Misik J


Full name : Misik Jan

First name : Jan

Mail : University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove

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Country : Czech Republic

Email : honzamisik@seznam.cz

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References (19)

Title : Oxidative stress induced by oxime reactivators of acetylcholinesterase in vitro - Muckova_2019_Toxicol.In.Vitro_56_110
Author(s) : Muckova L , Vanova N , Misik J , Herman D , Pejchal J , Jun D
Ref : Toxicol In Vitro , 56 :110 , 2019
Abstract : In this study, we determined the effect of methoxime (MMB-4), asoxime (HI-6), obidoxime (LuH-6), trimedoxime (TMB-4), and pralidoxime (2-PAM) on redox homeostasis in vitro. Cultured human hepatoma cells (HepG2) were exposed to oximes at concentrations equivalent to their IC50 (assessed using MTT assay) and evaluated 1, 4 and 24h after incubation. Additionally, intact, early and late apoptotic and necrotic cells were quantified by microcapillary flow cytometry. Intracellular levels of oxygen/nitrogen species were determined using two fluorescent probes (2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium). Malondialdehyde and 3-nitrotyrosine were measured by LC-MS/MS. Non-protein thiols and non-protein disulfides were evaluated using HPLC-UV to reflect antioxidant capacity. Oxidative and nitrosative stress was induced by LuH-6, TMB-4 and MMB-4, whereas 2-PAM and HI-6 appeared as weak oxidative stressors with no activity towards nitrosative stress in HepG2 cells. Based on these results, bisquartenary oxime reactivators containing two functional oxime groups at the position 4 of pyridinium ring appear as more intense oxidative and nitrosative inducers. Activation of apoptosis and necrosis do not seem to correlate with generation of RONS. On the other hand, both processes rather reflect MDA concentrations, i.e. the damage of biomolecules.
ESTHER : Muckova_2019_Toxicol.In.Vitro_56_110
PubMedSearch : Muckova_2019_Toxicol.In.Vitro_56_110
PubMedID: 30682493

Title : Orexin supplementation in narcolepsy treatment: A review - Nepovimova_2019_Med.Res.Rev_39_961
Author(s) : Nepovimova E , Janockova J , Misik J , Kubik S , Stuchlik A , Vales K , Korabecny J , Mezeiova E , Dolezal R , Soukup O , Kobrlova T , Pham NL , Nguyen TD , Konecny J , Kuca K
Ref : Med Res Rev , 39 :961 , 2019
Abstract : Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.
ESTHER : Nepovimova_2019_Med.Res.Rev_39_961
PubMedSearch : Nepovimova_2019_Med.Res.Rev_39_961
PubMedID: 30426515

Title : Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators - Hepnarova_2019_Toxicol.Appl.Pharmacol__114776
Author(s) : Hepnarova V , Muckova L , Ring A , Pejchal J , Herman D , Misik J , Hrabinova M , Jun D , Soukup O
Ref : Toxicol Appl Pharmacol , :114776 , 2019
Abstract : The major function of compounds with an oxime moiety attached to a quarternary nitrogen pyridinium ring is to reactivate acetylcholinesterase inhibited by organophosphorus agent (OP). However, other oxime mechanisms (e.g. modulation of cholinergic or glutamatergic receptor) may be involved in the recovery. The main disadvantage of positively charged reactivators is their low ability to penetrate into the brain although crossing the blood brain barrier could be supported via increasing the dose of administered oxime. Thus, this study presents maximal tolerated doses (MTD) for marketed oximes (TMB-4, MMB-4, LuH-6, HI-6, 2-PAM) and the most promising K-oximes (K027, K048, K203) which can be used in OP therapy in the future. No signs of sarin intoxication were observed in mice treated with 100% MTD of HI-6 in contrast to those treated with atropine and only 5% LD50 of HI-6. 100% MTD of HI-6 resulted in levels of 500muM and 12muM in plasma and brain, respectively. This concentration is by a far margin safe with respect to direct effects on neuronal cell viability and, on the other hand, does not have any effects on central NMDA receptors or central nACh receptors. However, a weak antimuscarinic activity in case of LuH-6 and a weak peripheral antinicotinic action in case of TMB-4 and 2-PAM could be observed at their respective 100% MTD dose. These high doses, represented by MTD, are, however, irrelevant to clinical practice since they led to mild to moderate toxic side effects. Therefore, we conclude that clinically used doses of marketed oxime reactivators have no significant direct pharmacological effect on the tested receptors.
ESTHER : Hepnarova_2019_Toxicol.Appl.Pharmacol__114776
PubMedSearch : Hepnarova_2019_Toxicol.Appl.Pharmacol__114776
PubMedID: 31629733

