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Jiri Kassa - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the influence of three newly developed bispyridinium anti nicotinic compounds mb408 mb442 mb444 on the efficacy of antidotal treatment of nerve agent poisoning in mice
Basic & Clinical Pharmacology & Toxicology, 2018Co-Authors: Jiri Kassa, Christopher M Timperley, Mike Bird, Rebecca L Williams, Christopher A Green, John E H TattersallAbstract:The influence of three newly-developed bispyridinium antinicotinic compounds (the non-Oximes MB408, MB442 and MB444) on the therapeutic efficacy of a standard antidotal treatment (atropine in combination with an oxime) of acute poisoning by the organophosphorus nerve agents tabun and soman was studied in mice. The therapeutic efficacy of atropine in combination with an oxime with or without one of the bispyridinium non-Oximes was evaluated by determination of the LD50 values of the nerve agents and measurement of the survival time after supralethal poisoning. Addition of all the tested non-Oximes increased significantly the therapeutic efficacy of atropine in combination with an oxime against tabun poisoning. They also positively influenced the number of surviving mice 6 hr after supralethal poisoning with tabun. However, they were only slightly effective for the treatment of soman poisoning. The benefit of the tested bispyridinium non-Oximes was dose-dependent. To conclude, the addition of bispyridinium non-Oximes to the standard antidotal treatment of acute poisoning with tabun was beneficial regardless of the chosen non-oxime, but only slightly beneficial in the case of soman poisoning. This article is protected by copyright. All rights reserved.
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A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium Oximes (K305, K307) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice
Journal of Applied Biomedicine, 2017Co-Authors: Jiri Kassa, Vendula Sepsova, Anna Horova, Kamil MusilekAbstract: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.
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A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium Oximes (K920, K923) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice
Journal of Applied Biomedicine, 2015Co-Authors: Jiri Kassa, Vendula Sepsova, Anna Horova, Kamil MusilekAbstract:The potency of two novel Oximes (K920, K923) to reactivate tabun-inhibited acetylcholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited peripheral acetylcholinesterase (diaphragm) and central acetylcholinesterase (brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed Oximes is lower than the reactivating potency of the oxime K203 and trimedoxime. The therapeutic efficacy of both newly developed Oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun in mice was lower compared to the oxime K203 and trimedoxime. All differences in reactivating efficacy of Oximes and different protective ratios were found for selected doses of Oximes used in this study. Based on the results obtained, we can conclude that the reactivating and therapeutic potency of both 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. The conclusion is only relevant for the experimental animals used in this study because of remarkable species differences in reactivating properties of Oximes.
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Neuroprotective efficacy of newly developed Oximes in comparison with currently available Oximes in tabun-poisoned rats
Journal of Applied Biomedicine, 2015Co-Authors: Jiri Kassa, Jan Misik, Jana Zdarova KarasovaAbstract:The ability of two newly developed Oximes (K361, K378) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the oxime K203 and trimedoxime using a functional observational battery. The neuroprotective effects of the Oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (310 μg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by functional observational battery at 2 h following tabun challenge. The results indicate that all tested Oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed Oximes (K361, K378) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime and the oxime K203. Therefore, the newly developed Oximes are not suitable for the replacement of commonly used Oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.
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A comparison of the reactivating and therapeutic efficacy of two newly developed Oximes (k727 and k733) with oxime k203 and trimedoxime in tabun-poisoned rats and mice.
Basic & clinical pharmacology & toxicology, 2014Co-Authors: Jiri Kassa, Vendula Sepsova, Martina Tumova, Anna Horova, Kamil MusilekAbstract:The reactivating and therapeutic efficacy of three original bispyridinium Oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed Oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all Oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all Oximes studied roughly corresponds to their reactivating efficacy. While both recently developed Oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed Oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used Oximes for the antidotal treatment of acute tabun poisoning.
Kamil Kuca - One of the best experts on this subject based on the ideXlab platform.
