Oximes antidotal effect

The analysis of literature indicates that the search of antidotes for the treatment of OPC intoxications during the second half of twentieth century was performed preferably among H-oximes and thiohydroxime esters. A great number of active compounds were synthesized and studied (2-PAM, TMB-4, HI-6, HGG-12, HGG-42, HLo-7, alloxime, aphine, carboxime, di-ethyxime, etc ). However, oximes may be only considered as one of the basic components of formulas. The usage of any of them as monotherapy does not ensure a high antidotic effect. 

Maksimovic M, Boskovic B, Rodovic L et al. (1980). Antidotal effects of bis-pyridinium 2-mono oxime carbonyl derivatives in intoxication with highly toxic organophosphorus compounds. Acute Pharm Jagoslav, 30, 151-160. 

Pyridostigmine pre-treatment increased the antidotal efficacy of oxime-atropine combinations in various studies, especially in soman-poisoned animals (Gordon et al, 1978 Dimhuber et al., 1979 Inns and Leadbeater, 1983 Leadbeater et al., 1985), but some reports indicate that pyridostigmine reduced the antidotal effect in sarin, VX and VR poisoning (Anderson et al, 1992 Koplovitz and Stewart, 1992 Maxwell et al, 1997). 

PHARMACOLOGY, TOXICOLOGY, AND DISPOSITION The reactivating action of oximes in vivo is most marked at the skeletal neuromuscular junction. Following a dose of an organophosphorus compound that produces total blockade of transmission, the intravenous injection of an oxime restores responsiveness of the motor nerve to stimulation within minutes. Antidotal effects are less striking at autonomic effector sites, and the quaternary ammonium group restricts entry into the CNS. 

The therapeutic efficacy of diverse mono and bis-quaternary pyridine aldoximes as antidotes against OP poisoning has been established in hundreds of publications, and three of them, 2-PAM (38), toxogonin (40) and HI-6 (41), are available in autoinjectors for post-exposure self-treatment or treatment by medical staff. For further information on the clinical use and potential side effects of these oximes the reader is referred to the reviews of Kassa, Eyer and of Marrs and colleagues . ... 

In the search of antidotes for these cholinesterase inhibitors, oximates as well as hydrox-ylamines and hydroxamates have become paramount, since these are 100- or greater-fold more reactive under mild conditions than the common base, hydroxide Structures of commonly studied oximes including pyridinium aldoximes are given in Scheme 4. The pyridinium moiety confers advantages of solubility as well as in lowering the oxime pTsTa. thus effecting higher reactivity under milder conditions of pH. 

Synthetic studies for the discovery of effective antidotes for cholinesterase inhibitors are continuing . Various reactivity studies of oximates with different functional organophosphorus compounds, such as phosphinates, phosphonates, phosphates and thiono analogues (shown in Scheme 5), have been reported . ... 

Loomis, T.A., Salafsky, B. 1963. Antidotal action of pyrldl-nium oximes in anticholinesterase poisoning comparative effects of soman, sarin, and neostigmine on neuromuscular function. 

The phosphorylated esterases formed by the action of organophosphorus inhibitors are very stable, but some antidotes can reverse the inhibition. The oxime of 2-formyl-l-methylpyridinium ion (pralidoxime) is very effective.6 Its positive charge permits it to bind to the site normally occupied by the quartemary nitrogen of acetylcholine and to displace the dialkylphospho group ... 

Oximes bind to AChE as reversible inhibitors and form complexes with AChE either at the acylation (catalytic) site, at the allosteric site, or at both sites of the enzyme and protect AChE from phosphorylation. When the reversible inhibitor binds to the catalytic site, the protection is due to direct competition between OP and reversible inhibitor. Binding of a reversible inhibitor to the allosteric site induces indirect protection of the active site. Differences in the mechanisms of enzyme reactivation and protection demonstrate how stereochemical arrangements of oximes can play a role in the potency of their therapeutic efficacy. Direct pharmacological effects, such as direct reaction with OPs (Van Helden et al., 1996), anticholinergic and sympathomimetic effects may also be relevant for the interpretation of antidotal potency of oximes. 

The only two randomized controlled clinical trials performed so far did not result in a final proof of the efficacy of the oximes in the treatment of poisonings induced by the OP insecticides in humans due to methodological problems (Eddleston et al., 2002). However, experimental and clinical experience suggests that among the pyridinium oximes, obidoxime andtrimedoxime, although relatively toxic, could provide reactivation and antidotal protection against most of the OP insecticides. In addition, HI-6 has proved to be effective in the treatment of soman-poisoned animals and safe and effective in patients poisoned with diethoxy OPs. 

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