Kassa J

General

Full name : Kassa Jiri

First name : Jiri

Mail : Department of Toxicology\; Faculty of Military Health Sciences\; Trebesska 1575\; 500 01 Hradec Kralove.: +420973255150

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Country : Czech Republic

Email : kassa@pmfhk.cz

Phone : +420973251500

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References (137)

Title : Combination of acetylcholinesterase inhibitors and NMDA receptor antagonists increases survival rate in soman-poisoned mice - Kassa_2023_Toxicol.Mech.Methods__1
Author(s) : Kassa J , Karasova JZ
Ref : Toxicol Mech Methods , :1 , 2023
Abstract : Organophosphorus nerve agents pose a global threat to both military personnel and civilian population, because of their high acute toxicity and insufficient medical countermeasures. Commonly used drugs could ameliorate the intoxication and overall medical outcomes. In this study, we tested the drugs able to alleviate the symptoms of Alzheimer's disease (donepezil, huperzine A, memantine) or Parkinson's disease (procyclidine). They were administered to mice before soman intoxication in terms of their: i) protection potential against soman toxicity and ii) influence on post-exposure therapy consisting of atropine and asoxime (also known as oxime HI-6). Their pretreatment effect was not significant, when administered alone, but in combination (acetylcholinesterase inhibitor such as denepezil or huperzine A with NMDA antagonist such as memantine or procyclidine) they lowered the soman toxicity more than twice. These combinations also positively influenced the efficacy of post-exposure treatment in a similar fashion; the combinations increased the therapeutic effectiveness of antidotal treatment. In conclusion, the most effective combination - huperzine A and procyclidine - lowered the toxicity three times and improved the post-exposure therapy efficacy more than six times. These results are unprecedented in the published literature.
ESTHER : Kassa_2023_Toxicol.Mech.Methods__1
PubMedSearch : Kassa_2023_Toxicol.Mech.Methods__1
PubMedID: 37051629

Title : Toxicity, pharmacokinetics, and effectiveness of the ortho-chlorinated bispyridinium oxime, K870 - Karasova_2022_Food.Chem.Toxicol__113236
Author(s) : Karasova JZ , Kassa J , Hepnarova V , Pejchal J , Junova L , Andrys R , Malinak D , Bzonek P , Kohoutova Z , Musilek K
Ref : Food & Chemical Toxicology , :113236 , 2022
Abstract : Oxime reactivators are causal antidotes for organophosphate intoxication. Herein, the toxicity, pharmacokinetics, and reactivation effectiveness of o-chlorinated bispyridinium oxime K870 are reported. Oxime K870 was found to have a safe profile at a dose of 30 mg/kg in rats. It exhibited rapid absorption and renal clearance similar to those of other charged oximes after intramuscular administration. Its isoxazole-pyridinium degradation product was identified in vivo. Although it showed some improvement in brain targeting, it was nevertheless rapidly effluxed from the central nervous system. Its reactivation effectiveness was evaluated in rats and mice intoxicated with sarin, tabun, VX, and paraoxon and compared with pralidoxime and asoxime. K870 was found to be less effective in reversing tabun poisoning compared to its parent unchlorinated oxime K203. However, K870 efficiently reactivated blood acetylcholinesterase for all tested organophosphates in rats. In addition, K870 significantly protected against intoxication by all tested organophosphates in mice. For these reasons, oxime K870 seems to have a broader reactivation spectrum against multiple organophosphates. It seems important to properly modulate the oximate forming properties (pK(a)) to obtain more versatile oxime reactivators.
ESTHER : Karasova_2022_Food.Chem.Toxicol__113236
PubMedSearch : Karasova_2022_Food.Chem.Toxicol__113236
PubMedID: 35738326

Title : Influence of Experimental End Point on the Therapeutic Efficacy of Essential and Additional Antidotes in Organophosphorus Nerve Agent-Intoxicated Mice - Kassa_2022_Toxics_10_
Author(s) : Kassa J , Timperley CM , Bird M , Green AC , Tattersall JEH
Ref : Toxics , 10 : , 2022
Abstract : The therapeutic efficacy of treatments for acute intoxication with highly toxic organophosphorus compounds, called nerve agents, usually involves determination of LD(50) values 24 h after nerve agent challenge without and with a single administration of the treatment. Herein, the LD(50) values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated intoxication were investigated in mice for experimental end points of 6 and 24 h. The LD(50) values of the nerve agents were evaluated by probit-logarithmical analysis of deaths within 6 and 24 h of i.m. challenge of the nerve agent at five different doses, using six mice per dose. The efficiency of atropine alone or atropine in combination with an oxime was practically the same at 6 and 24 h. The therapeutic efficacy of the higher dose of the antinicotinic compound MB327 was slightly higher at the 6 h end point compared to the 24 h end point for soman and tabun intoxication. A higher dose of MB327 increased the therapeutic efficacy of atropine alone for sarin, soman and tabun intoxication, and that of the standard antidotal treatment (atropine and oxime) for sarin and tabun intoxication. The therapeutic efficacy of MB327 was lower than the oxime-based antidotal treatment. To compare the 6 and 24 h end points, the influence of the experimental end point was not observed, with the exception of the higher dose of MB327. In addition, only a negligible beneficial impact of the compound MB327 was observed. Nevertheless, antinicotinics may offer an additional avenue for countering poisoning by nerve agents that are difficult to treat, and synthetic and biological studies towards the development of such novel drugs based on the core bispyridinium structure or other molecular scaffolds should continue.
ESTHER : Kassa_2022_Toxics_10_
PubMedSearch : Kassa_2022_Toxics_10_
PubMedID: 35448453

Title : A Comparison of the Neuroprotective and Reactivating Efficacy of a Novel Bispyridinium Oxime K870 with Commonly Used Pralidoxime and the Oxime HI-6 in Tabun-Poisoned Rats - Kassa_2021_Acta.Medica.(Hradec.Kralove)_64_145
Author(s) : Kassa J , Hatlapatkova J , Karasova JZ , Hepnarova V , Caisberger F , Pejchal J
Ref : Acta Medica (Hradec Kralove) , 64 :145 , 2021
Abstract : AIM: The comparison of neuroprotective and central reactivating effects of the oxime K870 in combination with atropine with the efficacy of standard antidotal treatment in tabun-poisoned rats. METHODS: The neuroprotective effects of antidotal treatment were determined in rats poisoned with tabun at a sublethal dose using a functional observational battery 2 h and 24 h after tabun administration, the tabun-induced brain damage was investigated by the histopathological evaluation and central reactivating effects of oximes was evaluated by the determination of acetylcholinesterase activity in the brain using a standard spectrophotometric method. RESULTS: The central reactivating efficacy of a newly developed oxime K870 roughly corresponds to the central reactivating efficacy of pralidoxime while the ability of the oxime HI-6 to reactivate tabun-inhibited acetylcholinesterase in the brain was negligible. The ability of the oxime K870 to decrease tabun-induced acute neurotoxicity was slightly higher than that of pralidoxime and similar to the oxime HI-6. These results roughly correspond to the histopathological evaluation of tabun-induced brain damage. CONCLUSION: The newly synthesized oxime K870 is not a suitable replacement for commonly used oximes in the antidotal treatment of acute tabun poisonings because its neuroprotective efficacy is only slightly higher or similar compared to studied currently used oximes.
ESTHER : Kassa_2021_Acta.Medica.(Hradec.Kralove)_64_145
PubMedSearch : Kassa_2021_Acta.Medica.(Hradec.Kralove)_64_145
PubMedID: 34779379

Title : Effect of Oxime Encapsulation on Acetylcholinesterase Reactivation: Pharmacokinetic Study of the Asoxime-Cucurbit[7]uril Complex in Mice Using Hydrophilic Interaction Liquid Chromatography-Mass Spectrometry - Andrys_2021_Mol.Pharm__
Author(s) : Andrys R , Klusonova A , Lisa M , Kassa J , Karasova JZ
Ref : Mol Pharm , : , 2021
Abstract : Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.
ESTHER : Andrys_2021_Mol.Pharm__
PubMedSearch : Andrys_2021_Mol.Pharm__
PubMedID: 34019427

Title : Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice - Kassa_2021_Neurotox.Res__
Author(s) : Kassa J , Karasova JZ
Ref : Neurotox Res , : , 2021
Abstract : Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.
ESTHER : Kassa_2021_Neurotox.Res__
PubMedSearch : Kassa_2021_Neurotox.Res__
PubMedID: 34292503

Title : Interaction of Cucurbit[7]uril with Oxime K027, Atropine, and Paraoxon: Risky or Advantageous Delivery System? - Karasova_2020_Int.J.Mol.Sci_21_
Author(s) : Karasova JZ , Mzik M , Kucera T , Vecera Z , Kassa J , Sestak V
Ref : Int J Mol Sci , 21 : , 2020
Abstract : Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
ESTHER : Karasova_2020_Int.J.Mol.Sci_21_
PubMedSearch : Karasova_2020_Int.J.Mol.Sci_21_
PubMedID: 33114215

Title : Encapsulation of oxime K027 into cucurbit[7]uril: In vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness - Karasova_2020_Toxicol.Lett_320_64
Author(s) : Karasova JZ , Hepnarova V , Andrys R , Lisa M , Jost P , Muckova L , Pejchal J , Herman D , Jun D , Kassa J , Kuca K
Ref : Toxicol Lett , 320 :64 , 2020
Abstract : Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.
ESTHER : Karasova_2020_Toxicol.Lett_320_64
PubMedSearch : Karasova_2020_Toxicol.Lett_320_64
PubMedID: 31794810