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Reactivation kinetics of 31 structurally different bispyridinium Oximes with organophosphate-inhibited human butyrylcholinesterase
Archives of Toxicology, 2015Co-Authors: Gabriele Horn, Horst Thiermann, Kamil Kuca, Timo Wille, Kamil Musilek, Franz WorekAbstract:Organophosphorus compounds (OP) are bound to human butyrylcholinesterase (BChE) and endogenous or exogenous BChE may act as a stoichiometric scavenger. Adequate amounts of BChE are required to minimize toxic OP effects. Simultaneous administration of BChE and Oximes may transfer the enzyme into a pseudo-catalytic scavenger. The present study was initiated to determine the reactivation kinetics of 31 structurally different bispyridinium Oximes with paraoxon-, tabun- and cyclosarin-inhibited human BChE. Human plasma was incubated with OP and the reactivation of inhibited BChE was tested with multiple oxime concentrations followed by nonlinear regression analysis for the determination of reactivity, affinity and overall reactivation constants. The generated data indicate that the tested Oximes have a low-to-negligible reactivating potency with paraoxon- and tabun-inhibited human BChE. Several Oximes showed a moderate-to-high potency with cyclosarin-inhibited BChE. Thus, the present study indicates that bispyridinium Oximes are obviously not suitable to serve as reactivators of human BChE inhibited by different OP and it is doubtful whether further modifications of the bispyridinium template will lead to more potent reactivators. In the end, novel structures of oxime and non-oxime reactivators are urgently needed for the development of human BChE into an effective pseudo-catalytic scavenger.
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Assessment of antidotal efficacy of cholinesterase reactivators against paraoxon: In vitro reactivation kinetics and physicochemical properties
Bioorganic & medicinal chemistry letters, 2014Co-Authors: Bhanushree Gupta, Kamil Kuca, Kamil Musilek, Rahul Sharma, Namrata Singh, Jyotiranjan Acharya, Blaženka Foretić, Manmohan L. Satnami, Kallol K GhoshAbstract:The search of proficient Oximes as reactivators of irreversibly inhibited-AChE by organophosphate poisoning necessitates an appropriate assessment of their physicochemical properties and reactivation kinetics. Therefore, herein acid dissociation constant; p K a , lipophilicity; log P , polar surface area, hydrogen bond donor and acceptor counts of structurally different Oximes (two tertiary Oximes and thirteen pyridinium aldoxime derivatives) have been evaluated. The experimentally obtained data for p K a has been comparatively analyzed by using non-linear regression. Further the tested Oximes were screened through in vitro reactivation kinetics against paraoxon-inhibited AChE. The p K a values of all the examined Oximes were within the range of 7.50–9.53. p K a values of uncharged and mono-pyridinium Oximes were in good correlation with their reactivation potency. The high negative log P values of pyridinium oxime reactivators indicate their high hydrophilic character; hence Oximes with improved lipophilicity should be designed for the development of novel and more potent antidotes. Propane and butane linked Oximes were superior reactivators than xylene linked bis-oxime reactivators. It is concluded from the present study that p K a value is not only ruled by the position of oximino functionality in the pyridinium ring, but also by the position of linker. Although, pyridinium Oximes are proved to be better reactivators but their lipophilicity has to be improved.
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in vitro reactivation kinetics of paraoxon and dfp inhibited electric eel ache using mono and bis pyridinium Oximes
Archives of Toxicology, 2014Co-Authors: Bhanushree Gupta, Kamil Kuca, Rahul Sharma, Namrata Singh, Jyotiranjan Acharya, Kallol K GhoshAbstract:Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel Oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various Oximes such as mono-quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4) and asymmetric (K027, K048, K203, K618, K628) Oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of Oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the Oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP-inhibited AChE is 3 or 4 carbon–carbon connecting linker between prydinium rings.
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Reactivation kinetics of a homologous series of bispyridinium bis-Oximes with nerve agent-inhibited human acetylcholinesterase
Archives of Toxicology, 2012Co-Authors: Franz Worek, Kamil Kuca, Kamil Musilek, Jens Wellen, Horst ThiermannAbstract:The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by Oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel Oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-Oximes bearing a ( E )-but-2-ene linker with tabun-, sarin-, and cyclosarin-inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated Oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested Oximes was equally effective against all used OPs. In addition, the data indicate that a ( E )-but-2-ene linker decreased in most cases the reactivating potency in comparison to Oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of Oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs.
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Two possibilities how to increase the efficacy of antidotal treatment of nerve agent poisonings.
