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Kamil Kuca - One of the best experts on this subject based on the ideXlab platform.
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Toxicology Mechanisms and Methods, 2009;19(3): 232–238
2016Co-Authors: Jiri Kassa, Kamil Kuca, Kamil Musilek, Jana Zdarova Karasova, Youngsik JungAbstract:A comparison of the neuroprotective efficacy of newly developed oximes (K117, K127) and currently available oxime (Obidoxime) in tabun-poisoned rat
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Entry of oxime K027 into the different parts of rat brain: Comparison with Obidoxime and oxime HI-6
Journal of Applied Biomedicine, 2014Co-Authors: Jana Žďárová Karasová, Jiří Kassa, Filip Zemek, Kamil KucaAbstract:Abstract Acetylcholinesterase reactivators (oximes) are highly hydrophilic compounds. This factor is considered to limit their distribution through the human body, especially into the central nervous system. However, some results contradict this hypothesis and confirm low concentrations of oximes inside the CNS. This study aims to verify oxime penetration through the blood–brain barrier, and into different brain regions. It has been confirmed that oximes can penetrate the BBB after therapeutic dose administration (0.73%, 0.69%, and 0.52% corresponding to Obidoxime, HI-6, and new oxime K027). Although the whole brain level of K027 seems to be lower compared with other oximes we have to keep in mind that these numbers represent only a percentage of the concentration found in plasma. So, for more adequate comparison it is essential to have a look at the actual concentration of oximes in the wet brain tissue: 106.6 ± 19.87 ng/g (K027), 49.88 ± 10.21 ng/g (Obidoxime) and 86.51 ± 42.37 ng/g (HI-6), where concentration of K027 was one order of magnitude higher than Obidoxime and HI-6. In spite of the fact that the distribution of oximes into the CNS is minimal and concentrations differ from section to section, reasonable reactivation should still occur.
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www.mdpi.com/journal/ijms In Vitro Ability of Currently Available Oximes to Reactivate
2013Co-Authors: Organophosphate Pesticide-inhibited Human, Lucie Musilova, Kamil Musilek, Daniel Jun, Kamil KucaAbstract:Abstract: We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, Obidoxime, methoxime, trimedoxime and HI-6) to reactivate human acetylcholinesterase (AChE), inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos). We also tested reactivation of human butyrylcholinesterase (BChE) with the aim of finding a potent oxime, suitable to serve as a ―pseudocatalytic ‖ bioscavenger in combination with this enzyme. Such a combination could allow an increase of prophylactic and therapeutic efficacy of the administered enzyme. According to our results, the best broad-spectrum AChE reactivators were trimedoxime and Obidoxime in the case of paraoxon, leptophos-oxon, and methamidophos-inhibited AChE. Methamidophos an
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characterization of the anticholinergic properties of Obidoxime functional examinations of the rat atria and the urinary bladder
Toxicology Mechanisms and Methods, 2010Co-Authors: Ondrej Soukup, Daniel Jun, J Fusek, Gunnar Tobin, Uday Killi Kumar, Kamil KucaAbstract:Obidoxime, a well-known bis-pyridinium reactivator, is often the preferred antidote of organophosphorus poisoning caused by pesticides and tabun. It is also considered to be an allosteric modulator of muscarinic receptors, preferably M2 sub-type. This study compared the effect of Obidoxime and atropine in vivo and in vitro on the cholinergic stimulation of the rat heart (M2) and the urinary bladder (M3). The results showed that Obidoxime exerts anti-muscarinic effects, that may play an important role in the treatment of organophosphourus poisoning, and that the muscarinic receptor inhibition profile shows M2 receptor selectivity. This anti-muscarinic effect is much smaller that the effect of atropine and might be due to the allosteric inhibition of the receptors. The results also indicate that the acetylcholinesterase inhibition and the muscarinic receptor antagonism occur at different concentrations and dose levels.
