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.

• Klíčová slova
• Antidote, Blood brain barrier, Organophosphate, Oxime, Reactivator,
• 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 cholinesterasy 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
• Názvy látek
• cholinesterasové inhibitory MeSH
• oximy MeSH
• reaktivátory cholinesterasy MeSH

Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator.

• Klíčová slova
• 2-PAM, Antidote, Nerve agent, Pesticide, Reactivator,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   metabolismus   MeSH
• lidé MeSH
• otrava organofosfáty * MeSH
• oximy farmakologie   chemie   MeSH
• pralidoximové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterasy * chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• reaktivátory cholinesterasy * MeSH

BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

• Klíčová slova
• Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota metabolismus   MeSH
• cholinesterasové inhibitory metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mozek enzymologie   MeSH
• organofosfáty metabolismus   MeSH
• oximy metabolismus   MeSH
• pyridinové sloučeniny metabolismus   MeSH
• reaktivátory cholinesterasy metabolismus   MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• tabun MeSH Prohlížeč

Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

• Klíčová slova
• Acetylcholinesterase, Nerve agents, Organophosphate, Pyridinium oximes, Reactivation, Uncharged reactivator,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• antidota chemie   farmakologie   terapeutické užití   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• lidé MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární struktura MeSH
• nervová bojová látka chemie   toxicita   MeSH
• organofosforové sloučeniny antagonisté a inhibitory   toxicita   MeSH
• otrava organofosfáty farmakoterapie   etiologie   metabolismus   MeSH
• pesticidy antagonisté a inhibitory   toxicita   MeSH
• pyridinové sloučeniny chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• reaktivátory cholinesterasy chemie   farmakologie   terapeutické užití   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• ligandy MeSH
• nervová bojová látka MeSH
• organofosforové sloučeniny MeSH
• pesticidy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy 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
• krysa rodu Rattus MeSH
• mozek metabolismus   MeSH
• obidoxim chlorid farmakologie   MeSH
• pesticidy otrava   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• chemické bojové látky MeSH
• obidoxim chlorid MeSH
• pesticidy MeSH
• reaktivátory cholinesterasy MeSH

Synthesis of a new asymmetric bisquaternary reactivator of tabun-inhibited acetylcholinesterase-1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide is described. Reactivation potency of this oxime is compared to the currently used reactivators-pralidoxime, obidoxime and H-oxime HI-6.

• MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• enzymové reaktivátory chemická syntéza   MeSH
• kinetika MeSH
• organofosfáty farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• enzymové reaktivátory MeSH
• organofosfáty MeSH
• tabun MeSH Prohlížeč

Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 μg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.

• Klíčová slova
• Acetylcholinesterase, Bispyridinium oximes, K869, Liquid chromatography, Mass spectrometry, Oxime, Pharmacokinetics, Reactivator,
• MeSH
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• chromatografie kapalinová MeSH
• krysa rodu Rattus MeSH
• oximy MeSH
• reaktivátory cholinesterasy * MeSH
• tandemová hmotnostní spektrometrie MeSH
• tělesné tekutiny * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• oximy MeSH
• reaktivátory cholinesterasy * 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
• pyridinové sloučeniny chemická syntéza   MeSH
• reaktivátory cholinesterasy chemická syntéza   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide MeSH Prohlížeč
• bromované uhlovodíky MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy 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
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• chemické bojové látky MeSH
• cholinesterasové inhibitory MeSH
• enzymové reaktivátory MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• pyridinové sloučeniny 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
• 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 cholinesterasy 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
• Názvy látek
• 4,4'-bis(hydroxyiminomethyl)-1,10-(1,2-phenylenedimethyl)bispyridinium MeSH Prohlížeč
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• receptor muskarinový M2 MeSH
• rekombinantní proteiny MeSH