• MeSH
• antidota MeSH
• organothiofosforové sloučeniny antagonisté a inhibitory   otrava   MeSH
• oximy MeSH
• psi MeSH
• pyridiny MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH

• MeSH
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• enzymové reaktivátory MeSH
• modely u zvířat MeSH
• neurotoxiny chemie   MeSH
• organofosforové sloučeniny chemie   metabolismus   MeSH
• oximy chemie   metabolismus   MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• acetylcholinesterasa terapeutické užití   MeSH
• otrava terapie   MeSH
• soman škodlivé účinky   MeSH

BACKGROUND: Obidoxime is the only one reactivator of acetylcholinesterase (AChE) approved in Czech Republic for the treatment of nerve agent and pesticide poisonings for civilian sector. Due to the fact that misuse of nerve agents by terrorists or by an accidental poisoning by farmers is possible, re-evaluation of its universality is needed. It is also needed by the fact that clinical findings considering this oxime are controversial. AIM: In this study, we wanted to summarize if obidoxime is a universal reactivator or if its reactivation potency in case of some organophosphorus inhibitors is limited. METHOD: Using our in vitro method, rat brain AChE was inhibited by eleven organophosphorus AChE inhibitors and then reactivated by obidoxime. RESULTS AND CONCLUSION: It was found that obidoxime could not be termed as universal antidote. Due to this, development of new promising candidates as replacement of obidoxime is recommended.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• chemické bojové látky otrava   MeSH
• financování organizované MeSH
• krysa rodu rattus MeSH
• mozek metabolismus   MeSH
• obidoxim chlorid farmakologie   MeSH
• pesticidy otrava   MeSH
• reaktivátory cholinesterázy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

A novel acetylcholinesterase (AChE) reactivator, a bispyridinium aldoxime named K048, was first synthesized in 2003. It is a promising antidote against tabun poisoning. Afterwards, other studies on several cholinesterases (ChE) of different species (humans, rats, etc.) and models (in vitro or in vivo) were conducted. We tested this oxime against nine different AChE inhibitors using in vitro tests on rat brain homogenate as source of enzyme. Our results showed that oxime K048 reached promising reactivation activity in case of all tested AChE inhibitors, except cyclosarin, at oxime concentration 10(-3) M. At a concentration of 10(-5) M, which is more common for human use, only methylchlorpyrifos-inhibited AChE was reactivated.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aktivace enzymů účinky léků   MeSH
• antidota farmakologie   MeSH
• chemické bojové látky farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• enzymové reaktivátory farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• organofosforové sloučeniny farmakologie   MeSH
• oximy farmakologie   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The newly developed and very promising acetylcholinesterase reactivator (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide was prepared using two different pathways via a two-step synthesis involving the appropriate (E)-1-(4-bromobut-2-enyl)-2- or 4-hydroxyiminomethyl-pyridinium bromides. Afterwards, purities and yields of the desired product prepared by both routes were compared. Finally, its potency to reactivate several nerve agent-inhibited acetylcholinesterases was tested.

• MeSH
• bromované uhlovodíky chemická syntéza   MeSH
• financování organizované MeSH
• pyridinové sloučeniny chemická syntéza   MeSH
• reaktivátory cholinesterázy chemická syntéza   MeSH

The treatment of organophosphate (OP) poisoning consists of the administration of a parasympatholytic agent, an anticonvulsant and an acetylcholinesterase (AChE) reactivator. Since there is no broad AChE reactivator available, a post-treatment strategy currently exploits administration of different types of oximes depending on the exposure of OP. In this contribution, we summarize all the available data about AChE reactivator HLö-7 including its synthesis, physico-chemical properties, pharmacokinetic and pharmacodynamics profile, and its efficacy in vitro and in vitro.