Title : Tacrine and its 7-methoxy derivate\; time-change concentration in plasma and brain tissue and basic toxicological profile in rats - Karasova_2019_Drug.Chem.Toxicol__1
Author(s) : Karasova JZ , Soukup O , Korabecny J , Hroch M , Krejciova M , Hrabinova M , Misik J , Novotny L , Hepnarova V , Kuca K
Ref : Drug & Chemical Toxicology , :1 , 2019
Abstract :
ESTHER : Karasova_2019_Drug.Chem.Toxicol__1
PubMedSearch : Karasova_2019_Drug.Chem.Toxicol__1
PubMedID: 31257938

Title : Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease - Chalupova_2019_Eur.J.Med.Chem_168_491
Author(s) : Chalupova K , Korabecny J , Bartolini M , Monti B , Lamba D , Caliandro R , Pesaresi A , Brazzolotto X , Gastellier AJ , Nachon F , Pejchal J , Jarosova M , Hepnarova V , Jun D , Hrabinova M , Dolezal R , Karasova JZ , Mzik M , Kristofikova Z , Misik J , Muckova L , Jost P , Soukup O , Benkova M , Setnicka V , Habartova L , Chvojkova M , Kleteckova L , Vales K , Mezeiova E , Uliassi E , Valis M , Nepovimova E , Bolognesi ML , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 168 :491 , 2019
Abstract : A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Abeta42 self-aggregation (58.6+/-5.1% at 50muM) as well as hAChE-induced Abeta40 aggregation (48.3+/-6.3% at 100muM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
ESTHER : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedSearch : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedID: 30851693
Gene_locus related to this paper: torca-ACHE

Title : Cholinesterase inhibitor 6-chlorotacrine - in vivo toxicological profile and behavioural effects - Misik_2018_Curr.Alzheimer.Res_15_552
Author(s) : Misik J , Nepovimova E , Pejchal J , Kassa J , Korabecny J , Soukup O
Ref : Curr Alzheimer Res , 15 :552 , 2018
Abstract : BACKGROUND: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti-Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. METHODS: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step-through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. RESULTS: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro-cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. CONCLUSION: Observed effects predetermine 6-chlorotacrine as a potent parent compound for synthesis of novel multifactorial drugs intended to treatment of Alzheimer's disease. Even though 6-chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration.
ESTHER : Misik_2018_Curr.Alzheimer.Res_15_552
PubMedSearch : Misik_2018_Curr.Alzheimer.Res_15_552
PubMedID: 29231138

Title : Activity of cholinesterases in a young and healthy middle-European population: Relevance for toxicology, pharmacology and clinical praxis - Karasova_2017_Toxicol.Lett_277_24
Author(s) : Karasova JZ , Maderycova Z , Tumova M , Jun D , Rehacek V , Kuca K , Misik J
Ref : Toxicol Lett , 277 :24 , 2017
Abstract : The activity of human cholinesterases, erythrocyte acetylcholinesterase (AChE; EC and plasma butyrylcholinesterase (BChE; EC represents an important marker when monitoring exposure to pesticides/nerve agents, and may also be used in occupational medicine in diagnosis and prognosis of some diseases. In this study "normal/baseline" AChE and BChE activity has been investigated in a young and healthy population, with subsequent evaluation of several intra-population factors including sex, age (categories 18-25, 26-35 and 36-45 years old) and smoker status. The modified Ellman's method was used for enzyme activity assessment in 387 young and healthy individuals (201 males and 186 females aged 18-45). A significant inter-sexual difference in AChE and BChE activity was found (AChE: 351+/-67 for males and 377+/-65 for females, (mumol/min)/(mumol of hemoglobin), p<0.001; BChE: 140+/-33 for males and 109+/-29 for females, mukat/l, p<0.001; mean+/-SD). Despite the finding that mean AChE activity somewhat decreased whereas BChE activity grew within the age categories of the tested subjects, no significant effect of age on cholinesterase activity was found (p>0.05). Smoking influenced cholinesterase activity - AChE activity in smokers was elevated (approx. 3% in males; 8% in females) relative to that in non-smokers (p<0.05). Smoking was found not to have any effect on BChE activity. Reference values based on confidence intervals for AChE and BChE activity were established. The presented results might be useful in routine clinical practice where the monitoring of blood AChE and plasma BChE activity is crucial for prognosis and diagnosis of organophosphate poisoning, in occupational medicine and in relevant mass casualty scenarios.
ESTHER : Karasova_2017_Toxicol.Lett_277_24
PubMedSearch : Karasova_2017_Toxicol.Lett_277_24
PubMedID: 28465191