Mini reviews in medicinal chemistry, 2012Co-Authors: Jiri Kassa, Jana Žďárová Karasová, Kamil Kuca, Kamil Musilek, Jiri BajgarAbstract:Highly toxic organophosphorus inhibitors of acetylcholinesterase referred as nerve agents are considered to be among the most dangerous chemical warfare agents. The Oximes represent very important part of medical countermeasures of nerve agent poisonings. They are used to reactivate the nerve agent-inhibited acetylcholinesterase. Despite long-term research activities, there is no single, broad-spectrum oxime suitable for the antidotal treatment of poisoning with all organophosphorus agents. There are two approaches how to increase and broaden the effectiveness of antidotal treatment of poisoning with nerve agents - to develop new structural analogues of currently available Oximes and/or to combine currently available or newly developed Oximes. The review describes the evaluation of the potency of newly developed Oximes (especially the oxime K203) or combinations of Oximes to reactivate nerve agent-inhibited acetylcholinesterase and to counteract the acute toxicity of nerve agents in comparison with single commonly used oxime (obidoxime, trimedoxime or HI-6).
Kamil Musilek - One of the best experts on this subject based on the ideXlab platform.
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A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium Oximes (K305, K307) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice
Journal of Applied Biomedicine, 2017Co-Authors: Jiri Kassa, Vendula Sepsova, Anna Horova, Kamil MusilekAbstract: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.
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A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium Oximes (K920, K923) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice
Journal of Applied Biomedicine, 2015Co-Authors: Jiri Kassa, Vendula Sepsova, Anna Horova, Kamil MusilekAbstract:The potency of two novel Oximes (K920, K923) to reactivate tabun-inhibited acetylcholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited peripheral acetylcholinesterase (diaphragm) and central acetylcholinesterase (brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed Oximes is lower than the reactivating potency of the oxime K203 and trimedoxime. The therapeutic efficacy of both newly developed Oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun in mice was lower compared to the oxime K203 and trimedoxime. All differences in reactivating efficacy of Oximes and different protective ratios were found for selected doses of Oximes used in this study. Based on the results obtained, we can conclude that the reactivating and therapeutic potency of both 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. The conclusion is only relevant for the experimental animals used in this study because of remarkable species differences in reactivating properties of Oximes.
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Reactivation kinetics of 31 structurally different bispyridinium Oximes with organophosphate-inhibited human butyrylcholinesterase
Archives of Toxicology, 2015Co-Authors: Gabriele Horn, Horst Thiermann, Kamil Kuca, Timo Wille, Kamil Musilek, Franz WorekAbstract:Organophosphorus compounds (OP) are bound to human butyrylcholinesterase (BChE) and endogenous or exogenous BChE may act as a stoichiometric scavenger. Adequate amounts of BChE are required to minimize toxic OP effects. Simultaneous administration of BChE and Oximes may transfer the enzyme into a pseudo-catalytic scavenger. The present study was initiated to determine the reactivation kinetics of 31 structurally different bispyridinium Oximes with paraoxon-, tabun- and cyclosarin-inhibited human BChE. Human plasma was incubated with OP and the reactivation of inhibited BChE was tested with multiple oxime concentrations followed by nonlinear regression analysis for the determination of reactivity, affinity and overall reactivation constants. The generated data indicate that the tested Oximes have a low-to-negligible reactivating potency with paraoxon- and tabun-inhibited human BChE. Several Oximes showed a moderate-to-high potency with cyclosarin-inhibited BChE. Thus, the present study indicates that bispyridinium Oximes are obviously not suitable to serve as reactivators of human BChE inhibited by different OP and it is doubtful whether further modifications of the bispyridinium template will lead to more potent reactivators. In the end, novel structures of oxime and non-oxime reactivators are urgently needed for the development of human BChE into an effective pseudo-catalytic scavenger.
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A comparison of the reactivating and therapeutic efficacy of two newly developed Oximes (k727 and k733) with oxime k203 and trimedoxime in tabun-poisoned rats and mice.
Basic & clinical pharmacology & toxicology, 2014Co-Authors: Jiri Kassa, Vendula Sepsova, Martina Tumova, Anna Horova, Kamil MusilekAbstract:The reactivating and therapeutic efficacy of three original bispyridinium Oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed Oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all Oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all Oximes studied roughly corresponds to their reactivating efficacy. While both recently developed Oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed Oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used Oximes for the antidotal treatment of acute tabun poisoning.
