The toxic effect of organophosphates is attributed to irreversible inhibition of acetylcholinesterase (AChE; EC 3.1.1.7), the enzyme that hydrolyses the neurotransmitter acetylcholine. Inhibition potency in vivo of one of the most toxic nerve agents--Russian VX (RVX;N,N-diethyl-2-[methyl-(2-methylpropoxy)phosphoryl]sulfanylethanamine) (1 x LD(50) dose administered intramuscularly, i.m.) was studied in rats. AChE in blood was inhibited by 50%, 3 min after i.m. RVX. Butylcholinesterase (BChE; EC 3.1.1.8) in plasma was inhibited less rapidly and only by 10-20%, 20 min after RVX. AChE and BChE activities in diaphragm were reduced only 35% and 15% at 30 min. While AChE and BChE activities were reduced only about 20% and 15%, respectively, the decline in activity was rapid, occurring within 3 min. These findings indicate that RVX most potently inhibits ChE outside the central nervous system.

• MeSH
• acetylcholinesterasa krev   MeSH
• bránice účinky léků   enzymologie   MeSH
• časové faktory MeSH
• chování zvířat účinky léků   MeSH
• játra účinky léků   enzymologie   MeSH
• krysa rodu Rattus MeSH
• LD50 MeSH
• mozek účinky léků   enzymologie   MeSH
• organothiofosforové sloučeniny toxicita   MeSH
• potkani Wistar MeSH
• tkáňová distribuce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• organothiofosforové sloučeniny MeSH
• S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate MeSH Prohlížeč

In this work, two oximes for the treatment of tabun-inhibited acetylcholinesterase (AChE; EC 3.1.1.7), K074 (1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide) and K075 ((E)-1,4-bis(4-hydroxyiminomethylpyridinium)but-2-en dibromide), were tested in vitro as reactivators of AChE. Comparison was made with currently used AChE reactivators (pralidoxime, HI-6, methoxime and obidoxime). Human brain homogenate was taken as an appropriate source of the cholinesterases. As resulted, oxime K074 appears to be the most potent reactivator of tabun-inhibited AChE, with reactivation potency comparable to that of obidoxime. A second AChE reactivator, K075, does not attain as great a reactivation potency as K074, although its maximal reactivation (17%) was achieved at relevant concentrations for humans.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• aktivace enzymů účinky léků   MeSH
• butany chemie   farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• lidé MeSH
• nucleus caudatus účinky léků   enzymologie   MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• organofosfáty toxicita   MeSH
• oximy chemie   farmakologie   MeSH
• pralidoximové sloučeniny chemie   farmakologie   MeSH
• pyridinové sloučeniny chemie   farmakologie   MeSH
• reaktivátory cholinesterasy chemie   farmakologie   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide MeSH Prohlížeč
• acetylcholinesterasa MeSH
• asoxime chloride MeSH Prohlížeč
• butany MeSH
• cholinesterasové inhibitory MeSH
• K075 compound MeSH Prohlížeč
• N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Prohlížeč
• obidoxim chlorid MeSH
• organofosfáty MeSH
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• tabun MeSH Prohlížeč

INTRODUCTION: Organophosphorus nerve agents inhibit the enzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators (also known as oximes) are generally used for the reactivation of an inhibited enzyme. METHODS: Two new AChE reactivators--K033 and K027--were tested for their in vitro reactivation of sarin-inhibited pig-brain AChE. Their reactivation potencies were compared with the commercially available AChE reactivators, pralidoxime, obidoxime, and HI-6. RESULTS: Of the oximes tested, the newly developed oxime K027 achieved the highest reactivation potency (100%; concentration of the oxime -10(-2) M). However, oxime HI-6 (33%) and obidoxime (23%) seem to be the best AChE reactivators for human relevant doses (10(-4) M and lower). CONCLUSION: For human relevant doses, newly developed oximes (K027 and K033) do not surpass the reactivation potency of the most promising oxime, HI-6.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• mozek účinky léků   enzymologie   MeSH
• obidoxim chlorid farmakologie   MeSH
• oximy farmakologie   MeSH
• pralidoximové sloučeniny farmakologie   MeSH
• prasata MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• sarin toxicita   MeSH
• techniky in vitro MeSH
• výzkumný projekt MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• 1,4-bis(2-hydroxyiminomethylpyridinium)butane MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• asoxime chloride MeSH Prohlížeč
• cholinesterasové inhibitory MeSH
• obidoxim chlorid MeSH
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• sarin MeSH

Oximes in combination with atropine, are an integral part of the treatment of acute intoxications with organophosphorus insecticides or with the nerve agents such as tabun, sarin, soman, cyclosarin or VX. Organophosphorus compounds are extremely potent inhibitors of the enzyme acetylcholinesterase (AChE, 3.1.1.7). The pharmacological action of oximes is multiple: they are able to reactivate the inhibited AChE, but they affect acetylcholine release in peripheral and central cholinergic synapses, allosterically modulate the muscarinic receptors in peripheral and central synapses, and influence the nicotinic receptor-associated ion-channels. In our study, we have determined the acute toxicity of different structures of oximes after intramuscular application in mice. The acute toxicity of oximes is crucial for the assesment of a dose applied as a treatment for organophosphorus intoxications. We have tested 7 oximes of different structures (HS-6, K033, BI-6, MMB-4, K048, HI-6 and obidoxime ) and during our experiments we have observed the intoxication process including typical signs of intoxication, and times of death. K033 was the most toxic oxime with an LD50 of only 48 mg/kg, while the least toxic oxime - HI-6 - has an LD50 value of 671 mg/kg. All the oximes tested were of the bispyridinium type, with different length or shape of the connecting chain and positions of oxime groups at the pyridinium rings. All these structural features play an important role in biological activity of these compounds performed by their acute toxicity as well as by their reactivation potency.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• myši MeSH
• reaktivátory cholinesterasy aplikace a dávkování   chemie   toxicita   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• reaktivátory cholinesterasy MeSH