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a comparison of the reactivating and therapeutic efficacy of newly developed oximes k347 k628 with commonly used oximes Obidoxime hi 6 against tabun in rats and mice
Drug and Chemical Toxicology, 2010Co-Authors: Jiri Kassa, Jana Žďárová Karasová, Kamil Kuca, Kamil MusilekAbstract:The potency of newly developed reactivators of nerve agent-inhibited acetylcholinesterase (K347, K628) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with currently available oximes (Obidoxime, the oxime HI-6), using in vivo methods. Studies that determined the percentage of reactivation of tabun-inhibited blood and tissue acetycholinesterase in poisoned rats showed that the reactivating efficacy of both newly developed oximes is comparable with the oxime HI-6, but it is significantly lower than the reactivating effects of Obidoxime. The monopyridinium oxime, K347, was also found to be able to reduce lethal toxic effects in tabun-poisoned mice, while the therapeutic efficacy of another newly developed bispyridinium oxime, K628, was negligible. The therapeutic efficacy of K347 was higher than the potency of the oxime, HI-6, but it was lower than the therapeutic effects of Obidoxime. Thus, the reactivating and therapeutic potency of both newly developed oximes (K347, K628) was not more effective then currently available oximes, and therefore, they are not suitable for the replacement of commonly used oximes (especially Obidoxime) for the treatment of acute tabun poisoning.
Franz Worek - One of the best experts on this subject based on the ideXlab platform.
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pseudocatalytic scavenging of the nerve agent vx with human blood components and the oximes Obidoxime and hi 6
Archives of Toxicology, 2017Co-Authors: Timo Wille, H Thiermann, Jens Von Der Wellen, Franz WorekAbstract:Despite six decades of extensive research in medical countermeasures against nerve agent poisoning, a broad spectrum acetylcholinesterase (AChE) reactivator is not yet available. One current approach is directed toward synthesizing oximes with high affinity and reactivatability toward butyrylcholinesterase (BChE) in plasma to generate an effective pseudocatalytic scavenger. An interim solution could be the administration of external AChE or BChE from blood products to augment pseudocatalytic scavenging with slower but clinically approved oximes to decrease nerve agent concentrations in the body. We here semiquantitatively investigate the ability of Obidoxime and HI-6 to decrease the inhibitory activity of VX with human AChE and BChE from whole blood, erythrocyte membranes, erythrocytes, plasma, clinically available fresh frozen plasma and packed red blood cells. The main findings are that whole blood showed a VX concentration-dependent decrease in inhibitory activity with HI-6 being more potent than Obidoxime. Using erythrocytes and erythrocyte membranes again, HI-6 was more potent compared to Obidoxime. With freshly prepared plasma, Obidoxime and HI-6 showed comparable results for the decrease in VX. The use of the clinically available blood products revealed that packed red blood cells showed similar kinetics as fresh erythrocytes. Fresh frozen plasma resulted in a slower and incomplete decrease in inhibitory plasma compared to freshly prepared plasma. In conclusion, the administration of blood products in combination with available oximes augments pseudocatalytic scavenging and might be useful to decrease the body load of persistent, highly toxic nerve agents.
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Reactivation of nerve agent-inhibited human acetylcholinesterase by Obidoxime, HI-6 and Obidoxime+HI-6: Kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics.
Toxicology, 2016Co-Authors: Franz Worek, H Thiermann, Marianne Koller, Timo WilleAbstract:Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of Obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of Obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of Obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.
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reactivation of nerve agent inhibited human acetylcholinesterase by Obidoxime hi 6 and Obidoxime hi 6 kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics
Toxicology, 2016Co-Authors: Franz Worek, H Thiermann, Marianne Koller, Timo WilleAbstract:Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of Obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of Obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of Obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.
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repetitive Obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning a case report
Toxicology Letters, 2016Co-Authors: Dirk Steinritz, H Thiermann, Franz Worek, Florian Eyer, Harald JohnAbstract:Abstract Accidental self-poisoning or deliberate use in suicidal intent of organophosphorus pesticides (OPP), which are widely used in agriculture, represent a health problem worldwide. Symptoms of poisoning are characterized by acute cholinergic crisis caused by inhibition of acetylcholinesterase. A 75-year-old male patient ingested 20 ml of an OPP solution containing 10% methamidophos in suicidal intent. In the course of poisoning typical clinical symptoms of cholinergic crisis (miosis, bradycardia, hypotension, hypersalivation and impairment of neurologic status) were evident. Butyryl (plasma) cholinesterase (BChE) and red blood cell acetylcholinesterase (RBC-AChE) revealed decreased activities, thus specific treatment with the enzyme reactivator Obidoxime was started. Inhibitory activity of the patient’s plasma indicated significant amounts of persisting methamidophos in the circulation and was still found on day 4 after ingestion. Due to missing spontaneous breathing on day 6, Obidoxime was administered again. Afterwards a significant increase of RBC-AChE activity was found. The patient was extubated on day 10 and a restitution ad integrum was achieved. In conclusion, Obidoxime is a potent reactivator of OPP-inhibited AChE. A repetitive and prolonged administration of Obidoxime should be considered in cases of severe methamidophos poisoning and should be tailored with an advanced analytical biomonitoring.