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Assessment of antidotal efficacy of cholinesterase reactivators against paraoxon: In vitro reactivation kinetics and physicochemical properties
Bioorganic & medicinal chemistry letters, 2014Co-Authors: Bhanushree Gupta, Kamil Kuca, Kamil Musilek, Rahul Sharma, Namrata Singh, Jyotiranjan Acharya, Blaženka Foretić, Manmohan L. Satnami, Kallol K GhoshAbstract:The search of proficient Oximes as reactivators of irreversibly inhibited-AChE by organophosphate poisoning necessitates an appropriate assessment of their physicochemical properties and reactivation kinetics. Therefore, herein acid dissociation constant; p K a , lipophilicity; log P , polar surface area, hydrogen bond donor and acceptor counts of structurally different Oximes (two tertiary Oximes and thirteen pyridinium aldoxime derivatives) have been evaluated. The experimentally obtained data for p K a has been comparatively analyzed by using non-linear regression. Further the tested Oximes were screened through in vitro reactivation kinetics against paraoxon-inhibited AChE. The p K a values of all the examined Oximes were within the range of 7.50–9.53. p K a values of uncharged and mono-pyridinium Oximes were in good correlation with their reactivation potency. The high negative log P values of pyridinium oxime reactivators indicate their high hydrophilic character; hence Oximes with improved lipophilicity should be designed for the development of novel and more potent antidotes. Propane and butane linked Oximes were superior reactivators than xylene linked bis-oxime reactivators. It is concluded from the present study that p K a value is not only ruled by the position of oximino functionality in the pyridinium ring, but also by the position of linker. Although, pyridinium Oximes are proved to be better reactivators but their lipophilicity has to be improved.
Jana Zdarova Karasova - One of the best experts on this subject based on the ideXlab platform.
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Encapsulation of oxime acetylcholinesterase reactivators: influence of physiological conditions on the stability of oxime-cucurbit[7]uril complexes
New Journal of Chemistry, 2020Co-Authors: Rudolf Andrýs, Aneta Klusoňová, Miroslav Lísa, Jana Zdarova KarasovaAbstract:Oxime-based acetylcholinesterase reactivators are a specific group of drugs used for the treatment of organophosphate intoxication. However, high hydrophilicity and poor blood–brain barrier penetration limit their physiological potential. Cucurbit[7]urile (CB[7]) was used in this work as a potential carrier of oxime molecules to increase their treatment effectiveness. The host–guest chemistry of CB[7] with five clinically used Oximes (trimedoxime, asoxime, obidoxime, pralidoxim and methoxime) and two new pre-clinical Oximes (K027 and K048) was characterized under simulated physiological conditions using titration experiments with UV-vis detection. CB[7] forms stable complexes of 1 : 1 stoichiometry with all tested Oximes. The decrease of complex stability was observed at a pH above the pKa of oxime, which limits the applicability of the complexation for Oximes with pKa below the physiological pH. The combination of physiological ionic strength and pH causes partial decrease of the complex stability. The effect of organic solvent used in the sample pretreatment step before spectral analysis of oxime–CB[7] complexes in biological samples was demonstrated. Methanol is a more suitable solvent with low effect on complex stability. Finally, the ability of mass spectrometry with electrospray ionization was demonstrated for the analysis of oxime–CB[7] complexes.
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Neuroprotective efficacy of newly developed Oximes in comparison with currently available Oximes in tabun-poisoned rats
Journal of Applied Biomedicine, 2015Co-Authors: Jiri Kassa, Jan Misik, Jana Zdarova KarasovaAbstract:The ability of two newly developed Oximes (K361, K378) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the oxime K203 and trimedoxime using a functional observational battery. The neuroprotective effects of the Oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (310 μg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by functional observational battery at 2 h following tabun challenge. The results indicate that all tested Oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed Oximes (K361, K378) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime and the oxime K203. Therefore, the newly developed Oximes are not suitable for the replacement of commonly used Oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.
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therapeutic efficacy of a novel bispyridinium oxime k203 and commonly used Oximes hi 6 obidoxime trimedoxime methoxime in soman poisoned male rats and mice
Journal of Applied Biomedicine, 2013Co-Authors: Jiří Kassa, Jana Zdarova Karasova, Marketa KrejciovaAbstract: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.
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a comparison of the potency of a novel bispyridinium oxime k203 and currently available Oximes obidoxime hi 6 to counteract the acute neurotoxicity of sarin in rats
Basic & Clinical Pharmacology & Toxicology, 2012Co-Authors: Jiri Kassa, Jan Misik, Jana Zdarova KarasovaAbstract:The neuroprotective effects of a newly developed oxime K203 and currently available Oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested Oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings.
