Methoxime
Dotaz
Zobrazit nápovědu
The potency of a novel oxime K203 in reactivating soman-inhibited acetylcholinesterase and reducing acute toxicity of soman was compared with commonly used oximes (HI-6, obidoxime, trimedoxime, methoxime) using in vivo methods. The study determining percentage of reactivation of soman-inhibited blood and tissue acetylcholinesterase in rats showed that the potency of the oxime K203 to reactivate soman-inhibited acetycholinesterase in the peripheral compartment is slightly higher than obidoxime and trimedoxime, especially in the diaphragm, slightly lower than methoxime and markedly lower compared to the oxime HI-6. The reactivating efficacy of the oximes studied in the peripheral compartment roughly corresponds to their potency to reduce acute toxicity of soman in mice. Based on the obtained data, we can conclude that the oxime K203 is not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute soman poisoning due to its relatively low potency to counteract acute toxicity of soman.
- MeSH
- antidota terapeutické užití MeSH
- atropin krev MeSH
- chemické bojové látky MeSH
- cholinesterasové inhibitory toxicita MeSH
- LD50 MeSH
- myši MeSH
- obidoxim chlorid aplikace a dávkování MeSH
- organofosfáty antagonisté a inhibitory toxicita MeSH
- oximy * aplikace a dávkování chemie terapeutické užití MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny aplikace a dávkování MeSH
- reaktivátory cholinesterasy * aplikace a dávkování terapeutické užití MeSH
- soman * toxicita MeSH
- statistika jako téma MeSH
- trimedoxim aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Using an immobilized acetylcholinesterase-tabun enzyme-inhibitor complex, the reactivation efficacy of a homologous series of bispyridinium reactivators with increasing length of the alkylene chain between the pyridinium rings has been studied. The number of the alkylene groups in the chain ranged from one to six. N,N'-Monomethylenebis(4-pyridiniumaldoxime) dibromide (MMB-4) and N,N'-trimethylenebis(4-pyridiniumaldoxime) dibromide (TMB-4) are the most efficient reactivators of the series.
- MeSH
- acetylcholinesterasa metabolismus účinky léků MeSH
- chemické bojové látky toxicita MeSH
- cholinesterasové inhibitory toxicita MeSH
- enzymy imobilizované MeSH
- organofosfáty toxicita MeSH
- oximy farmakologie MeSH
- prasata MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterasy farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- antidota MeSH
- cholinesterasové inhibitory MeSH
- dursban MeSH
- finanční podpora výzkumu jako téma MeSH
- organofosforové sloučeniny škodlivé účinky toxicita MeSH
- oximy farmakologie terapeutické užití MeSH
- reaktivátory cholinesterasy aplikace a dávkování farmakologie terapeutické užití MeSH
- techniky in vitro MeSH
Summary: Nerve agents and pesticides belong to the group of organophosphates. They are able to inhibit irreversibly the enzyme acetylcholinesterase (AChE). Acetylcholinesterase reactivators were designed for the treatment of nerve agent intoxications. Their potency to reactivate pesticide-inhibited AChE was many times evaluated. In this study, five commonly used AChE reactivators (pralidoxime, methoxime, HI-6, obidoxime, trimedoxime) for the reactivation of AChE inhibited by two pesticides (chlorpyrifos and methylchlorpyrifos) were used. Russian VX (nerve agent) as a member of nerve agents’ family was taken for comparison. Obtained results show that oximes developed against nerve agent intoxication are less effective for intoxication with organophosphorus pesticides. Especially, methylchlorpyrifos-inhibited AChE was found to be poorly reactivated by the compounds used.
- MeSH
- acetylcholinesterasa chemie MeSH
- chemické bojové látky chemie škodlivé účinky MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- organofosfáty klasifikace škodlivé účinky toxicita MeSH
- oximy aplikace a dávkování farmakokinetika terapeutické užití MeSH
- pesticidy chemie škodlivé účinky MeSH
- reaktivátory cholinesterasy aplikace a dávkování klasifikace terapeutické užití MeSH
- techniky in vitro MeSH
- Check Tag
- lidé MeSH
Organophosphorous compounds cause fatal intoxication based on inhibition of acetylcholinesterase, an essential enzyme of neurosynapses and neuromuscular junctions. There is an obvious need to develop appropriate treatment against them due to their application in agriculture and chemical industry or their misuse in terrorist or war attack. In the Czech army some medicaments have been established to be used against this poisoning; Obidoxime, Methoxime, Atropine and Benactyzine. In present in vitro study we focused on potential cytotoxic and genotoxic effect evaluation of these drugs by the clonogenic and comet assay, respectively. Obtained results show that oximes exhibit pronounced toxic effect, namely obidoxime in term of genotoxicity and methoxime in term of cytotoxicity.
