- MeSH
- acetylcholinesterasa metabolismus MeSH
- analýza dat MeSH
- bránice enzymologie MeSH
- GPI-vázané proteiny metabolismus MeSH
- maximální tolerovaná dávka MeSH
- oximy farmakologie toxicita MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny farmakologie toxicita MeSH
- reaktivátory cholinesterasy farmakologie toxicita MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The reactivating and therapeutic efficacy of two newly developed oximes (K305, K307) was compared with the oxime K203 and trimedoxime using in vivo methods The study determining percentage of reactivation of tabun-inhibited acetylcholinesterase in the peripheral as well as central nervous system (diaphragm, brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed oximes is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While the ability of the oxime K305 to reduce acute toxicity of tabun in mice is approaching to the therapeutic efficacy of trimedoxime, the ability of another novel bispyridinium oxime K307 to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and the oxime K203. Thus, the reactivating and therapeutic efficacy of both examined newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
- MeSH
- acetylcholinesterasa účinky léků MeSH
- antidota aplikace a dávkování farmakologie toxicita MeSH
- atropin aplikace a dávkování farmakologie toxicita MeSH
- bránice enzymologie MeSH
- modely u zvířat MeSH
- mozek enzymologie účinky léků MeSH
- mutantní kmeny myší MeSH
- nervová bojová látka farmakologie chemie toxicita MeSH
- organofosfáty farmakologie toxicita MeSH
- oximy * farmakologie chemie klasifikace MeSH
- potkani Wistar MeSH
- reaktivátory cholinesterasy aplikace a dávkování farmakologie toxicita MeSH
- trimedoxim farmakologie chemie klasifikace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.
- MeSH
- acetylcholinesterasa krev chemie metabolismus MeSH
- antagonisté muskarinových receptorů terapeutické užití MeSH
- antidota terapeutické užití MeSH
- atropin terapeutické užití MeSH
- bránice účinky léků enzymologie MeSH
- cholinesterasové inhibitory aplikace a dávkování chemie toxicita MeSH
- kombinovaná farmakoterapie MeSH
- mozek účinky léků enzymologie MeSH
- myši MeSH
- neurony účinky léků enzymologie MeSH
- neurotoxické syndromy krev farmakoterapie etiologie metabolismus MeSH
- obidoxim chlorid terapeutické užití MeSH
- outbrední kmeny zvířat MeSH
- oximy terapeutické užití MeSH
- potkani Wistar MeSH
- proteiny nervové tkáně agonisté antagonisté a inhibitory metabolismus MeSH
- pyridinové sloučeniny terapeutické užití MeSH
- reaktivátory cholinesterasy terapeutické užití MeSH
- sarin aplikace a dávkování antagonisté a inhibitory toxicita MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The potency of three newly developed bispyridinium compounds (K454, K456, K458) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm and brain acetylcholinesterase in poisoned rats showed that the reactivating efficacy of all newly developed oximes is comparable with K203 but lower than the reactivating potency of trimedoxime in diaphragm. In the brain, their potency to reactivate tabun-inhibited acetylcholinesterase is lower compared with trimedoxime and the oxime K203. All three newly developed oximes were also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy is consistent with the therapeutic potency of the oxime K203. On the other hand, their potency to reduce acute toxicity of tabun is significantly lower compared with trimedoxime. In conclusion, the reactivating and therapeutic potency of all three newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- bránice účinky léků enzymologie MeSH
- chemické bojové látky otrava MeSH
- cholinesterasové inhibitory toxicita MeSH
- inbrední kmeny myší MeSH
- krysa rodu rattus MeSH
- mozek účinky léků enzymologie MeSH
- myši MeSH
- organofosfáty toxicita MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny toxicita MeSH
- reaktivátory cholinesterasy toxicita MeSH
- trimedoxim toxicita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Derivative of 6-methyluracil, selective cholinesterase inhibitor C-547 potentiates miniature endplate currents (MEPCs) in rat external intercostal muscles (external ICM) more effectively than in internal intercostal muscles (internal ICM). Effect of the C-547 on intercostal muscles was compared with those on extensor digitorum longus (EDL) and diaphragm muscles. Half-effective concentrations for tau of MEPC decay arranged in increasing order were as follows: EDL, locomotor muscle, most sensitive = 1.3 nM, external ICM, inspiration muscle = 6.8 nM, diaphragm, main inspiration muscle = 28 nM, internal ICM, expiration muscle = 71 nM. External ICM might therefore be inhibited, similarly as the limb muscles, by nanomolar concentrations of the drug and do not participate in inspiration in the presence of the C-547. Moreover, internal ICM inhibition can hinder the expiration during exercise-induced fast breathing of C-547- treated experimental animals.
