title: Treatment with tertiary oximes prevents seizures and improves survival following sarin intoxication.
abstract: The capability of the tertiary oximes, monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), to reactivate acetylcholinesterase (AChE) inhibited by sarin (GB) in the blood, brain, and peripheral tissues of guinea pigs was compared with that of the quaternary oximes 2-PAM, HLö7, and MMB-4. Animals were injected subcutaneously (s.c.) with 1.0 x LD(50) of GB and treated intramuscularly (i.m.) 5 min later with one of these oximes. Sixty minutes after GB exposure, tissues were collected for AChE analysis. At low doses, MINA and DAM produced significant increases in AChE activity in all brain areas examined, but no significant AChE reactivation in peripheral tissues or blood. At higher doses, MINA and DAM increased AChE activity in the brain, peripheral tissues, and blood. In contrast, the quaternary oximes produced significant reactivation in peripheral tissues and blood AChE, but no significant reactivation of brain AChE. In another study, animals were pretreated i.m. with pyridostigmine 30 min prior to s.c. challenge with 2.0 x LD(50) of GB and treated i.m. 1 min later with atropine sulfate (2.0 mg/kg), plus a varied dose of oximes. MINA and DAM prevented or terminated GB-induced seizure activity and protected against GB lethality in a dose-dependent fashion. In contrast, none of the quaternary oximes prevented or stopped GB-induced seizures. Thus, tertiary oximes reactivated AChE in the brain, improved survival, and terminated seizures following GB intoxication.
authors.affiliation: Pharmacology Branch, Research Division, U.S. Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P, Aberdeen Proving Ground, MD 21010-5400, USA. tsungming.a.shih@us.army.mil
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Shih
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Skovira
authors.forename: John C
authors.initials: JC
authors.lastname: O'Donnell
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000187:drug effects; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000494:pharmacology* / Q000627:therapeutic use; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007273:Injections, Intramuscular; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D011220:Pralidoxime Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D012524:Sarin / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018727:Muscarinic Antagonists; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; C058577:HLo 7; C004717:diacetylmonoxime; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D001285:Atropine; D012524:Sarin; D000110:Acetylcholinesterase; D003931:Diacetyl; D011729:Pyridostigmine Bromide; C028797:pralidoxime
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