Title : Influence of experimental end point on the therapeutic efficacy of the antinicotinic compounds MB408, MB442 and MB444 in treating nerve agent poisoned mice - a comparison with oxime-based treatment - Kassa_2020_Toxicol.Mech.Methods_30_703
Author(s) : Kassa J , Timperley CM , Bird M , Green AC , Tattersall JEH
Ref : Toxicol Mech Methods , 30 :703 , 2020
Abstract : Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD(50) values of nerve agents over 24 h following poisoning without or with a single administration of antidotal treatment. In this study, LD(50) values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated poisoning were evaluated in mice for two experimental end points - 6 h and 24 h. While the efficacy of atropine or oxime-based antidotal treatment was the same regardless of the experimental end point, the therapeutic efficacy of all three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) was mostly slightly higher at the 6 h end point compared to the 24 h end point, although the therapeutic efficacy of MB compounds was not superior to oxime-based antidotal treatment. These results contrast with a study in guinea-pigs using a structurally-related compound, MB327, which showed a striking increase in protection at 6 h compared to 24 h. It is suggested that the disparity may be due to pharmacokinetic differences between the two animal species.
ESTHER : Kassa_2020_Toxicol.Mech.Methods_30_703
PubMedSearch : Kassa_2020_Toxicol.Mech.Methods_30_703
PubMedID: 32878547

Title : Some Possibilities to Study New Prophylactics against Nerve Agents - Bajgar_2019_Mini.Rev.Med.Chem_19_970
Author(s) : Bajgar J , Kassa J , Kucera T , Musilek K , Jun D , Kuca K
Ref : Mini Rev Med Chem , 19 :970 , 2019
Abstract : Nerve agents belong to the most dangerous chemical warfare agents and can be/were misused by terrorists. Effective prophylaxis and treatment is necessary to diminish their effect. General principles of prophylaxis are summarized (protection against acetylcholinesterase inhibition, detoxification, treatment "in advance" and use of different drugs). They are based on the knowledge of mechanism of action of nerve agents. Among different examinations, it is necessary to test prophylactic effectivity in vivo and compare the results with protection in vitro. Chemical and biological approaches to the development of new prophylactics would be applied simultaneously during this research. Though the number of possible prophylactics is relatively high, the only four drugs were introduced into military medical practice. At present, pyridostigmine seems to be common prophylactic antidote; prophylactics panpal (tablets with pyridostigmine, trihexyphenidyl and benactyzine), transant (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. Scavenger commercionally available is Protexia(R). Future development will be focused on scavengers, and on other drugs either reversible cholinesterase inhibitors (e.g., huperzine A, gallantamine, physostigmine, acridine derivatives) or other compounds.
ESTHER : Bajgar_2019_Mini.Rev.Med.Chem_19_970
PubMedSearch : Bajgar_2019_Mini.Rev.Med.Chem_19_970
PubMedID: 30827238

Title : Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings - Kuca_2018_Drug.Des.Devel.Ther_12_505
Author(s) : Kuca K , Karasova JZ , Soukup O , Kassa J , Novotna E , Sepsova V , Horova A , Pejchal J , Hrabinova M , Vodakova E , Jun D , Nepovimova E , Valis M , Musilek K
Ref : Drug Des Devel Ther , 12 :505 , 2018
Abstract : Background: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity.
ESTHER : Kuca_2018_Drug.Des.Devel.Ther_12_505
PubMedSearch : Kuca_2018_Drug.Des.Devel.Ther_12_505
PubMedID: 29563775

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 : Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice - Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_140
Author(s) : Kassa J , Korabecny J
Ref : Acta Medica (Hradec Kralove) , 60 :140 , 2017
Abstract : AIM: The influence of the dose on the ability of promising newly prepared reversible inhibitor of acetylcholinesterase (6-chlorotacrine) to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probit-logarithmical analysis of death occurring within 24 hrs after administration of soman. RESULTS: The dose of 6-chlorotacrine significantly influences the prophylactic efficacy of 6-chlorotacrine. Its highest dose was only able to significantly protect mice against acute toxicity of soman and increase the efficacy of antidotal treatment (atropine in combination with the oxime HI-6) of soman-poisoned mice. In addition, the highest dose of 6-chlorotacrine was significantly more effective to protect mice from soman poisoning than its lowest dose. CONCLUSION: These findings demonstrate the important influence of the dose of 6-chlorotacine on its prophylactic efficacy in the case of pharmacological pretreatment of soman poisoning in mice.
ESTHER : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_140
PubMedSearch : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_140
PubMedID: 29716679

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 : The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice - Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_37
Author(s) : Kassa J , Korabecny J , Nepovimova E
Ref : Acta Medica (Hradec Kralove) , 60 :37 , 2017
Abstract : AIM: The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated.
METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman.
RESULTS: 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. CONCLUSION: These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2.
ESTHER : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_37
PubMedSearch : Kassa_2017_Acta.Medica.(Hradec.Kralove)_60_37
PubMedID: 28418831

Title : Evaluation of the benefit of the bispyridinium compound MB327 for the antidotal treatment of nerve agent-poisoned mice - Kassa_2016_Toxicol.Mech.Methods_26_334
Author(s) : Kassa J , Pohanka M , Timperley CM , Bird M , Green AC , Tattersall JE
Ref : Toxicol Mech Methods , 26 :334 , 2016
Abstract : The potency of the bispyridinium non-oxime compound MB327 [1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) diiodide] to increase the therapeutic efficacy of the standard antidotal treatment (atropine in combination with an oxime) of acute poisoning with organophosphorus nerve agents was studied in vivo. The therapeutic efficacy of atropine alone - or atropine in combination with an oxime, MB327, or both an oxime and MB237 - was evaluated by the determination of LD50 values of several nerve agents (tabun, sarin and soman) in mice with and without treatment. The addition of MB327 increased the therapeutic efficacy of atropine alone, and atropine in combination with an oxime, against all three nerve agents, although differences in the LD50 values only reached statistical significance for sarin. In conclusion, the addition of the compound MB327 to the standard antidotal treatment of acute poisonings with nerve agents was beneficial regardless of the chemical structure of the nerve agent, although at the dose employed, MB327 in combination with atropine, or atropine and an oxime, provided only a modest increase in protection ratio. These results from mice, and previous ones from guinea-pigs, provide consistent evidence for additional, albeit modest, efficacy resulting from the inclusion of the antinicotinic compound MB327 in standard antidotal therapy. Given the typically steep probit slope for the dose-lethality relationship for nerve agents, such modest increases in protection ratio could provide significant survival benefit.
ESTHER : Kassa_2016_Toxicol.Mech.Methods_26_334
PubMedSearch : Kassa_2016_Toxicol.Mech.Methods_26_334
PubMedID: 27097774

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
PubMedID:

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 : Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity - Nepovimova_2015_J.Med.Chem_58_8985
Author(s) : Nepovimova E , Korabecny J , Dolezal R , Babkova K , Ondrejicek A , Jun D , Sepsova V , Horova A , Hrabinova M , Soukup O , Bukum N , Jost P , Muckova L , Kassa J , Malinak D , Andrs M , Kuca K
Ref : Journal of Medicinal Chemistry , 58 :8985 , 2015
Abstract : Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.
ESTHER : Nepovimova_2015_J.Med.Chem_58_8985
PubMedSearch : Nepovimova_2015_J.Med.Chem_58_8985
PubMedID: 26503905

Title : A comparison of the reactivating and therapeutic efficacy of two newly developed oximes (K727 and K733) with oxime k203 and trimedoxime in tabun-poisoned rats and mice - Kassa_2015_Basic.Clin.Pharmacol.Toxicol_116_367
Author(s) : Kassa J , Sepsova V , Tumova M , Horova A , Musilek K
Ref : Basic Clin Pharmacol Toxicol , 116 :367 , 2015
Abstract : The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.
ESTHER : Kassa_2015_Basic.Clin.Pharmacol.Toxicol_116_367
PubMedSearch : Kassa_2015_Basic.Clin.Pharmacol.Toxicol_116_367
PubMedID: 25225130

Title : A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K727, K733) with the oxime HI-6 and obidoxime in sarin-poisoned rats and mice - Kassa_2015_Toxicol.Mech.Methods_25_229
Author(s) : Kassa J , Sepsova V , Matouskova L , Horova A , Musilek K
Ref : Toxicol Mech Methods , 25 :229 , 2015
Abstract : The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 microg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.
ESTHER : Kassa_2015_Toxicol.Mech.Methods_25_229
PubMedSearch : Kassa_2015_Toxicol.Mech.Methods_25_229
PubMedID: 25894563

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 : The Evaluation of the Potency of Newly Developed Oximes (K727, K733) and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats - Kassa_2015_Acta.Medica.(Hradec.Kralove)_58_135
Author(s) : Kassa J , Hatlapatkova J , Karasova JZ
Ref : Acta Medica (Hradec Kralove) , 58 :135 , 2015
Abstract : AIM: The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. METHODS: The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 microg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. RESULTS: All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. CONCLUSION: The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.
ESTHER : Kassa_2015_Acta.Medica.(Hradec.Kralove)_58_135
PubMedSearch : Kassa_2015_Acta.Medica.(Hradec.Kralove)_58_135
PubMedID: 26960827

Title : The evaluation of the reactivating and therapeutic efficacy of two novel oximes (K361 and K378) in comparison with the oxime K203 and trimedoxime in tabun-poisoned rats and mice - Kassa_2014_Toxicol.Mech.Methods_24_173
Author(s) : Kassa J , Sepsova V , Tumova M , Musilek K , Horova A
Ref : Toxicol Mech Methods , 24 :173 , 2014
Abstract : Abstract The potency of two newly developed oximes (K361 and K378) to reactivate tabun-inhibited cholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm cholinesterase in poisoned rats showed that the reactivating efficacy of the oxime K378 is slightly lower than the reactivating potency of the oxime K203 and trimedoxime while the ability of the oxime K361 to reactivate tabun-inhibited cholinesterase is markedly lower compared with the oxime K203 and trimedoxime. In the brain, the potency of both newly developed oximes to reactivate tabun-inhibited cholinesterase was negligible. The therapeutic efficacy of both newly developed oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun was significantly lower compared with the oxime K203 as well as trimedoxime. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
ESTHER : Kassa_2014_Toxicol.Mech.Methods_24_173
PubMedSearch : Kassa_2014_Toxicol.Mech.Methods_24_173
PubMedID: 24295433

