Efficacy of structural homoloques and isomers of pralidoxime in reactivation of immobilised acetylcholinesterase inhibited with sarin, cyclosarin and soman.
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OBJECTIVES: Quantification of efficacy of monopyridinium isomers and homologs derived from clinically used Pralidoxime within reactivation of acetylcholinesterase inhibited with organophosphorus nerve agents. METHODS: This work uses the colorimetric biosensor called Detehit - cotton cloth with immobilized enzyme acetylcholinesterase. Biosensor is based on the modificated Ellman's method. RESULTS: The highest reactivation was observed with sarin-inhibited acetylcholinesterase. Substantially lower reactivation was found with the cyclosarin-inhibited enzyme whereas AChE, inhibited by soman could not be effectively reactivated under the given conditions (enzyme inhibition for 2 minutes and subsequent treatment with the reactivator for 15 minutes). CONCLUSION: Our work gives comparison of efficacy of reactivators in dependence on the lenght of alkylene chain and position of aldoxime functional group. Evaluation of effectivity of aldoxime reactivators is provided by simple means. The method allows rapid in vitro evaluation of the reactivators without being disturbed by excess of the organophosphate or reactivator.Keywords:
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The oxime K005 [1,3–bis(2–hydroxyiminomethylpyridinium) propane dibromide] for the reactivation of the enzyme acetylcholinesterase (AChE) inhibited by cyclosarin and VX was tested. Its reactivation potency was not better in comparison with the currently used AChE reactivator – pralidoxime. On the other hand, the oxime K005 has its maximum reactivation ability at the concentration 10 –4 M, which could be achieved for human use. The maximum concentration of pralidoxime was reached at the concentrations 10 –1 M (for cyclosarin) and 10 –3 M (for VX) but these concentrations are not available for the use in vivo.
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The efficacy of a new bispyridinium oxime 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide, called K048, and currently used oximes (pralidoxime, obidoxime, the oxime HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. The new oxime K048 was found to be a more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than pralidoxime (in the case of VX, tabun and cyclosarin), obidoxime (cyclosarin and tabun) and HI-6 (tabun) but it did not reach the efficacy of currently used oximes for the reactivation of acetylcholinesterase inhibited by sarin. Thus, the oxime K048 seems to be a relatively efficacious broad spectrum acetylcholinesterase reactivator and, therefore, it could be useful for the treatment of a nerve agent-exposed population if information about detection of the type of nerve agent is not available.
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Pralidoxime--the gold standard of acetylcholinesterase reactivators--reactivation in vitro efficacy.
In this work, we aim to summarize the universality of this compound, its reactivation potential when different cholinesterase inhibitors are used.Pralidoxime is considered as a gold standard of acetylcholinesterase reactivators--antidotes used in case of nerve agent poisonings. It has been commercially available for many years. However, several studies deem this oxime an old-fashion antidote.Pralidoxime was synthesized at our department. The reactivating efficacy was tested on 10% (w/v) rat brain homogenate that had been incubated with appropriate inhibitor for 30 minutes to reach 96% inhibition of AChE. Then, pralidoxime was added for 10 minutes. Measurements were performed at 25 degrees C, pH 8, and 10(-3) and 10(-5) M concentrations of AChE reactivators. The activities of brain AChE were measured by a potentiostatic method.No sufficient reactivation was achieved at the concentration of 10(-5) M, which is a concentration that can be reached after administration of therapeutic doses. At a higher dose (10(-3) M), pralidoxime reactivated AChE inhibited by paraoxon, chlorpyrifos, Russian VX, VX and sarin.From the obtained results, it is clear that pralidoxime seems to be a poor reactivator of AChE inhibited by organophosphorous AChE inhibitors and thus cannot be labeled as a universal reactivator (Tab. 1, Fig. 3, Ref. 31).
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Three potential reactivators of nerve agents-inhibited acetylcholinesterase: 2-[(hydroxyimino)phenylmethyl]-1-methylpyridinium iodide 3a, 2-[(hydroxyimino)pyridin-2-ylmethyl]-1-methylpyridinium iodide 3b and 2-[(1-hydroxyimino) ethyl]-1-methylpyridinium iodide 3c were synthesized. Their reactivation potency was examined using a standard in vitro reactivation test. A rat brain homogenate was used as the source of acetylcholinesterase. Their reactivation potency was compared with a currently used acetylcholinesterase reactivator - 2-PAM (pralidoxime) 4. All tested reactivators were less effective acetylcholinesterase reactivators compared to 2-PAM. In this study, we also tested the reactivation potency of the oxime 2-PAM against inhibition of acetylcholinesterase by sarin, cyclosarin, VX and tabun. Satisfactory results are shown only for the reactivation sarin- and VX-inhibited acetylcholinesterase.
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1. The efficacy of the oxime HLö-7 and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. 2. Both H oximes (HLö-7, HI-6) were found to be more efficacious reactivators of sarin and VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase is very low and does not reach the reactivating efficacy of obidoxime. In the case of cyclosarin, the oxime HI-6 was only found to be able to sufficiently reactivate cyclosarin-inhibited acetylcholinesterase in vitro. 3. Thus, the oxime HLö-7 does not seem to be more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than HI-6 according to in vitro evaluation of their reactivation potency and, therefore, it is not more suitable to be introduced for antidotal treatment of nerve agent-exposed people than HI-6.
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Searching for new potent acetylcholinesterase (AChE; E.C. 3.1.1.7) reactivators (oximes) is a very time-consuming process. At our department, we are able to synthesize more than 50 new AChE reactivators per year. Owing to this fact, we have to select promising reactivators using our in vitro method (potentiometric titration, pH 8 and temperature 25°C; source of cholinesterases, rat brain homogenate; time of inhibition by nerve agents, 30 min; time of reactivation, 10 min) prior to in vivo experiments. For this purpose, we are using two-phase in vitro evaluation of reactivator potency. In the first phase, reactivation potency of all newly synthesized AChE reactivators is tested at two concentrations: 10−3 M and 10−5 M. Afterwards, all reactivators achieving reactivation potency over 15% (especially at the concentration 10−5 M) are tested. The second phase consists of the measurement of the relationship between concentration of the oxime and its reactivation ability. In most cases, the reactivation bell-shaped curve is obtained. The most potent AChE reactivators are selected and provided for further experiments during our development process.
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Reactivation with bis quaternary aldoxime HI-6, chemical formula 1-(2-hydroxyamino-methylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride of immobilized enzyme acetylcholinesterase inhibited by nerve agent type "G" was studied. This aldoxime is effective in reactivation of sarin-inhibited acetylcholinesterase. Substantially lower reactivation potency was observed with cyclosarin-inhibited enzyme and almost no effect was found for that acetylcholinesterase is the enzyme complex. HI 6 is completely ineffective towards the soman-inhibited enzyme: After a 2-minute inhibition of the enzyme with soman no ability to define reactivator the inhibited enzymes and complexes.
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