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Transport study of adsorptively Obidoxime-loaded nanoparticles on an in vitro BBB model.
2013Co-Authors: Sylvia Wagner, Franz Worek, Jurgen Kufleitner, Jorg Kreuter, Anja Zensi, Miriam Dadparvar, Sascha Wien, Judith Bungert, Tikva Vogel, Hagen Von BriesenAbstract:Transport study of adsorptively Obidoxime-loaded nanoparticles on an in vitro BBB model.
Jiri Kassa - One of the best experts on this subject based on the ideXlab platform.
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Toxicology Mechanisms and Methods, 2009;19(3): 232–238
2016Co-Authors: Jiri Kassa, Kamil Kuca, Kamil Musilek, Jana Zdarova Karasova, Youngsik JungAbstract:A comparison of the neuroprotective efficacy of newly developed oximes (K117, K127) and currently available oxime (Obidoxime) in tabun-poisoned rat
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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 and therapeutic efficacy of newly developed oximes k347 k628 with commonly used oximes Obidoxime hi 6 against tabun in rats and mice
Drug and Chemical Toxicology, 2010Co-Authors: Jiri Kassa, Jana Žďárová Karasová, Kamil Kuca, Kamil MusilekAbstract:The potency of newly developed reactivators of nerve agent-inhibited acetylcholinesterase (K347, K628) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with currently available oximes (Obidoxime, the oxime HI-6), using in vivo methods. Studies that determined the percentage of reactivation of tabun-inhibited blood and tissue acetycholinesterase in poisoned rats showed that the reactivating efficacy of both newly developed oximes is comparable with the oxime HI-6, but it is significantly lower than the reactivating effects of Obidoxime. The monopyridinium oxime, K347, was also found to be able to reduce lethal toxic effects in tabun-poisoned mice, while the therapeutic efficacy of another newly developed bispyridinium oxime, K628, was negligible. The therapeutic efficacy of K347 was higher than the potency of the oxime, HI-6, but it was lower than the therapeutic effects of Obidoxime. Thus, the reactivating and therapeutic potency of both newly developed oximes (K347, K628) was not more effective then currently available oximes, and therefore, they are not suitable for the replacement of commonly used oximes (especially Obidoxime) for the treatment of acute tabun poisoning.
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a comparison of the potency of newly developed oximes k347 k628 and currently available oximes Obidoxime hi 6 to counteract acute neurotoxic effects of tabun in rats
Acta Medica (Hradec Kralove Czech Republic), 2010Co-Authors: Jiri Kassa, Jana Žďárová Karasová, Kamil Musilek, Sandra Tesarova, Kamil KucaAbstract:The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (Obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, Obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 microg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of Obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of Obidoxime, they are not a suitable replacement for Obidoxime for the treatment of acute tabun poisonings.
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a comparison of the neuroprotective efficacy of newly developed oximes k117 k127 and currently available oxime Obidoxime in tabun poisoned rats
Toxicology Mechanisms and Methods, 2009Co-Authors: Jiri Kassa, Jana Žďárová Karasová, Kamil Kuca, Kamil Musilek, And Youngsik JungAbstract:The potency of newly developed bispyridinium compounds (K117, K127) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oxime (Obidoxime) using functional observational battery. The neuroprotective effects of atropine alone and atropine combined with one of three bispyridinium oximes (K117, K127, Obidoxime) on rats poisoned with tabun at a sublethal dose (180 microg/kg i.m.; 80% of LD(50) value) were studied. Tabun-induced neurotoxicity was monitored using a functional observational battery and automatic measurement of motor activity at 24 h following tabun challenge. The results indicated that all tested oximes combined with atropine enabled tabun-poisoned rats to survive 24 h following tabun challenge while one tabun-poisoned rats died within 24 h after tabun poisoning when the rats were treated with atropine alone. Newly developed oxime K127 combined with atropine was the most effective in decreasing tabun-induced neurotoxicity in the case of sublethal poisonings among all oximes tested. Nevertheless, the differences of neuroprotective efficacy between K127 and Obidoxime are not sufficient to replace Obidoxime by K127 for the treatment of acute tabun poisonings.
H Thiermann - One of the best experts on this subject based on the ideXlab platform.