- MeSH
- bránice enzymologie účinky léků MeSH
- časové faktory MeSH
- cholinesterasové inhibitory farmakologie MeSH
- financování organizované MeSH
- kosterní svaly enzymologie účinky léků MeSH
- krysa rodu rattus MeSH
- kvartérní amoniové sloučeniny farmakologie MeSH
- mechanika dýchání účinky léků MeSH
- mezižeberní svaly enzymologie účinky léků MeSH
- miniaturní postsynaptické potenciály účinky léků MeSH
- potkani Wistar MeSH
- uracil analogy a deriváty farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
INTRODUCTION: The ability of currently available reactivators to reactivate cyclosarin is low. The aim of this study was to determine the reactivating and therapeutic efficacy of newly developed oximes (K206, K269) compared with currently available oximes against cyclosarin. METHODS: Rats and mice received atropine or atropine + oxime intramuscularly (i.m.) before or after an i.m. dose of cyclosarin. Acetylcholine activity levels in blood and tissues were measured to calculate the reactivation efficacy and potency. RESULTS AND DISCUSSION: In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase (AChE) in poisoned rats showed that the potency of both newly developed oximes (K206, K269) to reactivate cyclosarin-inhibited AChE is comparable with that of obidoxime in blood and diaphragm, but slightly higher than that of obidoxime in brain. Their reactivating efficacy is significantly lower compared with that of the oxime HI-6. K206 and K269 are relatively effective in reducing cyclosarin-induced lethal toxic effects in mice. Their therapeutic efficacies exceed the therapeutic potency of obidoxime but not that of HI-6. CONCLUSIONS: K206 and K269 are as effective in the reactivation of cyclosarin-inhibited AChE in rats and in the reduction of lethal toxic effects of cyclosarin in mice as obidoxime, but because their reactivating and therapeutic potency is significantly lower than that of HI-6, they are not suitable replacements for the currently available oximes for the treatment of cyclosarin poisoning.
- MeSH
- atropin aplikace a dávkování terapeutické užití MeSH
- bránice enzymologie MeSH
- chemické bojové látky otrava MeSH
- cholinesterasové inhibitory otrava MeSH
- cholinesterasy krev metabolismus MeSH
- financování organizované MeSH
- inbrední kmeny myší MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- molekulární struktura MeSH
- mozek enzymologie MeSH
- myši MeSH
- obidoxim chlorid aplikace a dávkování chemie terapeutické užití toxicita MeSH
- organofosforové sloučeniny MeSH
- otrava organofosfáty MeSH
- otrava enzymologie farmakoterapie MeSH
- oximy aplikace a dávkování chemie terapeutické užití toxicita MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny aplikace a dávkování chemie terapeutické užití toxicita MeSH
- reaktivátory cholinesterasy aplikace a dávkování chemie terapeutické užití toxicita MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
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 enzymologie účinky léků MeSH
- časové faktory MeSH
- chování zvířat účinky léků MeSH
- játra enzymologie účinky léků MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- mozek enzymologie účinky léků 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
- práce podpořená grantem MeSH
Nerve agents can be divided into G-agents (sarin, soman, tabun, cyclosarin etc.) and V-agents. The studies dealing with V-agents (O-alkyl S-2-dialkylaminoethyl methyl phosphonothiolates) are limited to one or two representatives only (VX, Russian VX). Anticholinesterase properties of 11 V-agents were studied in rats in vivo. Following intoxication with these agents in doses of 1 x LD(50) (intramuscular administration), activities of cholinesterases in the blood were continuously monitored and half-lives (t(0.5)) of inhibition were determined. These values varied from 3 min (VX and some other agents) to 10-14 min (derivatives substituted on the phosphorus head by O-ethyl- or O-isopropyl-, and by dimethyl-, diethyl- and dibutyl- on the nitrogen). Acetylcholinesterase activities in selected parts of the brain and diaphragm (30 min after the intoxication) were also detected. A correlation between toxicities and rates of inhibition of the blood enzymes was demonstrated. A similar relationship between acetylcholinesterase inhibition in vitro (from literature data) and half-lives of the blood cholinesterases was also observed. Though the chemical similarity of V compounds is evident, marked differences were observed among different derivatives; however, all agents examined had high inhibition potency corresponding to their toxicities. (c) 2007 John Wiley & Sons, Ltd.
- MeSH
- bránice enzymologie MeSH
- cholinesterasové inhibitory otrava MeSH
- cholinesterasy krev MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- mozek enzymologie MeSH
- organothiofosforové sloučeniny otrava MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
The potency of newly developed asymmetric bispyridinium oximes (K027, K048) in reactivating tabun-inhibited acetylcholinesterase (AChE) and in eliminating tabun-induced acute toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determined the percent of reactivation of tabun-inhibited blood and tissue AChE in poisoned rats and showed that the reactivating efficacy of both newly developed oximes is comparable with obidoxime and trimedoxime, the most efficacious known reactivators of tabun-inhibited AChE. These were also found to be sufficiently efficacious in the elimination of acute lethal toxic effects in tabun-poisoned rats. The oxime HI-6, relatively efficacious against soman, did not seem to be an adequately effective oxime in reactivation of tabun-inhibited AChE and in counteracting acute lethal effects of tabun. In addition, our results confirm that the efficacy of oximes in reactivating tabun-inhibited AChE in blood, diaphragm, and brain correlates with the potency of oximes in protecting rats poisoned with supralethal doses of tabun.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- aktivace enzymů MeSH
- bránice enzymologie MeSH
- chemické bojové látky otrava MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- mozek enzymologie MeSH
- organofosfáty MeSH
- otrava organofosfáty MeSH
- otrava farmakoterapie MeSH
- oximy farmakologie MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