Title : The Evaluation of the Reactivating and Neuroprotective Efficacy of Two Newly Prepared Bispyridinium Oximes (K305, K307) in Tabun-Poisoned Rats-A Comparison with Trimedoxime and the Oxime K203 - Kassa_2017_Molecules_22_
Author(s) : Kassa J , Misik J , Hatlapatkova J , Karasova JZ , Sepsova V , Caisberger F , Pejchal J
Ref : Molecules , 22 : , 2017
Abstract : The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.
ESTHER : Kassa_2017_Molecules_22_
PubMedSearch : Kassa_2017_Molecules_22_
PubMedID: 28696367

Title : A comparison of neuroprotective efficacy of two novel reactivators of acetylcholinesterase called K920 and K923 with the oxime K203 and trimedoxime in tabun-poisoned rats - Kassa_2017_Toxicol.Mech.Methods__1
Author(s) : Kassa J , Misik J , Hatlapatkova J , Karasova JZ
Ref : Toxicol Mech Methods , :1 , 2017
Abstract : The ability of two newly developed bispyridinium oximes (K920, K923) 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 (130 mug/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by functional observational battery at 2 hours after tabun administration. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment while one non-treated tabun-poisoned rat died within 2 hours. Both newly developed oximes (K920, K923) combined with atropine were able to markedly decrease tabun-induced neurotoxicity in the case of sublethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity did not prevail the neuroprotective efficacy of trimedoxime and the oxime K203. Therefore, the newly developed oximes are not suitable for the replacement of currently available oximes (especially trimedoxime) in the treatment of acute tabun poisonings.
ESTHER : Kassa_2017_Toxicol.Mech.Methods__1
PubMedSearch : Kassa_2017_Toxicol.Mech.Methods__1
PubMedID: 28043192

Title : Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy - Mezeiova_2017_Molecules_22_
Author(s) : Mezeiova E , Korabecny J , Sepsova V , Hrabinova M , Jost P , Muckova L , Kucera T , Dolezal R , Misik J , Spilovska K , Pham NL , Pokrievkova L , Roh J , Jun D , Soukup O , Kaping D , Kuca K
Ref : Molecules , 22 : , 2017
Abstract : Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.
ESTHER : Mezeiova_2017_Molecules_22_
PubMedSearch : Mezeiova_2017_Molecules_22_
PubMedID: 28788095

Title : HI-6 treatment does not reactivate sarin inhibited acetylcholinesterase activity in dog brain when administered in human therapeutical dose 30 minutes after the poisoning - Caisberger_2016_Mil.Med.Sci.Lett_85_2
Author(s) : Caisberger F , Novotny L , Hajek P , Misik J , Kassa J , Pejchal J
Ref : Military Medical Science Letters , 85 :2 , 2016
Abstract : Purpose: The aim of our study was to determine and compare the activity of acetylcholinesterase (AChE) in different parts of dog brain after the exposure to nerve agent sarin with or without HI-6 oxime treatment. Material and methods: Before intoxication, beagle dogs were intravenously anaesthetized and premedicated with atropine sulphate (0.01 mg/kg). Three experimental groups were established - control, sarin (0.03 mg/kg, intramuscularly, 5 min after anaesthesia onset), and sarin + HI-6 dichloride (11.4 mg/kg, intramuscularly, 30 min after sarin poisoning). Brain (amygdaloid body, head of caudate nucleus, somatosensory cortex, Amon's horn of hippocampus, hypothalamus, brain stem ventral respiratory group, and medial nuclei of thalamus) samples were taken 4 h after sarin administration. AChE activity was detected by histochemistry using the Karnovsky-Roots method and computer image analysis. Results: Sarin poisoning decreased AChE activity in all selected brain areas. HI-6 did not affect this outcome. Conclusion: HI-6 does not reactivate brain AChE in dogs when administered 30 min after sarin poisoning.
ESTHER : Caisberger_2016_Mil.Med.Sci.Lett_85_2
PubMedSearch : Caisberger_2016_Mil.Med.Sci.Lett_85_2

