Tabun belongs to the most toxic nerve agents. Its mechanism of action is based on acetylcholinesterase (AChE) inhibition at the peripheral and central nervous systems. Therapeutic countermeasures comprise administration of atropine with cholinesterase reactivators able to reactivate the inhibited enzyme. Reactivation of AChE is determined mostly biochemically without specification of different brain structures. Histochemical determination allows a fine search for different structures but is performed mostly without quantitative evaluation. In rats intoxicated with tabun and treated with a combination of atropine and HI-6, obidoxime, or new oxime K048, AChE activities in different brain structures were determined using biochemical and quantitative histochemical methods. Inhibition of AChE following untreated tabun intoxication was different in the various brain structures, having the highest degree in the frontal cortex and reticular formation and lowest in the basal ganglia and substantia nigra. Treatment resulted in an increase of AChE activity detected by both methods. The highest increase was observed in the frontal cortex. This reactivation was increased in the order HI-6 < K048 < obidoxime; however, this order was not uniform for all brain parts studied. A correlation between AChE activity detected by histochemical and biochemical methods was demonstrated. The results suggest that for the mechanism of action of the nerve agent tabun, reactivation in various parts of the brain is not of the same physiological importance. AChE activity in the pontomedullar area and frontal cortex seems to be the most important for the therapeutic effect of the reactivators. HI-6 was not a good reactivator for the treatment of tabun intoxication.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- atropin MeSH
- čelní lalok účinky léků enzymologie patologie MeSH
- chemické bojové látky toxicita MeSH
- cholinesterasové inhibitory aplikace a dávkování toxicita MeSH
- GPI-vázané proteiny metabolismus MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- mozek účinky léků enzymologie patologie MeSH
- obidoxim chlorid aplikace a dávkování farmakologie terapeutické užití MeSH
- organofosfáty aplikace a dávkování antagonisté a inhibitory toxicita MeSH
- orgánová specificita MeSH
- oximy aplikace a dávkování farmakologie terapeutické užití MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny aplikace a dávkování farmakologie terapeutické užití MeSH
- reaktivátory cholinesterasy aplikace a dávkování farmakologie terapeutické užití MeSH
- retikulární formace účinky léků enzymologie patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Oxime reactivators HI-6, obidoxime, trimedoxime, K347 and K628 were investigated as drugs designed for treatment of tabun intoxication. The experiments were performed on rats in order to simulate real conditions. Rats were intoxicated with one LD(50 )of tabun and treated with atropine and mentioned reactivators. Activities of erythrocyte acetylcholinesterase (AChE), plasma butyrylcholinesterase (BChE) and brain AChE were measured as markers of reactivation efficacy. An estimation of low molecular weight antioxidant levels using cyclic voltammetry was the second examination parameter. The evaluation of cholinesterases activity showed good reactivation potency of blood AChE and plasma BChE by commercially available obidoxime and newly synthesized K347. The potency of oximes to reactivate brain AChE was lower due to the poor blood-brain barrier penetration of used compounds. Commercially available reactivator HI-6 and newly synthesized K628 caused oxidative stress measured by cyclic voltammetry as antioxidant level. The oxidative stress provoked by HI-6 and K628 was found to be significant on probability level P = 0.05. The others reactivators did not affect antioxidant levels. Copyright 2009 John Wiley & Sons, Ltd.
- MeSH
- acetylcholinesterasa krev metabolismus MeSH
- antidota aplikace a dávkování chemie terapeutické užití MeSH
- atropin aplikace a dávkování chemie terapeutické užití MeSH
- cholinesterasové inhibitory aplikace a dávkování chemie toxicita MeSH
- injekce intramuskulární MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- molekulární konformace MeSH
- molekulová hmotnost MeSH
- mozek metabolismus MeSH
- obidoxim chlorid aplikace a dávkování chemie terapeutické užití MeSH
- organofosfáty aplikace a dávkování chemie toxicita MeSH
- oxidační stres účinky léků MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny aplikace a dávkování chemie terapeutické užití MeSH
- reaktivátory cholinesterasy farmakologie chemie MeSH
- testy akutní toxicity MeSH
- trimedoxim aplikace a dávkování chemie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
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.
- MeSH
- acetylcholinesterasa krev metabolismus MeSH
- antidota aplikace a dávkování chemie terapeutické užití MeSH
- atropin aplikace a dávkování chemie terapeutické užití MeSH
- cholinesterasové inhibitory aplikace a dávkování chemie otrava MeSH
- druhová specificita MeSH
- financování organizované MeSH
- injekce intramuskulární MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- molekulární struktura MeSH
- myši MeSH
- obidoxim chlorid aplikace a dávkování chemie terapeutické užití MeSH
- organofosfáty aplikace a dávkování chemie MeSH
- otrava organofosfáty MeSH
- oximy aplikace a dávkování chemie terapeutické užití MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny aplikace a dávkování chemie terapeutické užití MeSH
- reaktivátory cholinesterasy aplikace a dávkování chemie terapeutické užití MeSH
- testy akutní toxicity metody MeSH
- trimedoxim aplikace a dávkování chemie terapeutické užití MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- záchvaty enzymologie chemicky indukované prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- finanční podpora výzkumu jako téma MeSH
- inhalační expozice MeSH
- katecholaminy metabolismus MeSH
- kortikosteron krev metabolismus MeSH
- krysa rodu rattus MeSH
- organofosfáty aplikace a dávkování toxicita MeSH
- psychický stres MeSH
- transaminasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