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pseudocatalytic scavenging of the nerve agent vx with human blood components and the oximes Obidoxime and hi 6
Archives of Toxicology, 2017Co-Authors: Timo Wille, H Thiermann, Jens Von Der Wellen, Franz WorekAbstract:Despite six decades of extensive research in medical countermeasures against nerve agent poisoning, a broad spectrum acetylcholinesterase (AChE) reactivator is not yet available. One current approach is directed toward synthesizing oximes with high affinity and reactivatability toward butyrylcholinesterase (BChE) in plasma to generate an effective pseudocatalytic scavenger. An interim solution could be the administration of external AChE or BChE from blood products to augment pseudocatalytic scavenging with slower but clinically approved oximes to decrease nerve agent concentrations in the body. We here semiquantitatively investigate the ability of Obidoxime and HI-6 to decrease the inhibitory activity of VX with human AChE and BChE from whole blood, erythrocyte membranes, erythrocytes, plasma, clinically available fresh frozen plasma and packed red blood cells. The main findings are that whole blood showed a VX concentration-dependent decrease in inhibitory activity with HI-6 being more potent than Obidoxime. Using erythrocytes and erythrocyte membranes again, HI-6 was more potent compared to Obidoxime. With freshly prepared plasma, Obidoxime and HI-6 showed comparable results for the decrease in VX. The use of the clinically available blood products revealed that packed red blood cells showed similar kinetics as fresh erythrocytes. Fresh frozen plasma resulted in a slower and incomplete decrease in inhibitory plasma compared to freshly prepared plasma. In conclusion, the administration of blood products in combination with available oximes augments pseudocatalytic scavenging and might be useful to decrease the body load of persistent, highly toxic nerve agents.
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Reactivation of nerve agent-inhibited human acetylcholinesterase by Obidoxime, HI-6 and Obidoxime+HI-6: Kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics.
Toxicology, 2016Co-Authors: Franz Worek, H Thiermann, Marianne Koller, Timo WilleAbstract:Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of Obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of Obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of Obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.
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reactivation of nerve agent inhibited human acetylcholinesterase by Obidoxime hi 6 and Obidoxime hi 6 kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics
Toxicology, 2016Co-Authors: Franz Worek, H Thiermann, Marianne Koller, Timo WilleAbstract:Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of Obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of Obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of Obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.
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repetitive Obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning a case report
Toxicology Letters, 2016Co-Authors: Dirk Steinritz, H Thiermann, Franz Worek, Florian Eyer, Harald JohnAbstract:Abstract Accidental self-poisoning or deliberate use in suicidal intent of organophosphorus pesticides (OPP), which are widely used in agriculture, represent a health problem worldwide. Symptoms of poisoning are characterized by acute cholinergic crisis caused by inhibition of acetylcholinesterase. A 75-year-old male patient ingested 20 ml of an OPP solution containing 10% methamidophos in suicidal intent. In the course of poisoning typical clinical symptoms of cholinergic crisis (miosis, bradycardia, hypotension, hypersalivation and impairment of neurologic status) were evident. Butyryl (plasma) cholinesterase (BChE) and red blood cell acetylcholinesterase (RBC-AChE) revealed decreased activities, thus specific treatment with the enzyme reactivator Obidoxime was started. Inhibitory activity of the patient’s plasma indicated significant amounts of persisting methamidophos in the circulation and was still found on day 4 after ingestion. Due to missing spontaneous breathing on day 6, Obidoxime was administered again. Afterwards a significant increase of RBC-AChE activity was found. The patient was extubated on day 10 and a restitution ad integrum was achieved. In conclusion, Obidoxime is a potent reactivator of OPP-inhibited AChE. A repetitive and prolonged administration of Obidoxime should be considered in cases of severe methamidophos poisoning and should be tailored with an advanced analytical biomonitoring.
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pharmacokinetics of Obidoxime in patients poisoned with organophosphorus compounds
Toxicology Letters, 2010Co-Authors: H Thiermann, N Felgenhauer, T Zilker, Florian Eyer, Rudolf Pfab, Peter Eyer, Franz WorekAbstract:Abstract Objectives Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An Obidoxime plasma level in the range of 10–20 μM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients. Methods After admission to the intensive care unit (ICU) the Obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24 h) was started and maintained as long as reactivation was possible. Plasma concentrations of Obidoxime were determined by HPLC. Results A total amount of 2269 ± 1726 mg Obidoxime was infused over 65 h ± 55 h resulting in a steady state plasma concentration of 14.5 ± 7.3 μM. Obidoxime was eliminated with t 1/2(1) 2.2 and t 1/2(2) 14 h. The volumes of distribution amounted to 0.32 ± 0.1 L/kg ( V (1) ) and 0.28 ± 0.12 ( V (2) ) L/kg. Postmortem examination of tissue in one patient showed Obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration. Conclusions Using the suggested Obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties.
