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INTRODUCTION

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Pralidoxime chloride (2-PAM) is the only cholinesterase-reactivating xenobiotic currently available in the United States. It is used concomitantly with atropine in the management of patients poisoned by organic phosphorus (OP) compounds. Administration should be initiated as soon as possible after exposure, but can be effective even days after an exposure and therefore should be administered to all symptomatic patients independent of delay. Continuous infusion is preferable to intermittent administration for patients with serious toxicity, and a prolonged therapeutic course may be required.

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HISTORY

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It was recognized in the 1950s that certain phosphate esters were potent and irreversible inhibitors of acetylcholinesterase (AChE).84,85 Identification of an anionic site on AChE led to the theory that a compound could be developed that would bind to this site and remove the phosphate ester, thereby reactivating AChE. A few hydroxylamine derivatives were studied and led to the design of pralidoxime.85

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PHARMACOLOGY

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Chemistry

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Pralidoxime chloride is a quaternary pyridinium oxime with a molecular weight of 173 Da. The chloride salt exhibits excellent water solubility and physiologic compatibility. Pralidoxime iodide has a molecular weight of 264 Da, is less water soluble, and can potentially induce iodism.3

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Related Xenobiotics

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Organic phosphorous pesticides and nerve agents both cross the CNS. A disadvantage of pralidoxime is that in vivo rat studies it demonstrates only a 10% CNS penetration.66 Strategies to enhance the penetration of oximes across the blood–brain barrier (BBB) include enhancing lipophilicity by adding a fluorine atom into the ring structure, designing a glucose-oxime drug which could use facilitated glucose transporters to cross the BBB, designing a prodrug of pralidoxime that could be oxidized to the active drug once it had crossed the BBB, conjugating the oxime with amidine, and by using a targeted nanoparticle drug delivery system.50

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Obidoxime (Toxogonin, LuH-6) is an oxime used outside the United States that contains two active sites per molecule and is considered by some to be more effective than pralidoxime.23,24,88 An in vitro study using human erythrocyte AChE supported the superiority of obidoxime to pralidoxime in reactivating AChE inhibited by the dimethyl phosphoryl (malaoxon, ­mevinphos) and diethyl phosphoryl OP compounds (paraoxon). On a molar basis, obidoxime is approximately 10 to 20 times more effective in reactivating AChE than pralidoxime.88 A potential disadvantage is the concern that the phosphorylobidoxime generated from the reactivation of AChE by obidoxime could reinhibit AChE if not metabolized by a plasma enzyme similar or identical to human paraoxonase 1 (PON1). PON1 exhibits ­polymorphism21 and one in 20 patients may not be able to metabolize this phosphorylobidoxime compound. Phosphorylpralidoxime is unstable and does not ­accumulate. A molecular docking simulation study demonstrated that pralidoxime had better positioning at the oxyanion hole compared to obidoxime, allowing better reactivation ...

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