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A comparison of the reactivating efficacy of a novel bispyridinium oxime K203 with currently available Oximes in VX agent-poisoned rats
Journal of Enzyme Inhibition and Medicinal Chemistry, 2012Co-Authors: Jiri Kassa, Jana Zdarova Karasova, Vendula SepsovaAbstract:The ability of a novel bispyridinium oxime K203 to reactivate VX agent-inhibited acetylcholinesterase was compared with the reactivating efficacy of four commonly used Oximes (obidoxime, trimedoxime, methoxime, HI-6) using in vivo model. Our results showed that the reactivating efficacy of the oxime HI-6 is higher than the reactivating efficacy of the other Oximes studied including the oxime K203 although the differrences between the oxime HI-6 and some other Oximes are not significant, especially in the blood. Based on the obtained data, we can conclude that the antidotal treatment involving the oxime HI-6 brings the higher benefit for the antidotal treatment of acute poisonings with VX agent than other Oximes.
Horst Thiermann - One of the best experts on this subject based on the ideXlab platform.
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Oximes in organophosphate poisoning 60 years of hope and despair
Chemico-Biological Interactions, 2016Co-Authors: Franz Worek, Horst Thiermann, Timo WilleAbstract:The high number of annual fatalities following suicidal poisoning by organophosphorus (OP) pesticides and the recent homicidal use of the chemical warfare nerve agent sarin against civilian population in Syria underlines the continuous threat by these highly toxic agents. The need for an effective treatment of OP poisoning resulted in the implementation of a combination therapy with the muscarinic receptor antagonist atropine and an oxime for the reactivation of OP-inhibited acetylcholinesterase (AChE). Since the invention of the first clinically used oxime pralidoxime (2-PAM) in the 1950s ongoing research attempted to identify more effective Oximes. In fact, several thousand Oximes were synthesized in the past six decades. These include charged and non-charged compounds, mono- and bispyridinium Oximes, asymmetric Oximes, Oximes with different substitutes and more recently non-oxime reactivators. Multiple in vitro and in vivo studies investigated the potential of Oximes to reactivate OP-inhibited AChE and to reverse OP-induced cholinergic signs. Depending on the experimental model, the investigated species and the tested OP largely variable results were obtained by different laboratories. These findings and the inconsistent effectiveness of Oximes in the treatment of OP-pesticide poisoned patients led to a continuous discussion on the value of Oximes. In order to provide a forward-looking evaluation of the significance of Oximes in OP poisoning multiple aspects, including intrinsic toxicity, in vitro reactivation potency, efficacy and pharmacokinetics, as well as the impact of the causative OP have to be considered. The different influencing factors in order to define the benefit and limitations of Oximes in OP poisoning will be discussed.
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Reactivation kinetics of 31 structurally different bispyridinium Oximes with organophosphate-inhibited human butyrylcholinesterase
Archives of Toxicology, 2015Co-Authors: Gabriele Horn, Horst Thiermann, Kamil Kuca, Timo Wille, Kamil Musilek, Franz WorekAbstract:Organophosphorus compounds (OP) are bound to human butyrylcholinesterase (BChE) and endogenous or exogenous BChE may act as a stoichiometric scavenger. Adequate amounts of BChE are required to minimize toxic OP effects. Simultaneous administration of BChE and Oximes may transfer the enzyme into a pseudo-catalytic scavenger. The present study was initiated to determine the reactivation kinetics of 31 structurally different bispyridinium Oximes with paraoxon-, tabun- and cyclosarin-inhibited human BChE. Human plasma was incubated with OP and the reactivation of inhibited BChE was tested with multiple oxime concentrations followed by nonlinear regression analysis for the determination of reactivity, affinity and overall reactivation constants. The generated data indicate that the tested Oximes have a low-to-negligible reactivating potency with paraoxon- and tabun-inhibited human BChE. Several Oximes showed a moderate-to-high potency with cyclosarin-inhibited BChE. Thus, the present study indicates that bispyridinium Oximes are obviously not suitable to serve as reactivators of human BChE inhibited by different OP and it is doubtful whether further modifications of the bispyridinium template will lead to more potent reactivators. In the end, novel structures of oxime and non-oxime reactivators are urgently needed for the development of human BChE into an effective pseudo-catalytic scavenger.