L Szinicz - One of the best experts on this subject based on the ideXlab platform.
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testing of antidotes for organophosphorus compounds experimental procedures and clinical reality
Toxicology, 2007Co-Authors: Peter Eyer, H Thiermann, L Szinicz, Franz Worek, T ZilkerAbstract:Abstract According to current knowledge, inhibition of acetylcholinesterase (AChE) is a very important toxic action of organphosphorus compounds (OP). Hence, it is obvious to follow the AChE activity in order to quantify the degree of inhibition and to assess possible reactivation. Red blood cell (RBC)-AChE provides an easily accessible source to follow the AChE status also in humans. There are many reports underlining the appropriateness of RBC-AChE as a surrogate parameter that mirrors the synaptic enzyme. With this tool at hand, we can study the kinetic parameters of inhibition, spontaneous and oxime-induced reactivation, as well as aging with human RBCs under physiological conditions in vitro . Moreover, we can simulate the influence of inhibitor and reactivator on enzyme activity and can calculate what happens when both components change with time. Finally, we can correlate under controlled conditions the AChE-status in intoxicated patients with the clinical signs and symptoms and determine the time-dependent changes of the oxime and OP concentration. Data of a clinical trial performed in Munich to analyze the value of Obidoxime has elucidated that Obidoxime worked as expected from in vitro studies. Following a 250 mg bolus, Obidoxime was administered by continuous infusion at 750 mg/24 h aimed at maintaining a plasma concentration of 10–20 μM Obidoxime. This oxime concentration reactivated RBC-AChE > 20% of normal in most cases of OP poisoning by diethylphosphoryl compounds within a few hours. The degree of reactivation fitted theoretical calculations very well when the Obidoxime and paraoxon concentrations were fed into the model. Only in a few cases reactivation was much lower than expected. The reason for this effect is probably based on the polymorphism of paraoxonase (PON1) in that the 192 arginine phenotype does hardly hydrolyze the arising diethylphosphoryl Obidoxime. While this variable may complicate a proper assessment even more, we are confident that the in vitro evaluation of all relevant kinetic data enables the prediction of probable effectiveness in humans. These studies also help to understand therapeutic failures and to define scenarios where oximes are virtually ineffective. These include poisonings with rapidly aging phosphylated AChE, late start with an effective oxime and too early discontinuation of oximes in poisonings with a persistent OP. The experience gathered with the experimental and therapeutic approaches to human poisoning by OP pesticides may be helpful when oximes have to be selected against nerve agents.
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Effect of organophosphorus hydrolysing enzymes on Obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase
Archives of Toxicology, 2004Co-Authors: S. Herkenhoff, L Szinicz, V. K. Rastogi, T.-c. Cheng, J. J. Defrank, F WorekAbstract:The reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) by oximes results inevitably in the formation of highly reactive phosphyloximes (POX), which may re-inhibit the enzyme. An impairment of net reactivation by stable POX was found with 4-pyridinium aldoximes, e.g. Obidoxime, and a variety of OP compounds. In this study the effect of organophosphorus hydrolase (OPH), organophosphorus acid anhydrolase (OPAA) and diisopropylfluorophosphatase (DFPase) on Obidoxime-induced reactivation of human acetylcholinesterase (AChE) inhibited by different OPs was investigated. Reactivation of paraoxon-, sarin-, soman- and VX-inhibited AChE by Obidoxime was impaired by POX-induced re-inhibition whereas no deviation of pseudo first-order kinetics was observed with tabun, cyclosarin and VR. OPH prevented (paraoxon) or markedly reduced the POX-induced re-inhibition (VX, sarin, soman), whereas OPAA and DFPase were without effect. Additional experiments with sarin-inhibited AChE indicate that the POX hydrolysis by OPH was concentration-dependent. The activity of OP-inhibited AChE was not affected by OPH in the absence of Obidoxime. In conclusion, OPH may be a valuable contribution to the therapeutic regimen against OP poisoning by accelerating the degradation of both the parent compound, OP, and the reaction product, POX.