• Klíčová slova
• Hlo-t,
• MeSH
• acetylcholinesterasa fyziologie   chemie   MeSH
• chemické bojové látky otrava   MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• LD50 MeSH
• lidé MeSH
• nervová bojová látka otrava   MeSH
• organofosforové sloučeniny MeSH
• otrava organofosfáty * farmakoterapie   MeSH
• oximy MeSH
• pesticidy otrava   MeSH
• pyridinové sloučeniny * farmakokinetika   farmakologie   chemická syntéza   chemie   terapeutické užití   MeSH
• reaktivátory cholinesterázy * farmakokinetika   farmakologie   chemická syntéza   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• benaktyzin aplikace a dávkování   terapeutické užití   MeSH
• cholinesterasové inhibitory MeSH
• deriváty atropinu aplikace a dávkování   terapeutické užití   MeSH
• dichlorvos terapie   toxicita   MeSH
• krysa rodu rattus MeSH
• obidoxim chlorid aplikace a dávkování   terapeutické užití   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

The misuse of organophosphate compounds still represents a current threat worldwide. Treatment of poisoning with organophosphates (OPs) remains unsatisfactorily resolved despite the extensive investment in research in academia. There are no universal, effective and centrally-active acetylcholinesterase (AChE) reactivators to countermeasure OP intoxication. One major obstacle is to overcome the blood-brain barrier (BBB). The central compartment is readily accessible by the OPs which are lipophilic bullets that can easily cross the BBB, whereas first-line therapeutics, namely oxime-based AChE reactivators and atropine, do not cross or do so rather slowly. The limitation of oxime-based AChE reactivators can be ascribed to their chemical nature, bearing a positive charge which is essential either for their AChE affinity or their reactivating potency. The aim of this article is to review the methods for targeting the brain by oxime reactivators that have been developed so far. Approaches using prodrugs, lipophilicity enhancement, or sugar-based oximes have been rather unsuccessful. However, other strategies have been more promising, such as the use of nanoparticles or co-administration of the reactivator with efflux transporter inhibitors. Encouraging results have also been associated with intranasal delivery, but research in this field is still at the beginning. Further research of auspicious approaches is inevitable.

• MeSH
• biologický transport MeSH
• cholinesterasové inhibitory otrava   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• otrava organofosfáty farmakoterapie   metabolismus   MeSH
• oximy aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The oxime reactivator K112 is a member of the new group of xylene linker-containing AChE reactivators. Its cholinergic properties could be of importance at OP poisoning and are not related to the AChE reactivation that has been studied. It has been found that, despite of reactivating potency, this compound has additional effects. These cholinergic effects include a weak inhibition of AChE (IC(50)=43.8 ± 4.88 μM), inhibition of binding to the porcine muscarinic M2 receptor (IC(50)=4.36 μM) and finally, the inhibition of HACU (68.4 ± 9.9%), a key regulatory step in the synthesis of ACh. The inhibition of the binding of (3H)-HC-3 (64.7 ± 4.7%) and the influence on the membrane fluidity have also been observed. Blocking properties of K112 on the muscarinic receptors have been revealed in the in vitro experiment (rat urinary bladder) and in the in vivo experiment (rat heart BPM) as well. All these cholinergic properties could significantly contribute to the antidotal effect of K112 at the poisoning by the organophosphates.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• fluidita membrány účinky léků   MeSH
• hipokampus účinky léků   enzymologie   MeSH
• hladké svalstvo účinky léků   enzymologie   MeSH
• krysa rodu rattus MeSH
• močový měchýř účinky léků   enzymologie   MeSH
• organofosforové sloučeniny MeSH
• otrava organofosfáty MeSH
• otrava farmakoterapie   enzymologie   MeSH
• oximy chemie   farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• prasata MeSH
• pyridinové sloučeniny chemie   farmakologie   MeSH
• reaktivátory cholinesterázy chemie   farmakologie   MeSH
• receptor muskarinový M2 antagonisté a inhibitory   MeSH
• rekombinantní proteiny antagonisté a inhibitory   MeSH
• srdce účinky léků   MeSH
• srdeční frekvence účinky léků   MeSH
• svalová kontrakce účinky léků   MeSH
• synaptozomy účinky léků   enzymologie   MeSH
• techniky in vitro MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH