Ondrej Soukup

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  Available from: Ondrej Soukup

  Article: The summary on non-reactivation cholinergic properties of oxime reactivators: the interaction with muscarinic and nicotinic receptors.

  O Soukup, D Jun, G Tobin, K Kuca
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  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.
  Archive für Toxikologie 11/2012; · 4.67 Impact Factor
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  Available from: Ondrej Soukup

  Article: The interaction of standard oxime reactivators with hemicholinium-3 sensitive choline carriers.

  O Soukup, Z Kristofikova, D Jun, V Tambor, D Ripova, K Kuca
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  ABSTRACT: Organophosphorus poisoning manifests as a cholinergic syndrome due to an inhibition of acetylcholinesterase. It is treated symptomatically by anticholinergics and oxime reactivators are used as causal antidotes. Reactivators possess a complex mechanism of action and interact at various levels of the cholinergic transmission. The aim of this study was to investigate the effect of standard oxime reactivators (HI-6, obidoxime, trimedoxime, methoxime and pralidoxime) on the hemicholinium-3 sensitive carriers, which are involved in the high-affinity choline uptake (HACU) transport, a key regulatory step in the synthesis of acetylcholine. The activity of the carriers was estimated in vitro on hippocampal synaptosomes using the substrate (3H)-choline and the competitive inhibitor (3H)-hemicholinium-3. Furthermore, the effect of the reactivators on the fluidity of hippocampal membranes was assessed. All tested compounds, except methoxime, showed an acute inhibitory effect on the carriers, however, only at μM concentrations. Trimedoxime showed the highest potency to inhibit HACU among all tested compounds (I(max) 62%, IC(50)=3 μM). All compounds, except HI-6, influenced also a membrane fluidity in the region of the hydrophilic heads of phospholipid bilayer, nevertheless, only methoxime was able to penetrate more deeply into the hydrocarbon core. We suggest that the direct interaction of oxime reactivators with the carrier protein (HI-6 and trimedoxime) and/or the changes in carrier conformation mediated by alterations in membrane fluidity (trimedoxime, obidoxime and pralidoxime) could occur here. The influence of reactivators on the carriers could be unfavorable in the case of their prolonged administration in vivo. From this point of view, the application of methoxime appears to be the best.
  Toxicology Letters 06/2012; 212(3):315-9. · 3.23 Impact Factor
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  Available from: Kamil Kuca

  Article: The effect of trimedoxime on acetylcholinesterase and on the cholinergic system of the rat bladder

  Soukup Ondrej, Holas Ondrej, Binder Jiri, Killy Kumar, Tobin Gunnar, Jun Daniel, Fusek Josef, Kuca Kamil
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  ABSTRACT: Trimedoxime is a bisquaternary oxime that is widely used in the treatment of organophosphorous poisoningcaused by tabun and paraoxon. We tested its affinity to acetylcholinesterase (AChE), its mechanism ofinteraction 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 weakinhibition. Its interaction with AChE seems to be very similar to obidoxime – one aromatic nucleus interactswith the peripheral anionic site and the other with the residues TYR337 and TYR341 inside the cavity. Alsothe oxime moiety is moving towards the catalytic triade ready for the reactivation of the inhibited AChE. Inthe organ bath experiment no significant effect of trimedoxime was observed on the contraction of thedetrusor caused by the muscarinic agonist metacholine.
  Journal of Applied Biomedicine. 01/2010;
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  Available from: Ondrej Soukup

  Article: Oxime reactivators and their in vivo and in vitro effects on nicotinic receptors.

  O Soukup, J Krůšek, M Kaniaková, U K Kumar, M Oz, D Jun, J Fusek, K Kuča, G Tobin
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  ABSTRACT: Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.
  Physiological research / Academia Scientiarum Bohemoslovaca 05/2011; 60(4):679-86. · 1.55 Impact Factor
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  Article: The effect of oxime reactivators on muscarinic receptors: functional and binding examinations.

  O Soukup, U K Kumar, J Proska, L Bratova, A Adem, D Jun, J Fusek, K Kuca, G Tobin
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  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.
  Environmental toxicology and pharmacology. 05/2011; 31(3):364-70.