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Reactivation kinetics of a homologous series of bispyridinium bis-Oximes with nerve agent-inhibited human acetylcholinesterase
Archives of Toxicology, 2012Co-Authors: Franz Worek, Kamil Kuca, Kamil Musilek, Jens Wellen, Horst ThiermannAbstract:The reactivation of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) by Oximes is inadequate in case of different OP nerve agents. This fact led to the synthesis of numerous novel Oximes by different research groups in order to identify more effective reactivators. In the present study, we investigated the reactivation kinetics of a homologous series of bispyridinium bis-Oximes bearing a ( E )-but-2-ene linker with tabun-, sarin-, and cyclosarin-inhibited human AChE. In part, marked differences in affinity and reactivity of the investigated Oximes toward OP-inhibited human AChE were recorded. These properties depended on the position of the oxime groups and the inhibitor. None of the tested Oximes was equally effective against all used OPs. In addition, the data indicate that a ( E )-but-2-ene linker decreased in most cases the reactivating potency in comparison to Oximes bearing an oxybismethylene linker, e.g., obidoxime and HI-6. The results of this study give further insight into structural requirements for oxime reactivators, underline the necessity to investigate the kinetic interactions of Oximes and AChE with structurally different OP inhibitors, and point to the difficulty to develop an oxime reactivator which is efficient against a broad spectrum of OPs.
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Structural requirements for effective Oximes – Evaluation of kinetic in vitro data with phosphylated human AChE and structurally different Oximes
Chemico-Biological Interactions, 2012Co-Authors: Franz Worek, Marianne Koller, Timo Wille, Horst ThiermannAbstract:Abstract Treatment of poisoning by various organophosphorus (OP) nerve agents with established acetylcholinesterase (AChE) reactivators (Oximes) is insufficient. In consequence, extensive research programs have been undertaken in various countries in the past decades to identify more effective Oximes. The efficacy of new compounds has been investigated with different in vitro and in vivo models which hamper the comparison of results from different laboratories. The crucial mechanism of action of Oximes is the reactivation of phosphylated AChE. The kinetic properties of these compounds can be quantified in vitro with isolated AChE from different origin. It was tempting to evaluate the reactivation kinetics of a series of Oximes with various OP inhibitors performed under identical experimental conditions in order to get insight into structural requirements for adequate affinity and reactivity towards inhibited AChE. The determination of reactivation rate constants with bispyridinium Oximes having different linkers, bearing oxime group(s) at different positions and having in part additional substituents revealed that (a) the reactivating potency was dependent on the position of the oxime groups and of additional substituents, (b) small modifications of the oxime structure had an in part marked effect on the kinetic properties and (c) no single oxime had an adequate reactivating potency with AChE inhibited by structurally different OP. These and previous studies underline the necessity to investigate in detail the kinetic properties of novel Oximes and that the identification of a single oxime being effective against a broad range of structurally different OP will remain a major challenge.
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evaluation of medical countermeasures against organophosphorus compounds the value of experimental data and computer simulations
Chemico-Biological Interactions, 2010Co-Authors: Franz Worek, Nadine Aurbek, Nadja M Herkert, Harald John, Michael Eddleston, Peter Eyer, Horst ThiermannAbstract:Despite extensive research for more than six decades on medical countermeasures against poisoning by organophosphorus compounds (OP) the treatment options are meagre. The presently established acetylcholinesterase (AChE) reactivators (Oximes), e.g. obidoxime and pralidoxime, are insufficient against a number of nerve agents and there is ongoing debate on the benefit of oxime treatment in human OP pesticide poisoning. Up to now, the therapeutic efficacy of Oximes was mostly evaluated in animal models but substantial species differences prevent direct extrapolation of animal data to humans. Hence, it was considered essential to establish relevant experimental in vitro models for the investigation of Oximes as antidotes and to develop computer models for the simulation of oxime efficacy in different scenarios of OP poisoning. Kinetic studies on the various interactions between erythrocyte AChE from various species, structurally different OP and different Oximes provided a basis for the initial assessment of the ability of Oximes to reactivate inhibited AChE. In the present study, in vitro enzyme-kinetic and pharmacokinetic data from a minipig model of dimethoate poisoning and oxime treatment were used to calculate dynamic changes of AChE activities. It could be shown that there is a close agreement between calculated and in vivo AChE activities. Moreover, computer simulations provided insight into the potential and limitations of oxime treatment. In the end, such data may be a versatile tool for the ongoing discussion of the pros and cons of oxime treatment in human OP pesticide poisoning.
