylcholinesterase (AChE). There is an ongoing discussion on the benefit of oxime therapy in OP pesticide poisoning, and experimental data indicate a limited efficacy of oximes against various nerve agents. Oxime effectiveness can be quantified in vitro by determination of the reactivity (k(r)) and affinity constants (1/K(D)). These constants can be used to calculate reactivation velocities and oxime concentrations necessary for the reactivation of a desired fraction of inhibited AChE. Model calculations indicate that a k(r) > 0.1 min(-1) and K(D) < 100 µM are minimal requirements for oxime effectiveness when reactivation is performed in the absence of free OP. In addition, the findings demonstrate that selective increase of either reactivity or affinity of an oxime would be insufficient. Hereby, it has to be taken into account that an increase of affinity to OP-inhibited AChE is generally accompanied by an increased affinity to native AChE and subsequent reduction in oxime tolerance. Hence, future developments of more effective oximes should consider kinetic demands by attempting to achieve a certain level of reactivity and affinity, preferentially towards OP-inhibited AChE.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. franzworek@bundeswehr.org
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Nadine
authors.initials: N
authors.lastname: Aurbek
authors.forename: Timo
authors.initials: T
authors.lastname: Wille
authors.forename: Peter
authors.initials: P
authors.lastname: Eyer
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D000110:Acetylcholinesterase