title: Effectiveness of a substituted β-cyclodextrin to prevent cyclosarin toxicity in vivo.
abstract: Standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and an oxime has a limited efficacy. An alternative approach is the development of stoichiometric or catalytic (bio-)scavengers which should be able to prevent systemic toxicity. Recently, a β-cyclodextrin derivative, 6-OxP-CD, bearing a pyridinium oximate in 6-position of one glucose unit was synthetized and shown to possess a promising detoxification potential against a variety of alkyl methylfluorophosphonates in vitro. In order to investigate the suitability of 6-OxP-CD as a small molecule scavenger an in vivo guinea pig model was established to determine the protective effect of 6-OxP-CD against the highly toxic nerve agent cyclosarin. Prophylactic i.v. injection of 6-OxP-CD (100mg/kg) prevented systemic toxicity in cyclosarin (∼2LD50) poisoned guinea pigs, preserved brain acetylcholinesterase (AChE) activity but did not protect erythrocyte AChE activity. A lower 6-OxP-CD dose (50mg/kg) reduced systemic toxicity and prevented mortality in all animals. Thus, the results of this proof of concept study indicate that 6-OxP-CD may be considered as a potential small molecule scavenger to protect against the toxic effects of a range of highly toxic OP nerve agents.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. Electronic address: franzworek@bundeswehr.org.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seeger
authors.affiliation: Fachbereich Chemie - Organische Chemie, Technische Universität Kaiserlautern, Kaiserslautern, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zengerle
authors.affiliation: Fachbereich Chemie - Organische Chemie, Technische Universität Kaiserlautern, Kaiserslautern, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubik
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Wille
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D019610:Cytoprotection; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006168:Guinea Pigs; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D062025:Organophosphate Poisoning / Q000201:enzymology / Q000517:prevention & control*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D013997:Time Factors; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D047392:beta-Cyclodextrins; D000110:Acetylcholinesterase; C053914:cyclohexyl methylphosphonofluoridate
keywords: Cyclodextrin; Detoxification; Nerve agents; Protection; Small molecule scavenger