Title : Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats-Is there a potential for Alzheimer's disease treatment? - Misik_2016_Neurosci.Lett_612_261
Author(s) : Misik J , Korabecny J , Nepovimova E , Kracmarova A , Kassa J
Ref : Neuroscience Letters , 612 :261 , 2016
Abstract : Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed.
ESTHER : Misik_2016_Neurosci.Lett_612_261
PubMedSearch : Misik_2016_Neurosci.Lett_612_261
PubMedID: 26708634

Title : Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning - Katalinic_2015_Arh.Hig.Rada.Toksikol_66_291
Author(s) : Katalinic M , Macek Hrvat N , Karasova JZ , Misik J , Kovarik Z
Ref : Arh Hig Rada Toksikol , 66 :291 , 2015
Abstract : Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody's benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy.
ESTHER : Katalinic_2015_Arh.Hig.Rada.Toksikol_66_291
PubMedSearch : Katalinic_2015_Arh.Hig.Rada.Toksikol_66_291
PubMedID: 26751861

Title : The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test - Misik_2015_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_159_547
Author(s) : Misik J , Korabecny J , Nepovimova E , Cabelova P , Kassa J
Ref : Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub , 159 :547 , 2015
Abstract : AIMS: The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil.
METHODS: Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method.
RESULTS: QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. CONCLUSION: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.
ESTHER : Misik_2015_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_159_547
PubMedSearch : Misik_2015_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_159_547
PubMedID: 25690521

Title : Evaluation of the potency of two novel bispyridinium oximes (K456, K458) in comparison with oxime K203 and trimedoxime to counteract tabun-induced neurotoxicity in rats - Kassa_2013_Basic.Clin.Pharmacol.Toxicol_113_201
Author(s) : Kassa J , Misik J , Karasova JZ
Ref : Basic Clin Pharmacol Toxicol , 113 :201 , 2013
Abstract : The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 microg/kg i.m.; 85% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery and automatic measurement of motor activity at 2 hr after 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 (K456, K458) 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 higher than that of trimedoxime and oxime K203, but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.
ESTHER : Kassa_2013_Basic.Clin.Pharmacol.Toxicol_113_201
PubMedSearch : Kassa_2013_Basic.Clin.Pharmacol.Toxicol_113_201
PubMedID: 23647829

Title : In vivo decontamination of the nerve agent VX using the domestic swine model - Misik_2012_Clin.Toxicol.(Phila)_50_807
Author(s) : Misik J , Pavlik M , Novotny L , Pavlikova R , Chilcott RP , Cabal J , Kuca K
Ref : Clinical Toxicology (Phila) , 50 :807 , 2012
Abstract : The purpose of this in vivo study was to assess a new, putatively optimised method for mass casualty decontamination ("ORCHIDS protocol") for effectiveness in removing the chemical warfare agent VX from the skin of anaesthetised, domestic white pigs. ORCHIDS protocol consists of a 1.5-minute shower with a mild detergent (Argos) supplemented by physical removal. A standard method of wet decontamination was used for comparison. Experimental animals were divided into four groups (A-D). Two groups were exposed to a supra-lethal percutaneous dose (5 x LD(50); 300 mug kg(-1)) of VX for 1 h prior to decontamination with either the ORCHIDS (C) or standard protocol (D). A third (B, positive control) group was exposed but not subject to decontamination. Blank controls (A) received anaesthesia and the corresponding dose of normal saline instead of VX. Observations of the clinical signs of intoxication were supplemented by measurements of whole blood cholinesterase (ChE) performed on samples of arterial blood acquired at 30-minute intervals for the duration of the study (up to 6 h). Untreated (B) animals displayed typical cholinergic signs consistent with VX intoxication (local fasciculation, mastication, salivation, pilo-erection and motor convulsions) and died 165-240 min post exposure. All animals in both decontamination treatment groups (C, D) survived the duration of the study and exhibited less severe signs of cholinergic poisoning. Thus, both the standard and ORCHIDS protocol were demonstrably effective against exposure to the potent nerve agent VX, even after a delay of 1 h. A critical advantage of the ORCHIDS protocol is the relatively short shower duration (1(1/2) min compared to 3 min). In practice, this could substantially improve the rate at which individuals could be decontaminated by emergency responders following exposure to toxic materials such as chemical warfare agents.
ESTHER : Misik_2012_Clin.Toxicol.(Phila)_50_807
PubMedSearch : Misik_2012_Clin.Toxicol.(Phila)_50_807
PubMedID: 22963275

