title: New modified β-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (II). In vitro detoxification of cyclosarin (GF): general screening and toxicokinetic aspects of OP scavengers.
abstract: As standard therapy of intoxication with organophosphorus (OP) compounds is still insufficient, developing new treatment strategies is urgently required. For evaluating potential of OP detoxification of several compounds correctly, different toxicodynamic impact of OP enantiomers has to be considered thoroughly. It has already been demonstrated that β-cyclodextrin (β-CD) derivatives with attached nucleophilic substituent iodosobenzoic acid (IBA) can be regarded as potent OP scavengers due to an accelerating effect on decay of different OP. Herein, six CD derivatives permethylated or not on CD torus as well as differently attached nucleophilic substituent IBA derivative were investigated regarding detoxification of GF as an OP model substance. Acceleration of GF detoxification could be detected for all compounds with highest rate constants for propylene chain linked nucleophilic substituents on CD derivative. In addition, fast initial binding of GF on CD could be observed and is ascribed to formation of CD complexes. Furthermore, terminal plateau phase was detected of about 1% of each enantiomer reflecting the necessity of a quantitative determination at low concentrations. Moreover, this molecular depot formation may represent an additional detoxification pathway for OP.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: François
authors.initials: F
authors.lastname: Estour
authors.forename: Raman Kumar
authors.initials: RK
authors.lastname: Kalakuntla
authors.forename: Romain
authors.initials: R
authors.lastname: Le Provost
authors.forename: Olivier
authors.initials: O
authors.lastname: Lafont
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Georg
authors.initials: G
authors.lastname: Reiter
mesh_terms: D002619:Chemical Warfare Agents / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D047392:beta-Cyclodextrins / Q000493:pharmacokinetics*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D047392:beta-Cyclodextrins; C053914:cyclohexyl methylphosphonofluoridate