Soman reactivity

Another disadvantage of the first generation reactivators lies in their lacking of antidotic effect in respect to affections induced by soman, which causes fast aging of the phosphorylated enzyme. 

A positive property of the most active reactivators of the second generation lies in their ability to reduce 2 to 2.5 times aging rate of AChE inhibited with soman. 

The kinetic scheme for the reactivation of OP-inhibited AChE is depicted in equation 20 for pyridinium-based aldoximes, where R = CH3 or an alkoxy group, and = alkyl or aryl. The nerve agents that generate the covalent OP-AChE conjugates are those with R = CH3 and R = ethyl(VX), isopropyl (sarin), cyclohexyl (cyclosarin) and pinacolyl (soman). For tabun-inhibited AChE, R = Af,A-dimethylamido and R = ethyl. 

A recent study has revisited the reactivity of oximate nucleophiles toward detoxification of sarin, soman and DFP, using a fluoride-selective electrode to kinetically monitor decomposition of the neurotoxin . Results are shown in Table 1. 

Loomis, T.A., and Johnson, D.D. Reversal of a soman-induced effect on neuromuscular function without reactivation of cholinesterase. Toxicol. Appl. Pharmacol. 8 528-532, 1966. 

In dogs poisoned with soman (Intravenously at 30 pg/kg) and treated with I at 104 mg/kg (Intravenously 31/2 min after soman), the large dose of I stopped aging of Inhibited cholinesterase and reactivated 24.0% and 35.6% of the red-cell and diaphragm cholinesterase activities, respectively. It failed to reactivate brain cholinesterase. Indeed, the brain acetylcholinesterase activity after the treatment with 1 was lower than that just before the injection of I. The last finding indicates the inability of I to cross the blood-brain barrier in significant quantities. 

Fleisher, J.H., Harris, L.W., Murtha, E.F. 1967. Reactivation by pyridlnium aldoxlme methochloride (PAM) of inhibited cholinesterase activity in dogs after poisoning with pinacolyl methylphosphonofluoridate (soman). J. Pharmacol. Exp. Therap. 156 345-351. 

Harris, L.W., Heyl, W.C., Stitcher, D.L., Broomfield, C.A. (1978). Effects of l,l-oxydimethylene-bis-(4-tert-butyl pyridinium chloride) (SAD-128) and decamethonium on reactivation of soman- and sarin-inhibited cholinesterase by oximes. Biochem. Pharmacol. 27 757-61. 

Hoffman, R.S. (1999). Soman poisoning and autoinjectors and reactivators. In Proceedings, NACCT Meeting, La Jolla, CA. 

The presence of sarin, soman, and VX in the brain demonstrates the necessity for antidotes, especially AChE reactivators, to be capable of passing the blood-brain barrier, representing a current scientific challenge (Lorke et al, 2008 Okuno et al, 2008). 

Interaction of CarbE with nerve agents follows a kinetic of first order characterized by inhibition of CarbE at the active site serine residue described by a bimolecular rate constant, ki (Maxwell and Brecht, 2001). For noncharged nerve agents (e.g. sarin and soman) the ki of rat serum CarbE was found to be >10 M min whereas cationic substrates (e.g. VX) are converted with poor reactivity (ki < 10" M min ). This specificity is explained by the electrostatic characteristics of the large active site containing only a few cation-II bonding and anionic residues (Maxwell and Brecht, 2001 Satoh and Hosokawa, 2006). 

Adams, T.K., Capacio, B.R., Smith, J.R., Whalley, C.E., Korte, W.D. (2004). The application of the fluoride reactivation process to the detection of sarin and soman nerve agent exposure in biological samples. Drug Chem. Toxicol. 27 77-91. 

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