Antidotes oximes

OP nerve agents, which are small lipophilic molecules, can easily penetrate the BBB by free diffusion and thereby inhibit AChE in the CNS (Mercey et al., 2012). Increased BBB permeability by OP nerve agents or other ChE inhibitors may lead to their enhanced entry into the brain, resulting in greater AChE inhibition and possibly resulting in subsequent maintenance of seizures and aggravation of their pathological consequences, such as edema and neuronal loss in certain brain structures. Evidently, increased BBB permeability may facilitate the entry of an antidote (oxime class) to the brain, which otherwise has limited access because of the BBB. 

Because of their weak lipophily, H-oximes overcome poorly the hematoencephalic barrier. Their antidotic action is based on reactivation of peripheral AChE (in blood and respiratory musculature). 

Pyridostigmine Bromide An antidote enhancer that blocks acetylcholinesterase, protecting it from nerve agents. When taken in advance of nerve agent exposure, pyridostigmine bromide increases survival provided that atropine and oxime and other measures are taken. 

Treatment — Patients should be decontaminated immediately prior to treatment using the decontamination method presented in Section 7.3.2. Ventilate the patient because of a possible increase in airway resistance due to constriction and the presence of secretions. If breathing is difficult, administer oxygen. Administer antidotes as soon as possible. The antidote for this agent is atropine alone or in combination with pralidoxime chloride (2-PAMC1) or another oxime. Diazepam may be required to control severe convulsions. 

AChE and direct the oximate anion toward the P atom, proved to be extremely efficient in terms of rate of displacement of the enzyme-bound phosphoryl group (i.e. reactivation) and, consequently, as an antidote. The pioneering work of Wilson and colleagues in the early 1950s served as the scientific foundation for the synthesis and evaluation of more than 1000 oxime-containing reactivators over the past 50 years, that have been described in hundreds of pubhcations. 2-PAM and several bis-quatemary oximes 39 , 40 and... 

The pX a (6.5-8.2) and nucleophilicity of MINA, 44, and of a series of aliphatic oximes derived from it, were found to be consistent with their ability to reactivate AChE inhibited by the nerve agents, sarin and VX. Yet, despite their ability to significantly reactivate AChE in the brains of sarin-intoxicated rats, these aliphatic oximes are not used as antidotes for treatment of OP poisoning in humans this is presumably due to their poor stability in aqueous solution and to their rapid clearance from the circulation. 

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 . ... 

HYDROXYLAMINES, HYDROXAMATES AND OXIMATES AS ANTIDOTES FOR INTOXICATION BY ORGANOPHOSPHORUS TOXINS (CHEMICAL WARFARE AGENTS) AND... 

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. 

McNamara, B.P. 1976. Oximes as antidotes In poisoning by anticholinesterase compounds. EB-SP-76004. 

Askew, B.M. Oximes and hydroxamic acids as antidotes in anticholinesterase poisoning. Br. J. Pharmacol. Chemother. 11 417-423, 1956. 

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 ... 

Depending on the specific organophosphate, some phosphorylated enzyme may be reactivated ("dephosphorylated") by certain oxime antidotes from one to two days after OP absorption. Thereafter a change in the nature of the enzyme-phosphoryl bond occurs, rendering the inactivation irreversible and necessitating the generation of new enzyme. 

Fig. 6 Concentration-time profile of antidotal atropine and its enantiomers S- and / -hyoscyamine in plasma of an in vivo swine study. Swine were topically exposed to the nerve agent VR (302 pg/ kg, t0) followed by administration of atropine sulphate (30 pg/kg) and the reactivating oxime HI 6 (12.8 mg/kg) via three i.m. injections into the rear leg at 30 (I), 180 (II) and 330 min (III). Blood samples were collected at distinct time points to generate EDTA plasma. Maximum concentrations were found 4 min after drug administration each. No differences of S- and R-Hyo concentrations were evident underlining similar elimination kinetics for both enantiomers. Data are mean and SD from duplicate measurement using the enantioselective LC-MS/MS approach of John et al. [47,49]. Black circles, total hyo grey circles, S-hyo grey triangles, R-hyo...

In the open literature little is known about these agents developed in the Soviet Union. They are assessed to be five to ten times more toxic than VX (Ellison, 2008 Smithson et al, 1995). The toxicity of these binary agents does not rely primarily on the inhibition of AChE, but it is thought that it causes permanent neuropathy. Consequently, conventional nerve agent antidotes may not work. Reactive oximes such as potassium 2,3-butanedione monoximate may be use fid in detoxification. No pubhshed information is available on cardiac pathologies caused by Novichok agents. 

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