Title : The Evaluation of Prophylactic Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase in Soman-Poisoned Mice - A Comparison with Commonly Used Pyridostigmine - Kassa_2014_Basic.Clin.Pharmacol.Toxicol_115_571
Author(s) : Kassa J , Korabecny J , Sepsova V , Tumova M
Ref : Basic Clin Pharmacol Toxicol , 115 :571 , 2014
Abstract : The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC-37, PC-48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD50 value of soman in mice. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman-induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising.
ESTHER : Kassa_2014_Basic.Clin.Pharmacol.Toxicol_115_571
PubMedSearch : Kassa_2014_Basic.Clin.Pharmacol.Toxicol_115_571
PubMedID: 24842281

Title : The evaluation of the reactivating and therapeutic efficacy of three novel bispyridinium oximes (K454, K456, K458) in comparison with the oxime K203 and trimedoxime in tabun-poisoned rats and mice - Kassa_2013_Toxicol.Mech.Methods_23_94
Author(s) : Kassa J , Sepsova V , Musilek K , Horova A
Ref : Toxicol Mech Methods , 23 :94 , 2013
Abstract : The potency of three newly developed bispyridinium compounds (K454, K456, K458) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm and brain acetylcholinesterase in poisoned rats showed that the reactivating efficacy of all newly developed oximes is comparable with K203 but lower than the reactivating potency of trimedoxime in diaphragm. In the brain, their potency to reactivate tabun-inhibited acetylcholinesterase is lower compared with trimedoxime and the oxime K203. All three newly developed oximes were also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy is consistent with the therapeutic potency of the oxime K203. On the other hand, their potency to reduce acute toxicity of tabun is significantly lower compared with trimedoxime. In conclusion, the reactivating and therapeutic potency of all three newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
ESTHER : Kassa_2013_Toxicol.Mech.Methods_23_94
PubMedSearch : Kassa_2013_Toxicol.Mech.Methods_23_94
PubMedID: 22901042

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 : From the research of cholinesterase reactivators to the effective therapy of organophosphate\/nerve agent poisoning - Bajgar_2012_Mil.Med.Sci.Lett_81_164
Author(s) : Bajgar J , Kassa J
Ref : Military Medical Science Letters , 81 :164 , 2012
Abstract : OBJECTIVES: The aim of this study is to inform about different techniques used to improve treatment of nerve agents intoxication at the Department of Toxicology.METHODS: Different methods are briefly mentioned and their importance for development of more effective reactivators is discussed. RESULTS: Basic characterization of nerve agents and therapeutic drugs is necessary after literature survey. Usage of different techniques and properties of various reactivators are studied and, on this basis, the most effective ones are tested in details and proposed for practical use. CONCLUSIONS: The results described in this study clearly demonstrate that for the development of new and more effective cholinesterase reactivators a complex approach using different methodical attitudes is necessary.
ESTHER : Bajgar_2012_Mil.Med.Sci.Lett_81_164
PubMedSearch : Bajgar_2012_Mil.Med.Sci.Lett_81_164
PubMedID:

Title : Combined approach to demonstrate acetylcholinesterase activity changes in the rat brain following tabun intoxication and its treatment - Bajgar_2012_Toxicol.Mech.Methods_22_60
Author(s) : Bajgar J , Hajek P , Kassa J , Slizova D , Krs O , Karasova JZ , Fusek J , Capek L , Voicu VA
Ref : Toxicol Mech Methods , 22 :60 , 2012
Abstract : Reactivation effects of K203 and currently available oximes (obidoxime, HI-6) in combination with atropine on acetylcholinesterase activities in the brain parts of rats poisoned with tabun were studied. The activity was determined by quantitative histochemical and biochemical methods correlating between them very well. The tabun-induced changes in acetylcholinsterase activity as well as in reactivation potency of reactivators used were different in various parts of the brain. Pontomedullar area seems to be important for observed changes following tabun intoxication and its treatment. From the oximes studied, the reactivation effect of K203 was comparable with obidoxime; HI-6 was ineffective. Combination of bio- and histochemical methods allow fine differentiation among the action of different oximes following tabun poisoning.
ESTHER : Bajgar_2012_Toxicol.Mech.Methods_22_60
PubMedSearch : Bajgar_2012_Toxicol.Mech.Methods_22_60
PubMedID: 21851296

Title : The ability of oxime mixtures to increase the reactivating and therapeutic efficacy of antidotal treatment of cyclosarin poisoning in rats and mice - Kassa_2012_Acta.Medica.(Hradec.Kralove)_55_27
Author(s) : Kassa J , Karasova JZ , Pavlikova R , Caisberger F , Bajgar J
Ref : Acta Medica (Hradec Kralove) , 55 :27 , 2012
Abstract : The reactivating and therapeutic efficacy of two combinations ofoximes (HI-6 + trimedoxime and HI-6 + K203) was compared with the effectiveness of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is slightly higher than the reactivating efficacy of the most effective individual oxime in blood, diaphragm as well as in brain. Moreover, both combinations of oximes were found to be slightly more efficacious in the reduction of acute lethal toxic effects in cyclosarin-poisoned mice than the antidotal treatment involving single oxime. Based on the obtained data, we can conclude that the antidotal treatment involving chosen combinations of oximes brings a beneficial effect for its ability to counteract the acute poisoning with cyclosarin.
ESTHER : Kassa_2012_Acta.Medica.(Hradec.Kralove)_55_27
PubMedSearch : Kassa_2012_Acta.Medica.(Hradec.Kralove)_55_27
PubMedID: 22696932

Title : Two possibilities how to increase the efficacy of antidotal treatment of nerve agent poisonings - Kassa_2012_Mini.Rev.Med.Chem_12_24
Author(s) : Kassa J , Musilek K , Karasova JZ , Kuca K , Bajgar J
Ref : Mini Rev Med Chem , 12 :24 , 2012
Abstract : Highly toxic organophosphorus inhibitors of acetylcholinesterase referred as nerve agents are considered to be among the most dangerous chemical warfare agents. The oximes represent very important part of medical countermeasures of nerve agent poisonings. They are used to reactivate the nerve agent-inhibited acetylcholinesterase. Despite long-term research activities, there is no single, broad-spectrum oxime suitable for the antidotal treatment of poisoning with all organophosphorus agents. There are two approaches how to increase and broaden the effectiveness of antidotal treatment of poisoning with nerve agents - to develop new structural analogues of currently available oximes and/or to combine currently available or newly developed oximes. The review describes the evaluation of the potency of newly developed oximes (especially the oxime K203) or combinations of oximes to reactivate nerve agent-inhibited acetylcholinesterase and to counteract the acute toxicity of nerve agents in comparison with single commonly used oxime (obidoxime, trimedoxime or HI-6).
ESTHER : Kassa_2012_Mini.Rev.Med.Chem_12_24
PubMedSearch : Kassa_2012_Mini.Rev.Med.Chem_12_24
PubMedID: 22360668

Title : A comparison of the efficacy of newly developed reversible inhibitors of acetylcholinesterase with commonly used pyridostigmine as pharmacological pre-treatment of soman-poisoned mice - Kassa_2012_Basic.Clin.Pharmacol.Toxicol_110_322
Author(s) : Kassa J , Musilek K , Koomlova M , Bajgar J
Ref : Basic Clin Pharmacol Toxicol , 110 :322 , 2012
Abstract : The ability of three newly developed reversible inhibitors of acetylcholinesterase (AChE) (K298, K344 and K474) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was compared. Neither pyridostigmine nor new reversible inhibitors of AChE were able to increase the LD(50) value of soman. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of AChE was not able to protect mice against soman-induced lethal acute toxicity. The pharmacological pre-treatment with pyridostigmine alone or with K474 was able to slightly increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice, but the increase in the efficacy of antidotal treatment was not significant. The other newly developed reversible inhibitors of AChF (K298, K344) were completely ineffective. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of AChF is not promising.
ESTHER : Kassa_2012_Basic.Clin.Pharmacol.Toxicol_110_322
PubMedSearch : Kassa_2012_Basic.Clin.Pharmacol.Toxicol_110_322
PubMedID: 21981462

Title : Biochemical insight into soman intoxication and treatment with atropine, HI-6, trimedoxime, and K203 in a rat model - Pohanka_2011_Bratisl.Lek.Listy_112_539
Author(s) : Pohanka M , Pikula J , Kuca K , Kassa J
Ref : Bratislavske Lekarske Listy , 112 :539 , 2011
Abstract : OBJECTIVE: The present experiment is based on biochemical assessment of nerve agent soman intoxication and atropine, respectively atropine and HI-6, trimedoxime or K203 treatment in rats. BACKGROUND: Nerve agents are toxic substances irreversibly inhibiting enzyme acetylcholinesterase (AChE). Treatment is typically based on application of atropine and oxime reactivator. Atropine is able to protect overstimulation of muscarinic acetylcholine receptors. Application of oxime reactivator enable return of AChE activity and full suppression of intoxication. METHODS: In a total, fifteen biochemical markers were assayed in plasma or blood of intoxicated animals. 42 rats were divided into 7 groups each 6 individuals. The first group was exposed to atropine; the second group was exposed to one LD50 of soman and atropine. The groups 3-5 were exposed in a same way as the second group and were treated with oxime reactivators: HI-6 (group 3), trimedoxime (4) and K203 (5). The sixth group was control treated with saline solution only. The last (seventh) group was intoxicated with soman only. RESULTS: The most striking shifts were found for blood acetylcholinesterase and plasma creatinine, glucose, inorganic phosphate as well as uric acid. Lactate dehydrogenase and aspartate aminotransferase assays were useless due to soman interference. CONCLUSION: It was demonstrated that treatment was able to protect poisoned animals from metabolic disorder represented by hyperglycemia and nephropathy represented by hyperuricemia and elevated creatinine. Soman exposure and treatment with the oxime reactivators and/or atropine contains quite complex and still not well understood side mechanisms (Tab. 2, Fig. 1, Ref. 25).
ESTHER : Pohanka_2011_Bratisl.Lek.Listy_112_539
PubMedSearch : Pohanka_2011_Bratisl.Lek.Listy_112_539
PubMedID: 21954536

