Detoxification of nerve agents by a substituted beta-cyclodextrin: application of a modified biological assay.
Chemical warfare agents (nerve agents) are still available and present a real threat to the population. Numerous in vitro and in vivo studies showed that various nerve agents, e.g. tabun and cyclosarin, are resistant towards standard therapy with atropine and oxime. Based on these facts we applied a modified biological assay for the easy, semi-quantitative testing of the detoxifying properties of the beta-cyclodextrin derivative CD-IBA. Cyclosarin, sarin, tabun and VX were incubated with CD-IBA for 1-50 min at 37 degrees C, then an aliquot was added to erythrocyte acetylcholinesterase (AChE) and the percentage of AChE inhibition was determined. The validity of the assay was confirmed by concomitant quantification of tabun by GC-MS. Different concentrations of cyclosarin were detoxified by CD-IBA in a concentration-dependent velocity. The ability to detoxify various nerve agents decreased in the order cyclosarin>sarin>tabun>>VX. Hereby, no detoxification of VX could be detected. Sarin was detoxified in a biphasic reaction with a fast reduction of inhibitory potential in the first phase and a slower detoxification in the second phase. CD-IBA detoxified tabun in a one phase decay and, compared to cyclosarin and sarin, a longer half-life was determined with tabun. The modified biological assay is appropriate for the initial semi-quantitative screening of candidate compounds for the detoxification of nerve agents. The beta-cyclodextrin derivative CD-IBA demonstrated its ability to detoxify different nerve agents.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
T
T
Wille
O
O
Tenberken
G
G
Reiter
S
S
Müller
R
R
Le Provost
O
O
Lafont
F
F
Estour
H
H
Thiermann
F
F
Worek
D000110:Acetylcholinesterase / Q000378:metabolism; D001681:Biological Assay; D002021:Buffers; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004910:Erythrocyte Membrane / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000633:toxicity; D012015:Reference Standards; D015203:Reproducibility of Results; D012524:Sarin / Q000737:chemistry / Q000633:toxicity; D013997:Time Factors; D047392:beta-Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology*
D000110:Acetylcholinesterase; D002021:Buffers; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D012524:Sarin; D047392:beta-Cyclodextrins; C545481:2-O-(3-carboxyl-4-iodosobenzyl)-beta-cyclodextrin; C009680:VX-agent; C031215:betadex; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate