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LETTER TO THE EDITOR

Pralidoxime Rescues Both Muscarinic and Nicotinic Systems

Department of Anesthesia and Critical Care; Harvard Medical School; Massachusetts General Hospital; Boston, MA; talston{at}partners.org

To the Editor:

Next year will be the 50th anniversary year of pralidoxime, a landmark case in biochemical pharmacology (1). Pralidoxime is an "oxime" antidote for organophosphorus inactivators of acetylcholinesterase. The invention by Irwin B. Wilson (2) of that rescue drug for nerve gas was hailed as representing "the first time in medical history that it has been possible to design a compound useful in treatment by paper-and-pencil calculations" (3). Wilson did not sketch the pralidoxime molecule as an analog of some serendipitously discovered existing drug. Instead, he applied his theory of enzyme action to design a peerless pharmaceutical. As Wilson predicted, organophosphorus-poisoned cholinesterase is not completely "dead." Instead, the poisoned enzyme retains catalytic ability to transfer its blocking organophosphorus group away from its enzyme active site and onto pralidoxime.

Pralidoxime takes time to reactivate cholinesterase, does not remove all types of organophosphorus groups with equal speed, and exhibits poor central nervous system penetration. Therefore, additional methods of dealing with organophosphorus poisoning are desirable, and Petroianu et al. describe a very interesting strategy (4). However, one statement, not critical to the crux of their paper, may blur the elegant pralidoxime mechanism: "The effects of an oxime are not apparent in organs with muscarinic receptors; oximes do not cause a decrease in secretions, for example." The same misleading sentence is circulated by the United States Army (5). Yet, as would be expected in view of the Wilson mechanism, pralidoxime does reverse both muscarinic and nicotinic actions of nerve gases (6). Atropine is indeed recommended as an adjunct to pralidoxime. After all, atropine has relatively rapid action, good central nervous system activity, and some value against pralidoxime-resistant anticholinesterases. However, muscarinic value of pralidoxime rescue is not lacking (6).

References

1. Wilson IB, Ginsburg S. A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase. Biochim Biophys Acta 1955;18:168–70.[Medline]
2. Kitz RJ. On the maturation of the profession. In: Fink BR, Caton D, McGoldrick KE, eds. Careers in anesthesiology, Vol. 8. Park Ridge, IL: Wood Library-Museum of Anesthesiology, 2004:59–181.
3. Plumb RK. Nerve-gas relief marks milestone: PAM antidote is specifically designed for purpose and then proved effective: report on Columbia finding cites discovery without trial-and-error tests. New York Times October 3, 1958, p. 31.
4. Petroianu GA, Hasan MY, Nurulain SM, et al. Protective drugs in acute large-dose exposure to organophosphates: a comparison of metoclopramide and tiapride with pralidoxime in rats. Anesth Analg 2005;100:382–6.[Abstract/Free Full Text]
5. US Army Medical Research Institute of Chemical Defense. Nerve agents: medical management of chemical casualties handbook, 3rd edition. Aberdeen Proving Ground, MD: US Army Medical Research Institute of Chemical Defense, 2000;102–135.
6. Sekita K. Experimental studies on the efficacy of PAM against sumithion poisoning [in Japanese]. Nippon Hoigaku Zasshi 1992;46:14–31.[Medline]

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