Title : The benefit of combinations of oximes for the reactivating and therapeutic efficacy of antidotal treatment of sarin poisoning in rats and mice - Kassa_2011_Basic.Clin.Pharmacol.Toxicol_109_30
Author(s) : Kassa J , Karasova JZ , Sepsova V , Caisberger F
Ref : Basic Clin Pharmacol Toxicol , 109 :30 , 2011
Abstract : The influence of the combinations of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute sarin poisoning was evaluated in this study. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate sarin-inhibited acetylcholinesterase and reduce acute toxicity of sarin was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. Studies determining percentage of reactivation of sarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of the combination of oximes involving HI-6 and K203 is slightly higher than the reactivating efficacy of the most effective individual oxime in diaphragm and brain but the difference between them is not significant. The ability of combination of oximes involving HI-6 and trimedoxime to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating effects of the most effective individual oxime in blood as well as tissues. Moreover, both combinations of oximes were found to be as efficacious in the reduction of acute lethal toxic effects in sarin-poisoned mice as the most effective individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the oxime HI-6 is markedly more effective than the oxime K203 and trimedoxime. Based on the obtained data, we conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the ability of the most effective individual oxime (HI-6) to reactivate sarin-inhibited rat acetylcholinesterase and to reduce acute toxicity of sarin in mice.
ESTHER : Kassa_2011_Basic.Clin.Pharmacol.Toxicol_109_30
PubMedSearch : Kassa_2011_Basic.Clin.Pharmacol.Toxicol_109_30
PubMedID: 21235715

Title : A comparison of the reactivating and therapeutic efficacy of chosen combinations of oximes with individual oximes against VX in rats and mice - Kassa_2011_Int.J.Toxicol_30_562
Author(s) : Kassa J , Karasova JZ , Sepsova V , Caisberger F , Bajgar J
Ref : Int J Toxicol , 30 :562 , 2011
Abstract : The ability of 2 combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate VX-inhibited acetylcholinesterase and reduce acute toxicity of VX was compared with the reactivating and therapeutic efficacy of antidotal treatment involving a single oxime (HI-6, trimedoxime, K203) in rats and mice. Our results showed that the reactivating efficacy of both combinations of oximes studied in rats is significantly higher than the reactivating efficacy of all individual oximes in diaphragm and roughly corresponds to the most effective individual oxime in blood and brain. Both combinations of oximes were found to be more effective in the reduction of acute lethal toxicity of VX in mice than the antidotal treatment involving the most efficacious individual oxime although the difference is not significant. Based on the obtained data, we can conclude that the antidotal treatment involving the chosen combinations of oximes brings benefit for the reactivation of VX-inhibited acetylcholinesterase in rats and for the antidotal treatment of VX-induced acute poisoning in mice.
ESTHER : Kassa_2011_Int.J.Toxicol_30_562
PubMedSearch : Kassa_2011_Int.J.Toxicol_30_562
PubMedID: 22013137

Title : Evaluation of flow injection analysis for determination of cholinesterase activities in biological material - Cabal_2010_Chem.Biol.Interact_187_225
Author(s) : Cabal J , Bajgar J , Kassa J
Ref : Chemico-Biological Interactions , 187 :225 , 2010
Abstract : The method for automatic continual monitoring of acetylcholinesterase (AChE) activity in biological material is described. It is based on flexible system of plastic pipes mixing samples of biological material with reagents for enzyme determination; reaction product penetrates through the semipermeable membrane and it is spectrophotometrically determined (Ellman's method). It consists of sampling (either in vitro or in vivo), adding the substrate and flowing to dialyzer; reaction product (thiocholine) is dialyzed and mixed with 5,5'-dithio-bis-2-nitrobenzoic acid (DTNB) transported to flow spectrophotometer. Flowing of all materials is realised using peristaltic pump. The method was validated: time for optimal hydratation of the cellophane membrane; type of the membrane; type of dialyzer; conditions for optimal permeation of reaction components; optimization of substrate and DTNB concentrations (linear dependence); efficacy of peristaltic pump; calibration of analytes after permeation through the membrane; excluding of the blood permeation through the membrane. Some examples of the evaluation of the effects of AChE inhibitors are described. It was demonstrated very good uniformity of peaks representing the enzyme activity (good reproducibility); time dependence of AChE inhibition caused by VX in vitro in the rat blood allowing to determine the half life of inhibition and thus, bimolecular rate constants of inhibition; reactivation of inhibited AChE by some reactivators, and continual monitoring of the activity in the whole blood in vivo in intact and VX-intoxicated rats. The method is simple and not expensive, allowing automatic determination of AChE activity in discrete or continual samples in vitro or in vivo. It will be evaluated for further research of cholinesterase inhibitors.
ESTHER : Cabal_2010_Chem.Biol.Interact_187_225
PubMedSearch : Cabal_2010_Chem.Biol.Interact_187_225
PubMedID: 20188079

Title : A Comparison of Neuroprotective Efficacy of the Oxime K203 and its Fluorinated Analogue (KR-22836) with Obidoxime in Tabun-Poisoned Rats - Kassa_2010_Basic.Clin.Pharmacol.Toxicol_107_861
Author(s) : Kassa J , Karasova JZ , Tesarova S , Musilek K , Kuca K , Jung YS
Ref : Basic Clin Pharmacol Toxicol , 107 :861 , 2010
Abstract : The ability of the newly developed bispyridinium compound K203 and its fluorinated analogue KR-22836 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the currently available reactivator of acetylcholinesterase-obidoxime. Tabun-induced neurotoxicity and the neuroprotective effects of all tested oximes in combination with atropine in rats poisoned with tabun at a sublethal dose (200 ug/kg intramuscularly (i.m.); 80% of LD(50) value) were monitored by a functional observational battery at 24 hr after tabun challenge. The results indicate that all tested oximes combined with atropine were able to survive tabun-poisoned rats 24 hr after tabun challenge while one non-treated tabun-poisoned rat died within 24 hr after tabun poisoning. All tested oximes combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. While the ability to reduce tabun-induced acute neurotoxicity of obidoxime and K203 was similar, the neuroprotective efficacy of KR-22836 was slightly higher compared to other tested oximes. Thus, the newly developed fluorinated analogue of K203, called KR-22836, is able to slightly increase the neuroprotective effectiveness of antidotal treatment of acute tabun poisonings compared to K203 and currently available obidoxime.
ESTHER : Kassa_2010_Basic.Clin.Pharmacol.Toxicol_107_861
PubMedSearch : Kassa_2010_Basic.Clin.Pharmacol.Toxicol_107_861
PubMedID: 22545968

Title : A comparison of reactivating and therapeutic efficacy of the oxime K203 and its fluorinated analog (KR-22836) with currently available oximes (obidoxime, trimedoxime, HI-6) against tabun in rats and mice - Kassa_2010_J.Enzyme.Inhib.Med.Chem_25_480
Author(s) : Kassa J , Karasova JZ , Caisberger F , Musilek K , Kuca K , Jung YS
Ref : J Enzyme Inhib Med Chem , 25 :480 , 2010
Abstract : The potency of newly developed bispyridinium compound K203 and its fluorinated analog KR-22836 in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in rats showed that the reactivating efficacy of K203 is higher than the reactivating efficacy of its fluorinated analog KR-22836 as well as currently available oximes studied. The therapeutic efficacy of the oxime K203 and its fluorinated analog corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase. According to the results, the oxime K203 is more suitable than KR-22836 for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning due to its relatively high potency to counteract the acute toxicity of tabun.
ESTHER : Kassa_2010_J.Enzyme.Inhib.Med.Chem_25_480
PubMedSearch : Kassa_2010_J.Enzyme.Inhib.Med.Chem_25_480
PubMedID: 20233085

Title : Is Oxime Fluorination the Proper Way to Increase Penetration of These Compounds in the Central Nervous System? - Karasova_2010_Mil.Med.Sci.Lett_79_23
Author(s) : Karasova JZ , Kassa J , Musilek K , Jung Y , Kuca K
Ref : Military Medical Science Letters , 79 :23 , 2010
Abstract : The penetration of acetylcholinesterase (AChE) reactivators through the blood-brain barrier is hotly discussed question nowadays. The increase of lipophilicity of these compounds is one of the possible ways how to increase their penetration and also their efficacy in the central nervous system.The aim of this study is to compare the reactivation potency of newly synthesized oxime - oxime K203 - after its fluorination. This AChE reactivator was prepared at the Research Institute of Chemical Technology (Korea) and is known as K22836. The fluorination of oxime K203 leads to reduction of its therapeutic efficacy. The reactivation potency of newly synthesized oxime K22836 was lower in the whole blood and also in the central nervous system. In summary, the most efficacious reactivator in case of tabun-inhibited AChE is still oxime K203 originally prepared at our department.
ESTHER : Karasova_2010_Mil.Med.Sci.Lett_79_23
PubMedSearch : Karasova_2010_Mil.Med.Sci.Lett_79_23
PubMedID:

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

Title : Tabun-inhibited rat tissue and blood cholinesterases and their reactivation with the combination of trimedoxime and HI-6 in vivo - Bajgar_2010_Chem.Biol.Interact_187_287
Author(s) : Bajgar J , Karasova JZ , Kassa J , Cabal J , Fusek J , Blaha V , Tesarova S
Ref : Chemico-Biological Interactions , 187 :287 , 2010
Abstract : Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro.
ESTHER : Bajgar_2010_Chem.Biol.Interact_187_287
PubMedSearch : Bajgar_2010_Chem.Biol.Interact_187_287
PubMedID: 20167212

Title : 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 - Kassa_2010_Drug.Chem.Toxicol_33_227
Author(s) : Kassa J , Karasova JZ , Kuca K , Musilek K
Ref : Drug & Chemical Toxicology , 33 :227 , 2010
Abstract : 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.
ESTHER : Kassa_2010_Drug.Chem.Toxicol_33_227
PubMedSearch : Kassa_2010_Drug.Chem.Toxicol_33_227
PubMedID: 20429807

