trimedoxime-bromide and Seizures

A common consequence of exposure to organophosphate nerve agents is the centrally mediated seizure activity that appears even after conventional treatment with atropine and oximes. We have previously demonstrated a major inflammatory response with subsequent brain damage which was correlated with the duration of the sarin-induced seizures (Chapman et al., 2006). In the present work seizures were induced by the nerve agent sarin (1.2 LD50) insufficiently treated 1 min later by atropine and trimedoxime bromide (TA), with additional midazolam treatment either 5 or 30 min after continuous seizure activity. The efficacy of both steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other drugs that were reported as beneficial in neuroprotection, were evaluated for their contribution as adjunct treatment against sarin induced seizures and the ensuing inflammatory brain damage. Results show that both steroids and NSAIDs were harmful when administered during convulsions, and steroids were at best ineffective if administered at their termination. However, if administered at termination of convulsions, the NSAID ibuprofen, the selective COX 2 inhibitor nimesulide and the PLA2 inhibitor quinacrine were partially effective in reducing brain inflammatory markers. Administration of exogenous analogs of prostaglandins (PGE2) immediately following sarin-induced convulsions was found to have a beneficial effect in reducing brain inflammatory markers measured at 24 h and one week post sarin exposure. These findings support the hypothesis that elevated levels of PGE2 have a beneficial role immediately following sarin induced seizures, and that early inhibition of PGE2 production by both steroids and NSAID is contraindicative.

Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Atropine; Brain Diseases; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dinoprostone; Encephalitis; Male; Midazolam; Nerve Agents; Neuroprotective Agents; Prostaglandins; Rats; Rats, Sprague-Dawley; Sarin; Seizures; Trimedoxime

The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Injections, Intramuscular; Lethal Dose 50; Male; Mice; Molecular Structure; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Seizures; Species Specificity; Toxicity Tests, Acute; Trimedoxime

Soman, a potent central acetylcholine esterase inhibitor, has a greater impact on brain regional glucose use than other organophosphates, such as diisopropylfluorophosphate (DFP) or phospholinium iodide. At near-lethal doses soman induced explosive persistent seizures that were associated with a greater than fourfold increase of glucose use in many brain structures. Single near-lethal doses of soman lead to conspicuous neuronal damage and a marked reduction in brain activity, 1 to 3 days after exposure. When soman (2 X LD50) was given to TAB (an antidotal mixture of trimedoxime, atropine, and benactyzine ) pretreated rats, there was a greater than twofold reduction of glucose use in almost every brain region. We suggest that soman seizures are mediated via activation of muscarinic receptors; also, the substantia nigra has a key role in the initiation/propagation of seizures. Soman has in addition, a depressive effect on some brain components which appears not to involve muscarinic receptors. We suggest that the conspicuous pathology that follows a single, near-lethal dose of soman results from a depletion of energy flow along with an influx of Ca2+ which sets into motion a cascade of destructive reactions, such as activation of proteases.

Topics: Animals; Atropine; Benactyzine; Brain; Cholinesterase Inhibitors; Deoxyglucose; Echothiophate Iodide; Glucose; Neostigmine; Organophosphorus Compounds; Rats; Seizures; Soman; Trimedoxime

Administration of large doses of Soman (2xLD50) to rats protected with TAB, a mixture of trimedoxime (TMB-4), atropine and benactyzine, results in approximately 2-fold reductions of local cerebral glucose utilization (LCGU) in most brain regions. This is in contrast to the marked increase in LCGU that is observed in conjunction with the seizures associated with an LD50 dose of Soman given to unprotected rats. This study reveals that TAB is effective in protecting against Soman-induced seizures, but only at the expense of a severe decrease in LCGU after Soman exposure.

Topics: Animals; Antidotes; Atropine; Benactyzine; Brain; Deoxyglucose; Depression, Chemical; Drug Combinations; Drug Interactions; Male; Organophosphorus Compounds; Oximes; Rats; Seizures; Soman; Trimedoxime