pralidoxime and diacetylmonoxime

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.

Topics: Acetylcholinesterase; Animals; Atropine; Brain; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diacetyl; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation; Guinea Pigs; Injections, Intramuscular; Male; Muscarinic Antagonists; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Pyridostigmine Bromide; Sarin; Seizures; Treatment Outcome; Up-Regulation

Topics: Acetylcholinesterase; Acetylthiocholine; Diacetyl; Obidoxime Chloride; Pralidoxime Compounds; Thiocholine

1. The effect of 2,3-butanedione monoxime (BDM), a 'chemical phosphatase', on Na(+)/Ca(2+) exchange current (I(NCX)) was investigated using the whole-cell voltage-clamp technique in single guinea-pig cardiac ventricular myocytes and in CCL39 fibroblast cells expressing canine NCX1. 2. I(NCX) was identified as a current sensitive to KB-R7943, a relatively selective NCX inhibitor, at 140 mM Na(+) and 2 mM Ca(2+) in the external solution and 20 mM Na(+) and 433 nM free Ca(2+) in the pipette solution. 3. In guinea-pig ventricular cells, BDM inhibited I(NCX) in a concentration-dependent manner. The IC(50) value was 2.4 mM with a Hill coefficients of 1. The average time for 50% inhibition by 10 mM BDM was 124+/-31 s (n=5). 4. The effect of BDM was not affected by 1 microM okadaic acid in the pipette solution, indicating that the inhibition was not via activation of okadaic acid-sensitive protein phosphatases. 5. Intracellular trypsin treatment via the pipette solution significantly suppressed the inhibitory effect of BDM, implicating an intracellular site of action of BDM. 6. PAM (pralidoxime), another oxime compound, also inhibited I(NCX) in a manner similar to BDM. 7. Isoprenaline at 50 microM and phorbol 12-myristate 13-acetate (PMA) at 8 microM did not reverse the inhibition of I(NCX) by BDM. 8. BDM inhibited I(NCX) in CCL39 cells expressing NCX1 and in its mutant in which its three major phosphorylatable serine residues were replaced with alanines. 9. We conclude that BDM inhibits I(NCX) but the mechanism of inhibition is not by dephosphorylation of the Na(+)/Ca(2+) exchanger as a 'chemical phosphatase'.

Topics: Adenosine Triphosphate; Animals; Cells, Cultured; Cholinesterase Reactivators; Diacetyl; Drug Interactions; Electrophysiology; Gene Expression; Guinea Pigs; Heart Ventricles; Hydrolysis; Isoproterenol; Myocardium; Okadaic Acid; Patch-Clamp Techniques; Pralidoxime Compounds; Sodium-Calcium Exchanger; Trypsin; Ventricular Function

Topics: Animals; Antidotes; Atropine; Buffaloes; Cholinesterase Reactivators; Diacetyl; Drug Combinations; Fasciculation; Male; Phosphamidon; Pralidoxime Compounds; Sialorrhea; Tremor

Oral administration of fenitrothion (435 mg/kg) produced a pronounced fall in rectal temperature and erythrocyte AChE activity in buffalo calves. Treatment with DAM alone or in conjunction with atropine at the time of severe toxicity (within 1 h) significantly (P less than 0.01) reversed fenitrothion-induced hypothermia and AChE inhibition. The temperature decrease and AChE inhibition were not significantly (P greater than 0.05) altered by either 2-PAM or atropine. It is concluded that DAM may be more effective than either 2-PAM or atropine in reversing hypothermic effect of OP insecticides.

Topics: Acetylcholinesterase; Animals; Atropine; Body Temperature; Buffaloes; Butanones; Cholinesterase Reactivators; Diacetyl; Erythrocytes; Fenitrothion; Hypothermia; Pralidoxime Compounds

Effects of 3 oximes, diacetylmonoxime (DAM), pyridine-2-aldoxime (PAM) and pyridine-2-aldoxime methochloride (2-PAM), on the normal electrical and mechanical activities and on the slow response action potentials were examined in the guinea pig ventricular muscles. DAM and long-term exposure to high concentrations of PAM produced decreases in contractile force, action potential duration and slow response action potentials, whereas 2-PAM and low concentrations of PAM tended to increase these parameters. Thus, these 3 oximes did not act uniformly on cardiac muscle. It was speculated that DAM and high concentrations of PAM may act as slow channel inhibitors, whereas 2-PAM and low concentrations of PAM may act as slow channel activators.

Topics: Action Potentials; Animals; Butanones; Diacetyl; Diltiazem; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardial Contraction; Pralidoxime Compounds; Time Factors; Verapamil

Topics: Acetylcholinesterase; Animals; Brain; Butanones; Cholinesterase Reactivators; Diacetyl; Liver; Male; Muscles; Paraoxon; Pralidoxime Compounds; Rats; Rats, Inbred Strains

Topics: Diacetyl; Hydroxylamines; Insecticides; Organophosphorus Compounds; Pralidoxime Compounds; Pyridines

Topics: Diacetyl; Hydroxylamines; Picolines; Pralidoxime Compounds

Topics: Animals; Animals, Laboratory; Diacetyl; Hydroxylamines; Pralidoxime Compounds; Pyridines

Topics: Diacetyl; Drug-Related Side Effects and Adverse Reactions; Hydroxylamines; Organophosphate Poisoning; Phosphates; Pralidoxime Compounds; Pyridines

Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.

Topics: Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Diacetyl; Drug-Related Side Effects and Adverse Reactions; Guinea Pigs; Hydroxylamines; Mice; Organophosphate Poisoning; Oximes; Phosphates; Pralidoxime Compounds; Rats; Sarin