Title : A comparison of tabun-inhibited rat brain acetylcholinesterase reactivation by three oximes (HI-6, obidoxime, and K048) in vivo detected by biochemical and histochemical techniques - Bajgar_2010_J.Enzyme.Inhib.Med.Chem_25_790
Author(s) : Bajgar J , Hajek P , Karasova JZ , Kassa J , Paseka A , Slizova D , Krs O , Kuca K , Jun D , Fusek J , Capek L
Ref : J Enzyme Inhib Med Chem , 25 :790 , 2010
Abstract : Tabun belongs to the most toxic nerve agents. Its mechanism of action is based on acetylcholinesterase (AChE) inhibition at the peripheral and central nervous systems. Therapeutic countermeasures comprise administration of atropine with cholinesterase reactivators able to reactivate the inhibited enzyme. Reactivation of AChE is determined mostly biochemically without specification of different brain structures. Histochemical determination allows a fine search for different structures but is performed mostly without quantitative evaluation. In rats intoxicated with tabun and treated with a combination of atropine and HI-6, obidoxime, or new oxime K048, AChE activities in different brain structures were determined using biochemical and quantitative histochemical methods. Inhibition of AChE following untreated tabun intoxication was different in the various brain structures, having the highest degree in the frontal cortex and reticular formation and lowest in the basal ganglia and substantia nigra. Treatment resulted in an increase of AChE activity detected by both methods. The highest increase was observed in the frontal cortex. This reactivation was increased in the order HI-6 < K048 < obidoxime; however, this order was not uniform for all brain parts studied. A correlation between AChE activity detected by histochemical and biochemical methods was demonstrated. The results suggest that for the mechanism of action of the nerve agent tabun, reactivation in various parts of the brain is not of the same physiological importance. AChE activity in the pontomedullar area and frontal cortex seems to be the most important for the therapeutic effect of the reactivators. HI-6 was not a good reactivator for the treatment of tabun intoxication.
ESTHER : Bajgar_2010_J.Enzyme.Inhib.Med.Chem_25_790
PubMedSearch : Bajgar_2010_J.Enzyme.Inhib.Med.Chem_25_790
PubMedID: 21054236

Title : A comparison of reactivating and therapeutic efficacy of newly-developed oximes (K156, K203) and commonly used oximes (obidoxime, HI-6) in cyclosarin-poisoned rats and mice - Kassa_2009_Toxicol.Mech.Methods_19_346
Author(s) : Kassa J , Karasova JZ , Musilek K , Kuca K
Ref : Toxicol Mech Methods , 19 :346 , 2009
Abstract : A potency of newly-developed oximes (K156, K203) and commonly used oximes (obidoxime, HI-6) to reactivate cyclosarin-inhibited acetylcholinesterase and to reduce cyclosarin-induced acute toxic effects was evaluated in this study. In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the potency of a newly-developed oxime (K203) to reactivate cyclosarin-inhibited acetylcholinesterase and to reduce the acute lethal effects of cyclosarin, corresponding to the relatively low reactivating and therapeutic efficacy of obidoxime. The potency of another newly-developed oxime (K156) to counteract the inhibitory and acute clinical effects of cyclosarin is almost negligible. On the other hand, the oxime HI-6 is a very efficient reactivator of cyclosarin-inhibited acetylcholinesterase in the peripheral (blood, diaphragm) as well as central (brain) compartment, and it is able to reduce the acute toxicity of cyclosarin more than three times. Although the reactivating and therapeutic efficacy of the oxime K203 is higher compared to another newly-developed oxime K156, the reactivating and therapeutic potency of both newly-developed oximes is significantly lower in comparison with the oxime HI-6 and, therefore, none of them is suitable for replacement of HI-6 in the case of the treatment of cyclosarin poisoning.
ESTHER : Kassa_2009_Toxicol.Mech.Methods_19_346
PubMedSearch : Kassa_2009_Toxicol.Mech.Methods_19_346
PubMedID: 19778210

Title : Effect of five acetylcholinesterase reactivators on tabun-intoxicated rats: induction of oxidative stress versus reactivation efficacy - Pohanka_2009_J.Appl.Toxicol_29_483
Author(s) : Pohanka M , Karasova JZ , Musilek K , Kuca K , Kassa J
Ref : J Appl Toxicol , 29 :483 , 2009
Abstract : Oxime reactivators HI-6, obidoxime, trimedoxime, K347 and K628 were investigated as drugs designed for treatment of tabun intoxication. The experiments were performed on rats in order to simulate real conditions. Rats were intoxicated with one LD(50 )of tabun and treated with atropine and mentioned reactivators. Activities of erythrocyte acetylcholinesterase (AChE), plasma butyrylcholinesterase (BChE) and brain AChE were measured as markers of reactivation efficacy. An estimation of low molecular weight antioxidant levels using cyclic voltammetry was the second examination parameter. The evaluation of cholinesterases activity showed good reactivation potency of blood AChE and plasma BChE by commercially available obidoxime and newly synthesized K347. The potency of oximes to reactivate brain AChE was lower due to the poor blood-brain barrier penetration of used compounds. Commercially available reactivator HI-6 and newly synthesized K628 caused oxidative stress measured by cyclic voltammetry as antioxidant level. The oxidative stress provoked by HI-6 and K628 was found to be significant on probability level P = 0.05. The others reactivators did not affect antioxidant levels.
ESTHER : Pohanka_2009_J.Appl.Toxicol_29_483
PubMedSearch : Pohanka_2009_J.Appl.Toxicol_29_483
PubMedID: 19338015

Title : Effect of seven newly synthesized and currently available oxime cholinesterase reactivators on cyclosarin-intoxicated rats - Karasova_2009_Int.J.Mol.Sci_10_3065
Author(s) : Karasova JZ , Kassa J , Musilek K , Pohanka M , Novotny L , Kuca K
Ref : Int J Mol Sci , 10 :3065 , 2009
Abstract : Seven new oxime-based acetylcholinesterase reactivators were compared with three currently available ones (obidoxime, trimedoxime, HI-6) for their ability to lessen cholinesterase inhibition in blood and brain of cyclosarin-treated rats. Oximes were given at doses of 5% their LD(50) along with 21 mg/kg atropine five min before the LD(50) of cyclosarin (120 ug/kg) was administered. Blood and brain samples were collected 30 minutes later. The greatest difference between acetylcholinesterase inhibition in blood of cyclosarin-treated rats was found after administration of HI-6 (40%), compared to 22% for trimedoxime and 6% for obidoxime. Only two of the seven newly synthesized oximes had any effect (K203 at 7%, K156 at 5%). Effective oximes against cyclosarin-inhibited plasma butyrylcholinesterase were HI-6 (42%), trimedoxime (11%), and K156 (4%). The oximes were less effective in brain than in blood, with reactivation values for HI-6 30% against acetylcholinesterase and 10% against butyrylcholinesterase. Values for newly synthesized oximes were less than 10% for K206, K269 and K203.
ESTHER : Karasova_2009_Int.J.Mol.Sci_10_3065
PubMedSearch : Karasova_2009_Int.J.Mol.Sci_10_3065
PubMedID: 19742125

Title : Chemical aspects of pharmacological prophylaxis against nerve agent poisoning - Bajgar_2009_Curr.Med.Chem_16_2977
Author(s) : Bajgar J , Fusek J , Kassa J , Kuca K , Jun D
Ref : Curr Med Chem , 16 :2977 , 2009
Abstract : Prophylactic approaches against intoxication with organophosphates (OP)/nerve agents can be based on following principles: keeping acetylcholinesterase (AChE), the key enzyme for toxic action of OP/nerve agents, intact (protection of cholinesterases) is a basic requirement for effective prophylaxis. It can be reached using simple chemicals such as reversible inhibitors (preferably carbamates), which are able to inhibit AChE reversibly. AChE inhibited by carbamates is resistant to OP/nerve agent inhibition. After spontaneous recovery of the activity, normal AChE serves as a source of the active enzyme. Detoxification is realised by administration of the enzymes splitting the OP or exploitating specific enzymes (cholinesterases). OP/nerve agent is bound to the exogenously administered proteins (enzymes) and, thus, the agent level in the organism is decreased ("scavenger" effect). The antidotes currently used for the treatment of OP poisoning (also simple chemicals) can be tested as prophylactics. This principle can be considered as a treatment "in advance". The problem with their use is the timing, duration and achievement of sufficient levels of these antidotes after the administration. At present, PYRIDOSTIGMINE seems to be common prophylactic antidote; prophylactics PANPAL (tablets with pyridostigmine, trihexyphenidyle and benactyzine), TRANSANT (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. Future development will be focused on scavengers (cholinesterases and other enzymes) acting before the binding of nerve agent to the target sites, and on other drugs reversible cholinesterase inhibitors (e.g. huperzine A, physostigmine, acridine derivatives etc.) including non-traditional routes of administration.
ESTHER : Bajgar_2009_Curr.Med.Chem_16_2977
PubMedSearch : Bajgar_2009_Curr.Med.Chem_16_2977
PubMedID: 19689278

Title : A comparison of the neuroprotective efficacy of newly developed oximes (K117, K127) and currently available oxime (obidoxime) in tabun-poisoned rats - Kassa_2009_Toxicol.Mech.Methods_19_232
Author(s) : Kassa J , Karasova JZ , Musilek K , Kuca K , Jung AY
Ref : Toxicol Mech Methods , 19 :232 , 2009
Abstract : 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.
ESTHER : Kassa_2009_Toxicol.Mech.Methods_19_232
PubMedSearch : Kassa_2009_Toxicol.Mech.Methods_19_232
PubMedID: 19730756

