Direct reaction of oximes with crotylsarin, cyclosarin, or VX in vitro

Abstract

The direct reaction of seven pyridinium oximes with the organophosphorus compounds (OPCs) crotylsarin, cyclosarin, and VX was studied by spectrophotometry. This method allows to quantify diVerent parameters: (a) the half-life times (t 1/2 ) of the oxime-OPC reactions on the basis of the changes in the absorption at the zwitterion (betaine) peak maximum, (b) the Wrst-and second-order rate constants (k 1 , k 2 ), and (c) the maximum reaction velocities (v max ). The results of the study show that the reaction velocity of the nerve agents with any of the oximes investigated decreased in the order crotylsarin > cyclosarin > VX. The comparison of the reaction rates of the three therapeutically used oximes (2-PAM, obidoxime, HI 6) with the respective OPC gave the highest rate for crotylsarin and cyclosarin with obidoxime and to a similar degree with HI 6, while in the case of VX the most reactive oxime was HI 6. The reaction velocity of the nerve agents with the monopyridinium oxime 2-PAM was lower as compared to the bispyridinium oximes (obidoxime, HI 6). The results obtained with the two sarin analogues indicate that the direct reaction with 2-PAM, obidoxime, or HI 6 could be used for non-corrosive decontamination purposes, especially, if sensitive biological surfaces like skin, mucous membranes, or wounds are considered. However, in view of the concentrations of nerve agents and oximes, which could be expected during OPC poisoning in man, the maximum reaction velocities would not be high enough to contribute markedly to the detoxication of nerve agents in vivo.

Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview

“…Phosphylation of the oxime group causes characteristic electronic alterations and therefore a hypsochromic shift of λ max to shorter wavelengths 11, 12, 14, 17, 26, 27. These changes were often used to monitor formation and decomposition of POX although the difference between both maxima was often quite small (Δλ ≈ 10 nm).…”

“…Accordingly, monitoring UV‐spectra of the reaction mixture allowed to analyze the reaction of OP nerve agents (sarin, crotylsarin, cyclosarin, soman, tabun, and VX) with several mono‐ and bispyridinium oximes in morpholinopropanesulfonic acid buffer (MOPS, pH 7.4) as described by Becker et al 11, 12 Corresponding kinetics of formation and decomposition of POX were calculated without further purification and without isolation of POXs. The lack of compound separation might be disadvantageous when unexpected decomposition or byproducts interfere.…”

“…The remaining molecule represents the OP moiety coupled to the oxime and is referred as phosphylated oxime (POX) (Figure 2). 5–10 Under physiological conditions, POX can either be degraded non‐enzymatically,11, 12 hydrolyzed enzymatically by plasma enzymes,1, 13, 14 or it may re‐inhibit ChE (reverse reaction of reactivation)15 as illustrated in Figure 2. The latter inhibitory reaction results in a diminished net reactivation of AChE and may thus potentially affect the efficacy of oxime therapy.…”

Combined Pre- and Posttreatment of Paraoxon Exposure

“…Phosphylated AChE can, however, be reactivated by oximes, which are nucleophilic agents removing the phosphyl moiety from the AChE molecule [21]. Therefore, the standard therapy of OPC intoxications consists of an oxime restoring the enzymatic function of the AChE enzyme in combination with atropine blocking muscarinic receptor stimulation and a benzodiazepine controlling convulsions [19,22,23].…”

Oxime treatment for organophosphorus compound exposure: Getting it (into the brain) might not be that good for you, after all

“…One possible basis for this paradigm-offending view is the formation of phosphylated oximes, which are generated by the reaction of oximes with organophosphorus-inhibited enzymes and which can be highly toxic (Kiderlen et al, 2005;Becker et al, 2007). Many phosphylated oximes are themselves potent inhibitors of AChE, sometimes much more potent than the initial offending organophosphate or organophosphonate, which generally translates into very high toxicity.…”