| 1. |
- Soukup, Ondrej, et al.
(författare)
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The effect of trimedoxime on acetylcholinesterase and on the cholinergic system of the rat bladder
- 2010
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Ingår i: Journal of Applied Biomedicine. - 1214-021X. ; 8:2, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- Trimedoxime is a bisquaternary oxime that is widely used in the treatment of organophosphorous poisoning caused by tabun and paraoxon. We tested its affinity to acetylcholinesterase (AChE), its mechanism of interaction and effect on the cholinergic system of the rat bladder. The half maximal inhibitory concentration (IC50) of trimedoxime to recombinant AChE was found to be 82.0 mM +/- 30.1 mM. This represents a weak inhibition. Its interaction with AChE seems to be very similar to obidoxime - one aromatic nucleus interacts with the peripheral anionic site and the other with the residues TYR337 and TYR341 inside the cavity. Also the oxime moiety is moving towards the catalytic triade ready for the reactivation of the inhibited AChE. In the organ bath experiment no significant effect of trimedoxime was observed on the contraction of the detrusor caused by the muscarinic agonist metacholine.
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| 2. |
- Killi, Uday Kumar, et al.
(författare)
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Invitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat.
- 2014
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Ingår i: Clinical and experimental pharmacology & physiology. - : Wiley. - 1440-1681 .- 0305-1870. ; 41:2, s. 139-46
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Tidskriftsartikel (refereegranskat)abstract
- Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the invitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (<5μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (<5μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (>5μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.
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| 3. |
- Kuca, Kamil, et al.
(författare)
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Pralidoxime – the gold standard of acetylcholinesterase reactivators – reactivation in vitro efficacy
- 2010
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Ingår i: Bratislava Medical Journal. - 0006-9248. ; 111:9, s. 502-504
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In this work, we aim to summarize the universality of this compound, its reactivation potential when different cholinesterase inhibitors are used. Background: 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. Methods: 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 °C, pH 8, and 10-3and 10-5M concentrations of AChE reactivators. The activities of brain AChE were measured by a potentio-static method. Results: 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. Conclusion: 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.
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| 4. |
- Soukup, Ondrej, et al.
(författare)
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A Resurrection of 7-MEOTA: A Comparison with Tacrine
- 2013
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Ingår i: Current Alzheimer Research. - 1567-2050. ; 10:8, s. 893-906
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer´s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound – tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and “safer” metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
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| 5. |
- Soukup, Ondrej, et al.
(författare)
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Characterization of the anticholinergic properties of obidoxime; functional examinations of the rat atria and the urinary bladder.
- 2010
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Ingår i: Toxicology mechanisms and methods. - : Informa UK Limited. - 1537-6524 .- 1537-6516. ; 20:7, s. 428-433
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 6. |
- Soukup, Ondrej, et al.
(författare)
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Interaction of Nerve Agent Antidotes with Cholinergic Systems
- 2010
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Ingår i: CURRENT MEDICINAL CHEMISTRY. - 0929-8673. ; 17:16, s. 1708-1718
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Forskningsöversikt (refereegranskat)abstract
- The poisoning with organophosphorus compounds represents a life threatening danger especially in the time of terroristic menace. No universal antidote has been developed yet and other therapeutic approaches not related to reactivation of acetylcholinesterase are being investigated. This review describes the main features of the cholinergic system, cholinergic receptors, cholinesterases and their inhibitors. It also focuses on the organophosphorus nerve agents, their properties, effects and a large part describes various possibilities in treatments, mainly traditional oxime therapies based on reactivation of AChE. Furthermore, non-cholinesterase coupled antidotal effects of the oximes are thoroughly discussed. These antidotal effects principally include oxime interactions with muscarinic and nicotinic receptors.
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| 7. |
- Soukup, Ondrej, et al.
(författare)
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The effect of oxime reactivators on muscarinic receptors: Functional and binding examinations.
- 2011
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Ingår i: Environmental toxicology and pharmacology. - : Elsevier BV. - 1872-7077 .- 1382-6689. ; 31:3, s. 364-70
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Tidskriftsartikel (refereegranskat)abstract
- The antidotal treatment of organophosphorus poisoning is still a problematic issue since no versatile antidote has been developed yet. In our study, we focused on an interesting property, which does not relate to the reactivation of inhibited acetylcholinesterase (AChE) of some oximes, but refers to their anti-muscarinic effects which may contribute considerably to their treatment efficacy. One standard reactivator (HI-6) and two new compounds (K027 and K203) have been investigated for their antimuscarinic properties. Anti-muscarinic effects were studies by means of an in vitro stimulated atrium preparation (functional test), the [(3)H]-QNB binding assay and G-protein coupled receptor assay (GPCR, beta-Arrestin Assay). Based on the functional data HI-6 demonstrates the highest anti-muscarinic effect. However, only when comparing [(3)H]-QNB binding results and GPCR data, K203 shows a very promising compound with regard to anti-muscarinic potency. The therapeutic impact of these findings has been discussed.
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| 8. |
- Soukup, Ondrej, et al.
(författare)
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The summary on non-reactivation cholinergic properties of oxime reactivators: the interaction with muscarinic and nicotinic receptors.
- 2013
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Ingår i: Archives of toxicology. - : Springer Science and Business Media LLC. - 1432-0738 .- 0340-5761. ; 87:4, s. 711-9
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Forskningsöversikt (refereegranskat)abstract
- Organophosphorus inhibitors (OP) of acetylcholinesterase (AChE) represent a group of highly toxic compounds. The treatment of OP intoxication is, however, insufficiently ensured. Currently, two main categories of drugs-anticholinergics and oxime reactivators- are employed as antidotes. Oximes have been reported to act at several levels of the cholinergic transmission, and among the non-reactivation effects, the interaction with cholinergic receptors stands out. This review addresses issues correlated with non-reactivating effects of oxime reactivators with a special focus on the muscarinic and nicotinic receptors, but involvement of other cholinergic structures such as AChE and choline uptake carriers are discussed too. It can be concluded that the oxime reactivators show a variation in their antagonistic effect on the muscarinic and nicotinic receptors, which is likely to be of significance in the treatment of OP poisoning. In vitro data reported oximes to exert higher efficacy on the muscarinic M2 subtype than on the AChE. However, this effect seemed to be subtype specific since the antagonistic M3 effect was lower. Also, and importantly, the antimuscarinic effect was larger than that on nicotinic receptors. Even though atropine showed a much higher muscarinic antagonism, it is supposed that non-reactivation properties of oxime reactivators play a significant role in the treatment of OP poisoning.
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