Title : The influence of combinations of oximes on the reactivating and therapeutic efficacy of antidotal treatment of soman poisoning in rats and mice - Kassa_2009_Toxicol.Mech.Methods_19_547
Author(s) : Kassa J , Karasova JZ , Caisberger F , Bajgar J
Ref : Toxicol Mech Methods , 19 :547 , 2009
Abstract : The influence of the combination of oximes on the reactivating and therapeutic efficacy of antidotal treatment of acute soman poisoning was evaluated. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate soman-inhibited acetylcholinesterase and reduce acute toxicity of soman was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo model. Studies determining percent of reactivation of soman-inhibited blood and diaphragm acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is slightly greater than the reactivating efficacy of the most effective individual oxime, but the difference among them is not significant. Both combinations of oximes were found to be as effective in the reduction of acute lethal toxic effects in soman-poisoned mice as the antidotal treatment involving the most efficacious individual oxime. Thus, the efficacy of oximes is comparative in rats vs mice. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the newly developed oxime K203 is approximately as effective as commonly used trimedoxime; nevertheless, their reactivating and therapeutic efficacy is markedly lower compared to the oxime HI-6. Based on the obtained data, one can conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the potency of the most effective individual oxime (HI-6) to reactivate soman-inhibited rat acetylcholinesterase and to reduce acute toxicity of soman.
ESTHER : Kassa_2009_Toxicol.Mech.Methods_19_547
PubMedSearch : Kassa_2009_Toxicol.Mech.Methods_19_547
PubMedID: 19839724

Title : An evaluation of reactivating and therapeutic efficacy of newly developed oximes (K206, K269) and commonly used oximes (obidoxime, HI-6) in cyclosarin-poisoned rats and mice - Kassa_2009_Clin.Toxicol.(Phila)_47_72
Author(s) : Kassa J , Karasova J , Musilek K , Kuca K , Bajgar J
Ref : Clinical Toxicology (Phila) , 47 :72 , 2009
Abstract : INTRODUCTION: The ability of currently available reactivators to reactivate cyclosarin is low. The aim of this study was to determine the reactivating and therapeutic efficacy of newly developed oximes (K206, K269) compared with currently available oximes against cyclosarin. METHODS: Rats and mice received atropine or atropine + oxime intramuscularly (i.m.) before or after an i.m. dose of cyclosarin. Acetylcholine activity levels in blood and tissues were measured to calculate the reactivation efficacy and potency. RESULTS AND DISCUSSION: In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase (AChE) in poisoned rats showed that the potency of both newly developed oximes (K206, K269) to reactivate cyclosarin-inhibited AChE is comparable with that of obidoxime in blood and diaphragm, but slightly higher than that of obidoxime in brain. Their reactivating efficacy is significantly lower compared with that of the oxime HI-6. K206 and K269 are relatively effective in reducing cyclosarin-induced lethal toxic effects in mice. Their therapeutic efficacies exceed the therapeutic potency of obidoxime but not that of HI-6. CONCLUSIONS: K206 and K269 are as effective in the reactivation of cyclosarin-inhibited AChE in rats and in the reduction of lethal toxic effects of cyclosarin in mice as obidoxime, but because their reactivating and therapeutic potency is significantly lower than that of HI-6, they are not suitable replacements for the currently available oximes for the treatment of cyclosarin poisoning.
ESTHER : Kassa_2009_Clin.Toxicol.(Phila)_47_72
PubMedSearch : Kassa_2009_Clin.Toxicol.(Phila)_47_72
PubMedID: 18686075

Title : Fluorinated pyridinium oximes as potential reactivators for acetylcholinesterases inhibited by paraoxon organophosphorus agent - Jeong_2009_Bioorg.Med.Chem_17_6213
Author(s) : Jeong HC , Park NJ , Chae CH , Musilek K , Kassa J , Kuca K , Jung YS
Ref : Bioorganic & Medicinal Chemistry , 17 :6213 , 2009
Abstract : A series of fluorinated oxime compounds was designed and synthesized in order to probe the effect of fluorine substitution on reactivation of inhibited acetylcholinesterase (AChE) by organophosphorus agents. Permeability measurements, using the Parallel Artificial Membrane Permeation Assays (PAMPA) method, were employed to experimentally demonstrate that membrane permeabilities of the series of oximes increase in proportional to the increase in the number of fluorine atoms. Among the compounds explored in this study, the mono-fluorinated carbamoyl aldoxime 4b was the most potent reactivator for paraoxon-inhibited red blood cell (RBC) AChE.
ESTHER : Jeong_2009_Bioorg.Med.Chem_17_6213
PubMedSearch : Jeong_2009_Bioorg.Med.Chem_17_6213
PubMedID: 19665386

Title : An evaluation of therapeutic and reactivating effects of newly developed oximes (K156, K203) and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice - Kassa_2008_Toxicology_243_311
Author(s) : Kassa J , Karasova J , Musilek K , Kuca K
Ref : Toxicology , 243 :311 , 2008
Abstract : The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) 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 newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.
ESTHER : Kassa_2008_Toxicology_243_311
PubMedSearch : Kassa_2008_Toxicology_243_311
PubMedID: 18054821

Title : New performance of biosensor technology for Alzheimer's disease drugs: in vitro comparison of tacrine and 7-methoxytacrine - Pohanka_2008_Neuro.Endocrinol.Lett_29_755
Author(s) : Pohanka M , Kuca K , Kassa J
Ref : Neuro Endocrinol Lett , 29 :755 , 2008
Abstract : Two drugs were tested using electrochemical biosensor with immobilized acetylcholinesterase (AChE). The first was commercialized drug tacrine (known also as Cognex) used for treatment of cognitive manifestation of Alzheimer\'s disease (AD). The second one was its 7-methoxy derivate (7-MEOTA) that has not been marketed. We determined the IC50 (6.67+/-0.92)x10-7 M for tacrine and (1.66+/-1.43)x10-9 M for 7-MEOTA. In this in vitro study, 7-MEOTA acts as stronger inhibitor of AChE and in this way could be more favorable for treatment of cognitive manifestation of AD. Our study shows that biosensor technology could be used as a quick and cheap tool for testing of promising AChE inhibitors (AD drug candidates).
ESTHER : Pohanka_2008_Neuro.Endocrinol.Lett_29_755
PubMedSearch : Pohanka_2008_Neuro.Endocrinol.Lett_29_755
PubMedID: 18987590

Title : A comparison of reactivating efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in soman, cyclosarin and tabun-poisoned rats - Kassa_2008_Chem.Biol.Interact_175_425
Author(s) : Kassa J , Jun D , Karasova J , Bajgar J , Kuca K
Ref : Chemico-Biological Interactions , 175 :425 , 2008
Abstract : The potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to reactivate nerve agent-inhibited acetylcholinesterase was evaluated in rats poisoned with soman, tabun or cyclosarin at a lethal dose corresponding to their LD(50) value. In vivo determined percentage of reactivation of soman-inhibited blood and brain acetylcholinesterase in poisoned rats showed that only the oxime HI-6 was able to reactivate soman-inhibited acetylcholinesterase in the peripheral (blood) as well as central (brain) compartment. In vivo determined percentage of reactivation of tabun-inhibited blood and brain acetylcholinesterase in poisoned rats showed that obidoxime is the most efficacious reactivator of tabun-inhibited acetylcholinesterase among studied oximes in the peripheral compartment (blood) while K074 seems to be the most efficacious reactivator of tabun-inhibited acetylcholinesterase among studied oximes in the central compartment (brain). In vivo determined percentage of reactivation of cyclosarin-inhibited blood and brain acetylcholinesterase in poisoned rats showed that HI-6 is the most efficacious reactivator of cyclosarin-inhibited acetylcholinesterase among studied oximes. Due to their reactivating effects, both newly developed K oximes can be considered to be promising oximes for the antidotal treatment of acute tabun poisonings while the oxime HI-6 is still the most promising oxime for the treatment of acute soman and cyclosarin poisonings.
ESTHER : Kassa_2008_Chem.Biol.Interact_175_425
PubMedSearch : Kassa_2008_Chem.Biol.Interact_175_425
PubMedID: 18547554

Title : The development of new oximes and the evaluation of their reactivating, therapeutic and neuroprotective efficacy against tabun - Kassa_2008_Mini.Rev.Med.Chem_8_1134
Author(s) : Kassa J , Kuca K , Karasova J , Musilek K
Ref : Mini Rev Med Chem , 8 :1134 , 2008
Abstract : Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. The antidotal treatment of tabun acute poisonings still represents a serious problem and the development of new, more effective AChE reactivators to achieve the satisfactorily effective antidotal treatment of acute poisonings with tabun still represents very important goal. Since 2003, we have prepared around 200 new AChE reactivators. Their potency to reactivate tabun-inhibited acetylcholinesterase has been subsequently evaluated using our in vitro screening test. Afterwards, promising compounds were selected and kinetic parameters and reactivation constants were determined. Then, the best reactivators were subjected to the in vivo studies (toxicity test, the evaluation of therapeutic, reactivating and neuroprotective efficacy) and their potency to counteract the acute toxicity of tabun is compared to the therapeutic, reactivating and neuroprotective efficacy of commonly used oximes - obidoxime and the oxime HI-6. According to the results obtained, the newly synthesized oxime K075 showed the highest potency to reduce tabun-induced acute lethal toxicity while the therapeutic potency of obidoxime and the oxime HI-6 was significantly lower. The therapeutic efficacy of oximes studied corresponds to their reactivating efficacy in vivo as well as in vitro. The potency of all newly synthesized oximes to reactivate tabun-inhibited AChE is comparable with obidoxime with the exception of K074 that is significantly more efficacious in the brain. In addition, all newly synthesized oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced acute neurotoxicity. While the neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly synthesized oximes, the ability of the oxime HI-6 combined with atropine to counteract tabun-induced acute neurotoxicity is significantly lower. Due to their therapeutic, reactivating and neuroprotective efficacy, all newly synthesized oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisonings.
ESTHER : Kassa_2008_Mini.Rev.Med.Chem_8_1134
PubMedSearch : Kassa_2008_Mini.Rev.Med.Chem_8_1134
PubMedID: 18855728