Title : Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents - Trovaslet-Leroy_2011_Toxicol.Lett_206_14
Author(s) : Trovaslet-Leroy M , Musilova L , Renault F , Brazzolotto X , Misik J , Novotny L , Froment MT , Gillon E , Loiodice M , Verdier L , Masson P , Rochu D , Jun D , Nachon F
Ref : Toxicol Lett , 206 :14 , 2011
Abstract : Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120-fold. Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Thus, we stress that interest for hPON1 must not fade away, and in particular, the 3D structure of the hPON1 eventually in complex with OP has to be solved.
ESTHER : Trovaslet-Leroy_2011_Toxicol.Lett_206_14
PubMedSearch : Trovaslet-Leroy_2011_Toxicol.Lett_206_14
PubMedID: 21683774

Title : Monooxime-monocarbamoyl Bispyridinium Xylene-Linked Reactivators of Acetylcholinesterase-Synthesis, In vitro and Toxicity Evaluation, and Docking Studies - Musilek_2010_ChemMedChem_5_247
Author(s) : Musilek K , Holas O , Misik J , Pohanka M , Novotny L , Dohnal V , Opletalova V , Kuca K
Ref : ChemMedChem , 5 :247 , 2010
Abstract : Acetylcholinesterase (AChE) reactivators are crucial antidotes to organophosphate intoxication. A new series of 26 monooxime-monocarbamoyl xylene-linked bispyridinium compounds was prepared and tested in vitro, along with known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime, K107, K108 and K203), on a model of tabun- and paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Although their ability to reactivate tabun-inhibited AChE did not exceed that of the previously known compounds, some newly prepared compounds showed promising reactivation of pesticide-inhibited AChE. The acute toxicity of the novel compounds was also determined. Docking studies using tabun-inhibited AChE were performed for three compounds of interest. The structure-activity relationship (SAR) study confirmed the apparent influence of the xylene linkage and carbamoyl moiety on the reactivation ability and toxicity of the agents.
ESTHER : Musilek_2010_ChemMedChem_5_247
PubMedSearch : Musilek_2010_ChemMedChem_5_247
PubMedID: 20058292

Title : The influence of combinations of oximes on the reactivating and therapeutic efficacy of antidotal treatment of tabun poisoning in rats and mice - Kassa_2010_J.Appl.Toxicol_30_120
Author(s) : Kassa J , Karasova JZ , Pavlikova R , Misik J , Caisberger F , Bajgar J
Ref : J Appl Toxicol , 30 :120 , 2010
Abstract : The influence of the combination of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute tabun poisoning was evaluated. The ability of two combinations of oximes (HI-6 + obidoxime and HI-6 + K203) to reactivate tabun-inhibited acetylcholinesterase and reduce acute toxicity of tabun was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, obidoxime, K203) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is higher than the reactivating efficacy of the most effective individual oxime in blood and diaphragm and comparable with the reactivating effects of the most effective individual oxime in brain. Moreover, both combinations of oximes were found to be slightly more efficacious in the reduction of acute lethal toxic effects in tabun-poisoned mice than the antidotal treatment involving individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the newly developed oxime K203 is slightly more effective than commonly used obidoxime and both of them are markedly more effective than the oxime HI-6. Based on the obtained data, we can conclude that the antidotal treatment involving chosen combinations of oximes brings beneficial effects for the potency of antidotal treatment to reactivate tabun-inhibited acetylcholinesterase in rats and to reduce acute toxicity of tabun in mice.
ESTHER : Kassa_2010_J.Appl.Toxicol_30_120
PubMedSearch : Kassa_2010_J.Appl.Toxicol_30_120
PubMedID: 19746406