- Klíčová slova
- Obidoxime, Methoxime, Atropine, Benactyzine,
- MeSH
- analýza kolonii tvořících jednotek metody statistika a číselné údaje MeSH
- antidota chemie MeSH
- buňky Hep G2 účinky léků MeSH
- časové faktory MeSH
- financování organizované MeSH
- kometový test metody statistika a číselné údaje MeSH
- organofosfáty toxicita MeSH
- otrava organofosfáty MeSH
- otrava farmakoterapie MeSH
- oximy chemie MeSH
- poškození DNA účinky léků MeSH
- reaktivátory cholinesterasy terapeutické užití MeSH
- techniky in vitro MeSH
Pesticidy (např. parathion, chlorpyrifos, methylchlorpyrifos) stejně jako nervově paralytické látky (např. soman, sarin, tabun, VX) patří do skupiny organofosforových sloučenin. Tyto látky ireverzibilně inhibují enzym acetylcholinesterasu (AChE). Byly připraveny tři nové reaktivátory AChE s 3-oxapentanovým spojovacím řetězcem. Byla srovnána schopnost těchto nových potenciálních reaktivátorů AChE se současně užívanými sloučeninami (pralidoxim, methoxim, trimedoxim, obidoxim, HI-6) reaktivovat AChE inhibovanou pesticidy. Výsledky ukázaly, že nově připravené reaktivátory AChE převyšují reaktivátory v současnosti používané v případě methylchlorpyrifosem inhibované AChE při koncentraci 10-3 M, která však není použitelná pro in vivo experimenty. Při koncentraci (10-5 M) jsou všechny testované sloučeniny pro methylchlorpyrifosem inhibovanou AChE prakticky neúčinné. Naopak reaktivátory v současnosti používané převyšují nově připravené látky v případě chlorpyrifosem inhibované AChE při obou koncentracích.
Insecticides (e.g., parathion, chlorpyrifos, methylchlorpyrifos) and nerve agents (e.g., soman, sarin, tabun, VX) belong to the group of organophosphates. They are able to irreversibly inhibit the enzyme acetylcholinesterase (AChE). Three new reactivators with a 3-oxapentane connecting chain were prepared. The ability of the new compounds to reactivate AChE inhibited by pesticides was tested in vitro and compared to known oximes (pralidoxime, methoxime, trimedoxime, obidoxime, HI-6). The results show that the new substances are superior to known reactivators in the case of methylchlorpyrifos-inhibited AChE at a concentration of 10-3 M which is unfortunately not applicable to in vivo experiments. All tested compounds are practically ineffective for methylchlorpyrifos-inhibited AChE at the physiological concentration (10-5 M). On the other hand, the known reactivators surpass new substances in the case of chlorpyrifos-inhibited AChE at both concentrations.
Organophosphorus poisoning manifests as a cholinergic syndrome due to an inhibition of acetylcholinesterase. It is treated symptomatically by anticholinergics and oxime reactivators are used as causal antidotes. Reactivators possess a complex mechanism of action and interact at various levels of the cholinergic transmission. The aim of this study was to investigate the effect of standard oxime reactivators (HI-6, obidoxime, trimedoxime, methoxime and pralidoxime) on the hemicholinium-3 sensitive carriers, which are involved in the high-affinity choline uptake (HACU) transport, a key regulatory step in the synthesis of acetylcholine. The activity of the carriers was estimated in vitro on hippocampal synaptosomes using the substrate (3H)-choline and the competitive inhibitor (3H)-hemicholinium-3. Furthermore, the effect of the reactivators on the fluidity of hippocampal membranes was assessed. All tested compounds, except methoxime, showed an acute inhibitory effect on the carriers, however, only at μM concentrations. Trimedoxime showed the highest potency to inhibit HACU among all tested compounds (I(max) 62%, IC(50)=3 μM). All compounds, except HI-6, influenced also a membrane fluidity in the region of the hydrophilic heads of phospholipid bilayer, nevertheless, only methoxime was able to penetrate more deeply into the hydrocarbon core. We suggest that the direct interaction of oxime reactivators with the carrier protein (HI-6 and trimedoxime) and/or the changes in carrier conformation mediated by alterations in membrane fluidity (trimedoxime, obidoxime and pralidoxime) could occur here. The influence of reactivators on the carriers could be unfavorable in the case of their prolonged administration in vivo. From this point of view, the application of methoxime appears to be the best.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- anizotropie MeSH
- buněčná membrána účinky léků metabolismus MeSH
- cholin metabolismus MeSH
- fluidita membrány účinky léků fyziologie MeSH
- hemicholinium 3 metabolismus MeSH
- hipokampus účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- membránové transportní proteiny účinky léků metabolismus MeSH
- potkani Wistar MeSH
- reaktivátory cholinesterasy metabolismus farmakologie MeSH
- synaptozomy účinky léků metabolismus MeSH
- tritium diagnostické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Administration of acetylcholinesterase (AChE) reactivators (oximes) is usually used in order to counteract the poisoning effects of nerve agents. The possibility was suggested that oximes may show some therapeutic and/or adverse effects through their action in central nervous system. There are no sufficient data about interaction of oximes with monoaminergic neurotransmitter's systems in the brain. Oxime-type AChE reactivators pralidoxime, obidoxime, trimedoxime, methoxime and HI-6 were tested for their potential to affect the activity of monoamine oxidase of type A (MAO-A) and type B (MAO-B) in crude mitochondrial fraction of pig brains. The compounds were found to inhibit fully MAO-A with half maximal inhibitory concentration (IC(50)) of 0.375 mmol/l (pralidoxime), 1.53 mmol/l (HI-6), 2.31 mmol/l (methoxime), 2.42 mmol/l (obidoxime) and 4.98 mmol/l (trimedoxime). Activity of MAO-B was fully inhibited by HI-6 and pralidoxime only with IC(50) 4.81 mmol/l and 11.01 mmol/l, respectively. Methoxime, obidoxime and trimedoxime displayed non-monotonic concentration dependent effect on MAO-B activity. Because oximes concentrations effective for MAO inhibition could not be achieved in vivo at the cerebral level, we suppose that oximes investigated do not interfere with brain MAO at therapeutically relevant concentrations.
- MeSH
- inhibitory MAO farmakologie MeSH
- monoaminoxidasa metabolismus MeSH
- mozek enzymologie MeSH
- obidoxim chlorid farmakologie MeSH
- oximy farmakologie MeSH
- pralidoximové sloučeniny farmakologie MeSH
- prasata MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterasy farmakologie MeSH
- trimedoxim farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