Title : A comparison of the therapeutic and reactivating efficacy of newly developed oximes (K117, K127) and currently available oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice - Kassa_2008_Drug.Chem.Toxicol_31_371
Author(s) : Kassa J , Karasova J , Musilek K , Kuca K , Jung YS
Ref : Drug & Chemical Toxicology , 31 :371 , 2008
Abstract : The potency of newly developed bispyridinium compounds (K117, K127) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, trimedoxime, oxime HI-6) by using in vivo methods. A study that determined the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K127 is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. The potency of another newly developed K117 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in the diaphragm, but it is significantly lower than the reactivating potency of trimedoxime and obidoxime in the blood and brain. The oxime, K127, was also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Its therapeutic efficacy is consistent with the therapeutic potency of obidoxime. On the other hand, the potency of the oxime, K117, to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and obidoxime. The therapeutic efficacy of K117 and K127 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in the diaphragm and brain. Contrary to obidoxime and trimedoxime, the oxime, HI-6, is not an effective oxime in the reactivation of tabun-inhibited acetycholinesterase and in reducing the lethal effects of tabun. The reactivating and therapeutic potency of both newly developed oximes does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
ESTHER : Kassa_2008_Drug.Chem.Toxicol_31_371
PubMedSearch : Kassa_2008_Drug.Chem.Toxicol_31_371
PubMedID: 18622871

Title : Potency of several oximes to reactivate human acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon in vitro - Jun_2008_Chem.Biol.Interact_175_421
Author(s) : Jun D , Musilova L , Kuca K , Kassa J , Bajgar J
Ref : Chemico-Biological Interactions , 175 :421 , 2008
Abstract : Organophosphorus pesticides (e.g. chlorpyrifos, malathion, and parathion) and nerve agents (sarin, tabun, and VX) are highly toxic organophosphorus compounds with strong inhibition potency against two key enzymes in the human body-acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BuChE; EC 3.1.1.8). Subsequent accumulation of acetylcholine at synaptic clefts can result in cholinergic crisis and possible death of intoxicated organism. For the recovery of inhibited AChE, derivatives from the group of pyridinium or bispyridinium aldoximes (called oximes) are used. Their efficacy depends on their chemical structure and also type of organophosphorus inhibitor. In this study, we have tested potency of selected cholinesterase reactivators (pralidoxime, obidoxime, trimedoxime, methoxime and H-oxime HI-6) to reactivate human erythrocyte AChE and human plasma BuChE inhibited by pesticide paraoxon. For this purpose, modified Ellman's method was used and two different concentrations of oximes (10 and 100 microM), attainable in the plasma within antidotal treatment of pesticide intoxication were tested. Results demonstrated that obidoxime (96.8%) and trimedoxime (86%) only reached sufficient reactivation efficacy in case of paraoxon-inhibited AChE. Other oximes evaluated did not surpassed more than 25% of reactivation. In the case of BuChE reactivation, none of tested oximes surpassed 12.5% of reactivation. The highest reactivation efficacy was achieved for trimedoxime (12.4%) at the concentration 100 microM. From the data obtained, it is clear that only two from currently available oximes (obidoxime and trimedoxime) are good reactivators of paraoxon-inhibited AChE. In the case of BuChE, none of these reactivators could be used for its reactivation.
ESTHER : Jun_2008_Chem.Biol.Interact_175_421
PubMedSearch : Jun_2008_Chem.Biol.Interact_175_421
PubMedID: 18617161

Title : Temporal effects of newly developed oximes (K027, K048) on malathion-induced acetylcholinesterase inhibition and lipid peroxidation in mouse prefrontal cortex - da Silva_2008_Neurotoxicol_29_184
Author(s) : da Silva AP , Farina M , Franco JL , Dafre AL , Kassa J , Kuca K
Ref : Neurotoxicology , 29 :184 , 2008
Abstract : The potency of newly developed asymmetric bispyridinium oximes (K027, K048) in reactivating acetylcholinesterase and in eliminating oxidative stress induced by acute exposure to malathion was evaluated in mouse prefrontal cortex using in vivo methods. Malathion (1g/kg, dissolved in saline) was administered subcutaneously. The asymmetric bispyridinium oximes K027 or K048 (1/4 of LD(50), dissolved in saline, i.p.) were administered immediately after malathion and atropine sulfate (20mg/kg, dissolved in saline, i.p.). Control group received saline instead of malathion and antidotes. Acetylcholinesterase activity and biochemical parameters related to oxidative stress (glutathione levels, glutathione peroxidase and glutathione reductase activity and lipid peroxidation) were evaluated in mouse prefrontal cortex at two different time points (3 or 24 h after malathion poisoning). Malathion administration markedly inhibited cortical acetylcholinesterase activity (around 55%) at 3h after malathion challenge and such inhibition was maintained till 24 h after poisoning. Although neither atropine sulfate nor oximes were able to eliminate cortical acetylcholinesterase inhibition at 3h after malathion poisoning, K027 (in combination with atropine) completely eliminated the inhibitory effect of malathion exposure on cortical acetylcholinesterase activity at 24 h after malathion administration. K048 (in combination with atropine) significantly decreased acetylcholinesterase inhibition at 24 h after malathion poisoning. Even though glutathione levels and glutathione peroxidase and glutathione reductase activities were not affected, malathion administration markedly increased lipid peroxidation in the prefrontal cortex at 24 h after poisoning and the oxime K027 (in combination with atropine) was able to significantly decrease such phenomenon. Thus, our results clearly demonstrate that the newly developed asymmetric bispyridinium oximes K027 and K048 are able to reverse malathion-induced acetylcholinesterase inhibition in mouse prefrontal cortex. Moreover, the ameliorative effect of the oxime K027 on the increased lipid peroxidation observed at 24 h after malathion poisoning suggests a potential link between the hyperstimulation of cholinergic system and oxidative stress in the mouse prefrontal cortex after malathion exposure.
ESTHER : da Silva_2008_Neurotoxicol_29_184
PubMedSearch : da Silva_2008_Neurotoxicol_29_184
PubMedID: 18035420

Title : Effect of several new and currently available oxime cholinesterase reactivators on tabun-intoxicated rats - Karasova_2008_Int.J.Mol.Sci_9_2243
Author(s) : Karasova JZ , Kassa J , Jung YS , Musilek K , Pohanka M , Kuca K
Ref : Int J Mol Sci , 9 :2243 , 2008
Abstract : The therapeutical efficacies of eleven oxime-based acetylcholinesterase reactivators were compared in an in vivo (rat model) study of treatment of intoxication caused by tabun. In this group there were some currently available oximes (obidoxime, trimedoxime and HI-6) and the rest were newly synthesized compounds. The best reactivation efficacy for acetylcholinesterase in blood (expressed as percent of reactivation) among the currently available oximes was observed after administration of trimedoxime (16%) and of the newly synthesized K127 (22432) (25%). The reactivation of butyrylcholinesterase in plasma was also studied; the best reactivators were trimedoxime, K117 (22435), and K127 (22432), with overall reactivation efficacies of approximately 30%. Partial protection of brain ChE against tabun inhibition was observed after administration of trimedoxime (acetylcholinesterase 20%; butyrylcholinesterase 30%) and obidoxime (acetylcholinesterase 12%; butyrylcholinesterase 16%).
ESTHER : Karasova_2008_Int.J.Mol.Sci_9_2243
PubMedSearch : Karasova_2008_Int.J.Mol.Sci_9_2243
PubMedID: 19330072

Title : A comparison of the therapeutic and reactivating efficacy of newly developed bispyridinium compounds (K206, K269) with currently available oximes against tabun in rats and mice - Kassa_2008_J.Enzyme.Inhib.Med.Chem_23_776
Author(s) : Kassa J , Karasova J , Bajgar J , Kuca K , Musilek K
Ref : J Enzyme Inhib Med Chem , 23 :776 , 2008
Abstract : The potency of newly developed bispyridinium compounds (K206, K269) in reactivating tabun-inhibited acetylcholinesterase and eliminating tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies which determined percentage of reactivation of tabun-inhibited blood and tissue AChE in poisoned rats showed that the reactivating efficacy of both newly developed oximes is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. Nevertheless, the differences in reactivating efficacy of obidoxime, trimedoxime and K206 was not significant while the potency of K269 to reactivate tabun-inhibited acetylcholinesterase was significantly lower. Both newly developed oximes were also found to be relatively efficacious in elimination of the lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy corresponds to the therapeutic potency of obidoxime. The oxime HI-6, relatively efficacious against soman, did not seem to be an adequately effective oxime in reactivation of tabun-inhibited AChE and to counteract lethal effects of tabun. Both newly developed oximes (K206, K269) are significantly more efficacious in reactivating tabun-inhibited AChE in rats and to eliminate lethal toxic effects of tabun in mice than the oxime HI-6 but their reactivating and therapeutic potency does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.
ESTHER : Kassa_2008_J.Enzyme.Inhib.Med.Chem_23_776
PubMedSearch : Kassa_2008_J.Enzyme.Inhib.Med.Chem_23_776
PubMedID: 18608751

Title : The effect of HI-6 on cholinesterases and on the cholinergic system of the rat bladder - Soukup_2008_Neuro.Endocrinol.Lett_29_759
Author(s) : Soukup O , Pohanka M , Tobin G , Jun D , Fusek J , Musilek K , Marek J , Kassa J , Kuca K
Ref : Neuro Endocrinol Lett , 29 :759 , 2008
Abstract : OBJECTIVES: The current standard treatment of organophosphate poisoning consists of an administration of anticholinergic drugs and cholinesterase reactivators (oximes). Oximes can react - except their reactivating effect on cholinesterases - directly with cholinoreceptors. HI-6 is an oxime that may have an inhibitory effect on the muscarinic receptors, too. METHODS: In our work, we have investigated an influence of HI-6 on the acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and on the muscarinic receptors in vitro. The study was conducted using biosensor technique and on the rat bladder using in vitro test (tissue bath; methacholine as muscarinic agonist). IC50 for BChE from human serum was determined to be 1.01x10-6 M and for human erythrocytes AChE 3.31x10-6 M, respectively. CONCLUSION: We assume that the demonstrated contractile response can be attributed to the inhibition of the AChE at the lower concentration and to a predominant inhibition of muscarinic receptor at higher concentration of compound tested.
ESTHER : Soukup_2008_Neuro.Endocrinol.Lett_29_759
PubMedSearch : Soukup_2008_Neuro.Endocrinol.Lett_29_759
PubMedID: 18987577

