In vitro detoxification of cyclosarin (GF) by modified cyclodextrins

Elimination kinetics and molecular reaction mechanisms of cyclosarin (GF) by an oxime substituted β-cyclodextrin derivative in vitro

“…This fact supports the notion that some part of the GF may remain to be bound to 6-OxP-CD, for example, non-covalently as a molecular (inclusion) complex, which must be stable enough not to release GF during hexane extraction but does not survive the electrospray ionization process used for 6-OxP-CD quantification. In this context, the analogy to molecular complex formation of GF with organophosphate hydrolases (OPH) in plasma as intermediary step to GF degradation should be emphasized (Kranawetvogl et al, 2013;Müller et al, 2011;Reiter et al, 2014). Alternatively, GF could also remain bound to 6-OxP-CD in the form of the phosphonates detected mass spectrometrically as 6-OxP-CD conjugates.…”

“…A relatively new therapeutic approach focuses on fast high-affine binding (stoichiometric elimination) and/or decomposition (catalytic or stoichiometric) of OPs as soon as they are available in the systemic circulation (Müller et al, 2011, Zengerle et al, 2011. Stoichiometric binding by proteins like butyrylcholinesterase (BChE) or catalytic degradation by phosphotriesterases (PTE, e.g.…”

“…The potential of substituted CDs for therapy of OP intoxication was first mentioned by Saint-André, 1986 and1987). Later, systematic pharmacological studies were performed to introduce substituted CDs as a potential novel antidote class and a basis for new screening methods (Müller et al, 2011).…”

“…aldoximes, ketoximes, hydroxamates, iodosobenzyl partial structures) were synthesized and their impact on GF detoxification was investigated (Brandhuber et al, 2012, Kalakuntla et al, 2013Müller et al, 2011, Zengerle et al, 2011. Up to now, the most effective OP scavenging β-cyclodextrin derivative bears an aldoxime bound to pyridinium in the six position of a glucose unit (6-(3-(hydroxyimino)methylpyridinium-1-yl)-β-cyclodextrin, 6-OxP-CD; (Bierwisch et al, 2014;Zengerle et al, 2011).…”

Simultaneous quantification of VX and its toxic metabolite in blood and plasma samples and its application for in vivo and in vitro toxicological studies

“…Calibration curves were generated for each analytical run. To investigate the degradation of VX in plasma samples heparinised human, swine, guinea pig, rabbit, rat and mice plasma was diluted 1:5 with Tris-HCl buffer pH 7.40 and was incubated with 1 M VX for up to 6 h at 37 • C. The incubation details and the sampling were carried out as described before [35] with slight modification. 200 l diluted plasma was mixed with two sodium formate buffers [2] followed by the sample preparation described in Section 2.5.…”