title: Kinetic analysis of interactions of amodiaquine with human cholinesterases and organophosphorus compounds.
abstract: Standard therapy of poisoning by organophosphorus compounds (OP) is a combined administration of an anti-muscarinic drug (e.g. atropine) and an oxime as reactivator of inhibited acetylcholinesterase (AChE). Limited efficacy of clinically used oximes against a variety of OPs was shown in numerous studies, calling for research on novel reactivators of OP-inhibited AChE. Recently, reactivation of OP-inhibited AChE by the antimalarial drug amodiaquine was reported. In the present study, amodiaquine and its interactions with human cholinesterases in presence or absence of OP nerve agents was investigated in vitro. Thereby, reversible inhibition of human cholinesterases by amodiaquine (AChE ≫ BChE) was observed. Additionally, a mixed competitive-non-competitive inhibition type of amodiaquine with human AChE was determined. Slow and partial reactivation of sarin-, cyclosarin- and VX-inhibited cholinesterases by amodiaquine was recorded, amodiaquine failed to reactivate tabun-inhibited human cholinesterases. Amodiaquine, being a potent, reversible AChE inhibitor, was tested for its potential benefit as a pretreatment to prevent complete irreversible AChE inhibition by the nerve agent soman. Hereby, amodiaquine failed to prevent phosphonylation and resulted only in a slight increase of AChE activity after removal of amodiaquine and soman. At present the molecular mechanism of amodiaquine-induced reactivation of OP-inhibited AChE is not known, nevertheless amodiaquine could be considered as a template for the design of more potent non-oxime reactivators.
authors: Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, 80937 München, Germany.
authors: Anne
authors: A
authors: Bierwisch
authors: Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, 80937 München, Germany.
authors: Timo
authors: T
authors: Wille
authors: Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, 80937 München, Germany.
authors: Horst
authors: H
authors: Thiermann
authors: Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, 80937 München, Germany. Electronic address: franzworek@bundeswehr.org.
authors: Franz
authors: F
authors: Worek
mesh_terms: D000655:Amodiaquine / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012999:Soman / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D000655:Amodiaquine; D012999:Soman
keywords: Acetylcholinesterase; Amodiaquine; Inhibition; Kinetics; Organophosphorus compounds; Reactivation