Reactivation of OP-inhibited AChE

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. 

TABLE 3. Relative reduction in the optimal rate of reactivation of OP-inhibited AChE at pH = 7.4 for oximes with various pK values and OPs with various /S values... 

Although the major research and development effort on oxime reactivators has focused on the positively charged pyridinium ring, the poor ability of the charged oximes to cross the blood-brain barrier (BBB) has prompted several studies on noncharged aliphatic oximes in an effort to increase reactivation of OP-inhibited AChE in the central nervous system. The most smdied noncharged oximes are mono isonitrosoacetone (MINA, 44) and diacetyl monoxime (DAM, 45) " . 

Table 2 is a compilation of kinetic data for the reactivation of OP-inhibited AChE by the licensed oximes obidoxime and pralidoxime and the experimental compounds HI 6, HLo 7 and methoxime. These data demonstrate a large variability of the affinity (1/A d) and reactivity (kr) of the oximes depending on the... 

Experiments using site-directed mutagenesis and computational modelling have shown that oximes appear to have preferred entry routes for attack of the phosphyl moiety and that side-chain substitutions of the active site gorge of AChE may significantly alter the reactivity (Radic and Taylor, 1999 Taylor el. al., 1999 Wong et al., 2000 Kovarik el. al., 2004). Hence, marked species differences in reactivatability of phosphylated AChE towards oximes are to be expected. In fact, experimental data support the assumption of substantial species differences in reactivation of OP-inhibited AChE... 

Determination of reactivation rate constants of OP-inhibited AChE in vitro is a versatile tool for quantifying the ability of oximes to remove... 

Figure 3. Efficiencies, ka (mM 1 min 1) of the oximes for the reactivation of OP-inhibited human AChE. Data of the most effective oximes are given...

To increase the OP/enz5mie stoichiometry, polyurethane-immobilized enzymes were combined with oximes (enzyme reactivators such as HI-6 Peter et al., 2007) so that the catalytic activity of OP-inhibited AChE (or BChE) is rapidly and continuously restored before irreversible aging of the enzyme-OP complex can occur. Thus, the OP is continuously detoxified. A reusable immobilized-enzyme sponge of ChEs and oximes for OP decontamination is the envisioned product. Next, it... 

Standard post-exposure treatments include eoneurrent administration of anticholinergics, such as the musearinie cholinergic blocker atropine sulfate, and AChE reactivators, such as obidoxime and pyridine-2-aldoxime methochloride (also known as 2-PAM). Oximes cannot reactivate OP-inhibited AChE that has already aged . Therefore, traditional oxime treatment is considered to be less effective for those agents such as soman, for which aging is rapid (Worek et al, 2005). 

It has been almost 40 years since B. Wilson et al. observed that nucleophiles, oximes like hydroxamic acid, reactivated OP-inhibited AChE above and beyond that occurring from spontaneous reactivation, opening the way to a treatment for OP poisoning. The oxime registered for use in the United States is 2-PAM Cl (Protopam) its methanesulfonate salt (P2S) is used in Europe. Oxime therapy should be recommended with caution for carbamate poisonings. Although beneficial in the case of aldicarb, there is evidence that 2-PAM treatment increases the toxicity of carbaryl. 

MMB-4 was also less effective in reactivation of cyclosarin-inhibited rat brain AChE and sarin-inhibited human or monkey AChE compared with HI-6 (Kuca and Patocka, 2004 Lundy et al., 2011). MMBM was found to be a weak reactivator of tabun-inhibited human AChE (Worek et al., 2004). However, experimental data indicate that MMB-4 was superior to PAM-2 in reactivating OP-inhibited AChE and in preventing lethality in OP-poisoned animals (Worek et al., 2010). It was also reported that MMB-4 was the most effective oxime in reactivation of ChE in blood and peripheral tissues in guinea pigs poisoned by sarin, cyclosarin, VX, and VR (Shih et al., 2010). In addition, MMB-4 was reported to be a better AChE reactivator than PAM-2 in paraoxon-poisoned and methylparaoxon-poisoned rats (Petroianu et al., 2006,2007). 

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