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internal standard high performance liquid chromatography method for the determination of Obidoxime in urine of organophosphate poisoned patients
Journal of Chromatography B: Biomedical Sciences and Applications, 2001Co-Authors: C Grasshoff, H Thiermann, T Zilker, Thomas Gillessen, L SziniczAbstract:Obidoxime is an antidote approved for reactivation of inhibited acetylcholinesterase in organophosphate poisoning. HPLC methods were described for its determination in blood or aqueous solutions but not for the determination in urine. Since data for renal Obidoxime excretion ranged from 2.2 to 84% of administered dose in healthy volunteers depending on the route of administration and little is known about pharmacokinetics of Obidoxime in severely intoxicated patients we developed an internal standard (HI 6) reversed-phase HPLC method for determining Obidoxime in urine. The mobile phase consisted of methanol, the counter ion 1-heptane sulfonic acid and tetrabutylammonium phosphate, the stationary phase involved a 5 μm reversed-phase column (125×4 mm). Obidoxime was detected spectrophotometrically at 288 nm. The limit of quantification (LOQ) was 1 μM, the limit of detection (LOD) 0.5 μM. Linear calibration curves were obtained in a concentration range from 1 to 1000 μM. Intra- and inter-day precision C.V.s were below 4%. Accuracy was 95.9% in the LOQ range. Using this method, we were able to quantify Obidoxime in urine of an organophosphate poisoned patient. Based on this data we calculated that 58% of the administered dose was excreted in the urine.
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Modern strategies in therapy of organophosphate poisoning.
Toxicology letters, 1999Co-Authors: H Thiermann, L Szinicz, F Eyer, F Worek, P Eyer, N Felgenhauer, T ZilkerAbstract:Considering the various microscopic reactions as well as toxicokinetic and pharmacokinetic principles in therapy of organophosphate poisoning, the administration of Obidoxime by an initial bolus dose followed by continuous infusion appears rational. Using this protocol, six patients each with parathion or oxydemeton methyl poisoning were treated. In parathion poisoning, reactivation was possible up to 7 days. At paraoxon concentrations > 0.1 microM Obidoxime only partially reactivated acetylcholinesterase (AChE) of erythrocytes in vivo although reactivation could be assessed in vitro, which roughly fitted theoretical calculations. AChE-inhibitory material was detected up to 5 days. Cholinergic signs soon subsided when AChE was above 20% of normal, and atropine plasma levels could be kept below 7 ng/ml. In one patient brain damage persisted. Oxydemeton methyl poisoning responded to Obidoxime therapy only when the oxime was instituted shortly after poisoning. Out of six patients one died. No intermediate syndrome and no signs of permanent hepatic dysfunction were found in the 12 patients.
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reactivating potency of Obidoxime pralidoxime hi 6 and hlo 7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds
Archives of Toxicology, 1998Co-Authors: Franz Worek, R Widmann, O Knopff, L SziniczAbstract:The treatment of poisoning by highly toxic organophosphorus compounds (nerve agents) is unsatisfactory. Until now, the efficacy of new potential antidotes has primarily been evaluated in animals. However, the extrapolation of these results to humans is hampered by species differences. Since oximes are believed to act primarily through reactivation of inhibited acetylcholinesterase (AChE) and erythrocyte AChE is regarded to be a good marker for the synaptic enzyme, the reactivating potency can be investigated with human erythro‐cyte AChE in vitro. The present study was undertaken to evaluate the ability of various oximes at concentrations therapeutically relevant in humans to reactivate human erythrocyte AChE inhibited by different nerve agents. Isolated human erythrocyte AChE was inhibited with soman, sarin, cyclosarin, tabun or VX for 30 min and reactivated in the absence of inhibitory activity over 5–60 min by Obidoxime, pralidoxime, HI 6 or HLo 7 (10 and 30 μM). The AChE activity was determined photometrically. The reactivation of human AChE by oximes was dependent on the organophosphate used. After soman, sarin, cyclosarin, or VX the reactivating potency decreased in the order HLo 7 > HI 6 > Obidoxime > pralidoxime. Obidoxime and pralidoxime were weak reactivators of cyclosarin-inhibited AChE. Only Obidoxime and HLo 7 reactivated tabun-inhibited AChE partially (20%), while pralidoxime and HI 6 were almost ineffective (5%). Therefore, HLo 7 may serve as a broad-spectrum reactivator in nerve agent poisoning at doses therapeutically relevant in humans.