Title : An attempt to assess functionally minimal acetylcholinesterase activity necessary for survival of rats intoxicated with nerve agents - Bajgar_2008_Chem.Biol.Interact_175_281
Author(s) : Bajgar J , Fusek J , Kassa J , Jun D , Kuca K , Hajek P
Ref : Chemico-Biological Interactions , 175 :281 , 2008
Abstract : Acetylcholinesterase (AChE, EC 3.1.1.7) is an important enzyme for cholinergic nerve transmission. The action of toxic organophosphates such as nerve agents is based on AChE inhibition. The death following acute nerve agent poisoning is due to central or peripheral respiratory/cardiac failure. Therefore, the changes in AChE activity following nerve agents acting predominantly on the central (sarin, soman) or peripheral (VX) level were studied. It is known that AChE activity in different structures exists in relative excess. Female Wistar rats intoxicated with sarin, soman, and VX in different doses (0.5-2.0 x LD(50)) were divided into groups of survived and died animals. AChE activities in diaphragm, brain parts (pontomedullar area, frontal cortex, basal ganglia, in some cases other parts of the brain) were determined and the rest of activity (in %) was correlated with survival/death of animals. More precise elucidation of action of nerve agents and the assessment of minimal AChE activity in different organs compatible with the survival of organism poisoned with nerve agents were the aims of this study.
ESTHER : Bajgar_2008_Chem.Biol.Interact_175_281
PubMedSearch : Bajgar_2008_Chem.Biol.Interact_175_281
PubMedID: 18579126

Title : In vitro oxime reactivation of red blood cell acetylcholinesterase inhibited by methyl-paraoxon - Petroianu_2007_J.Appl.Toxicol_27_168
Author(s) : Petroianu GA , Arafat K , Nurulain SM , Kuca K , Kassa J
Ref : J Appl Toxicol , 27 :168 , 2007
Abstract : Oximes are cholinesterase reactivators of use in poisoning with organophosphorus ester enzyme inhibitors. Pralidoxime (PRX) is the oxime used in the United States. Clinical experience with pralidoxime (and other oximes) is disappointing and the routine use has been questioned. Furthermore oximes are not equally effective against all existent enzyme inhibitors. There is a clear demand for 'broad spectrum' cholinesterase reactivators with a higher efficacy than those clinically available. To meet this need over the years new reactivators of cholinesterase of potential clinical utility have been developed. The purpose of the study was to quantify 'in vitro' the extent of protection conferred by available (pralidoxime and methoxime) and experimental (K-27, K-33 and K-48) oximes, using methyl-paraoxon (methyl-POX) as an esterase inhibitor and to compare the results with those previously obtained using paraoxon (POX) as an inhibitor. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood were measured photometrically in the presence of different methyl-POX concentrations and IC(50) values calculated. Determinations were repeated in the presence of increasing oxime concentrations. The IC(50) of methyl-POX (59 nm) increased with the oxime concentration in a linear manner. The calculated IC(50) values were plotted against the oxime concentrations to obtain an IC(50) shift curve. The slope of the shift curve (tg alpha) was used to quantify the magnitude of the protective effect (nm IC(50) increase per microm reactivator). Based on our determinations the new K-series of reactivators is superior to pralidoxime (tg alpha = 1.9) and methoxime (tg alpha = 0.7), K-27 and K-48 being the outstanding compounds with a tg alpha value of 10 (nm IC(50) increase per microm reactivator), which is approximately five times the reactivator ability of PRX. The tg alpha value determined for K-33 was 6.3. The ranking of reactivator potencies of the examined oximes determined with methyl-POX as an inhibitor (K-27 = K-48 > K-33 > pralidoxime > methoxime) is similar to the ranking previously reported by us using POX as an inhibitor (K-27 > or = K-48 > K-33 > methoxime = pralidoxime). There is an (expected) inverse relationship between the binding constant K and the slope of the IC(50) shift curve (tg alpha) for all oximes examined. K-27 and K-48 (the most protective substances judging by the tg alpha) having the lowest K value (highest affinity). In vivo testing of the new oximes as methyl-paraoxon protective agents is necessary.
ESTHER : Petroianu_2007_J.Appl.Toxicol_27_168
PubMedSearch : Petroianu_2007_J.Appl.Toxicol_27_168
PubMedID: 17265452

Title : Design of a potent reactivator of tabun-inhibited acetylcholinesterase--synthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203) - Musilek_2007_J.Med.Chem_50_5514
Author(s) : Musilek K , Jun D , Cabal J , Kassa J , Gunn-Moore F , Kuca K
Ref : Journal of Medicinal Chemistry , 50 :5514 , 2007
Abstract : Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Among the organophosphates, with the exception of soman, tabun (GA) intoxications are the least responsive to treatment with commercially available therapeutics. A rational design was used to increase reactivation ability and decrease the toxicity of the novel reactivator. (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203) has better properties than previously tested compounds in vitro and, therefore, is a potential candidate for the treatment of GA intoxication in vivo.
ESTHER : Musilek_2007_J.Med.Chem_50_5514
PubMedSearch : Musilek_2007_J.Med.Chem_50_5514
PubMedID: 17924614

Title : A comparison of the potency of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) to counteract soman-induced neurotoxicity in rats - Kassa_2007_Drug.Chem.Toxicol_30_117
Author(s) : Kassa J , Karasova J
Ref : Drug & Chemical Toxicology , 30 :117 , 2007
Abstract : The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24 h and 7 days after soman challenge. The results indicate that the oxime HI-6 combined with atropine seems to be an effective antidote for a decrease in soman-induced neurotoxicity, whereas the ability of both newly developed oximes (K074, K075) as well as obidoxime to counteract soman-induced acute neurotoxicity is negligible. Due to the absence of their neuroprotective potency, both newly developed oximes are not suitable oximes for antidotal treatment after exposure to soman. The oxime HI-6 is still the best acetylcholinesterase reactivator for the antidotal treatment of acute poisonings with soman.
ESTHER : Kassa_2007_Drug.Chem.Toxicol_30_117
PubMedSearch : Kassa_2007_Drug.Chem.Toxicol_30_117
PubMedID: 17454028

Title : A comparison of reactivating efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in cyclosarin-and tabun-poisoned rats - Kassa_2007_J.Enzyme.Inhib.Med.Chem_22_297
Author(s) : Kassa J , Jun D , Kuca K
Ref : J Enzyme Inhib Med Chem , 22 :297 , 2007
Abstract : The potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to reactivate nerve agent-inhibited acetylcholinesterase was evaluated in rats poisoned with tabun or cyclosarin at a lethal dose corresponding to the LD50 value. In vivo determined percentage of reactivation of tabun-inhibited blood and brain acetylcholinesterase showed that obidoxime is the most efficacious reactivator of tabun-inhibited acetylcholinesterase among studied oximes in the peripheral compartment (blood) although the differences between obidoxime and newly developed oximes were not significant. On the other hand, one of the newly developed oximes (K074) seems to be a significantly more efficacious reactivator of tabun-inhibited acetylcholinesterase in the central compartment (brain) than the other studied oximes. In addition, the oxime HI-6 is unable to sufficiently reactivate tabun-inhibited acetylcholinesterase in rats. In vivo determined percentage of reactivation of cyclosarin-inhibited blood and brain acetylcholinesterase in poisoned rats showed that HI-6 is the most efficacious reactivator of cyclosarin-inhibited acetylcholinesterase among the studied oximes in the peripheral (blood) as well as central (brain) compartment although the differences between the oxime HI-6 and other tested oximes in the brain were not significant. Due to their reactivating effects, both newly developed K-oximes can be considered to be promising oximes for the antidotal treatment of acute tabun poisoning while the oximes HI-6 is still the most promising oxime for the treatment of acute cyclosarin poisonings due to its high potency in reactivating cyclosarin-inhibited acetylcholinesterase in the peripheral as well as central compartment.
ESTHER : Kassa_2007_J.Enzyme.Inhib.Med.Chem_22_297
PubMedSearch : Kassa_2007_J.Enzyme.Inhib.Med.Chem_22_297
PubMedID: 17674811

Title : A Comparison of Newly Synthesized Oximes (K074, K075) and Oximes Introduced into the Czech Army (Obidoxime, HI-6) to Reactivate Tabun or Soman-Inhibited Acetylcholinesterase in Rat's Blood and Brain - Kassa_2007_Mil.Med.Sci.Lett_76_27
Author(s) : Kassa J , Jun D
Ref : Military Medical Science Letters , 76 :27 , 2007
Abstract : The reactivating efficacy of newly synthesized oximes (K074, K075) and the oximes introduced into the Czech Army for the first aid (obidoxime) and medical care (HI-6) was evaluated in male Wistar rats. The potency of oximes to reactivate tabun or soman-inhibited acetylcholinesterase was evaluated by the comparison of the activity of acetylcholinesterase in rat's blood and brain measured 30 minutes following tabun or soman poisoning. The obtained results demonstrate that newly synthesized oximes are more effective than currently used oximes in the reactivation of tabun-inhibited brain acetylcholinesterase but less effective than the oxime HI-6 against soman.
ESTHER : Kassa_2007_Mil.Med.Sci.Lett_76_27
PubMedSearch : Kassa_2007_Mil.Med.Sci.Lett_76_27
PubMedID:

Title : Five oximes (K-27, K-48, obidoxime, HI-6 and trimedoxime) in comparison with pralidoxime: survival in rats exposed to methyl-paraoxon - Petroianu_2007_J.Appl.Toxicol_27_453
Author(s) : Petroianu GA , Nurulain SM , Nagelkerke N , Shafiullah M , Kassa J , Kuca K
Ref : J Appl Toxicol , 27 :453 , 2007
Abstract : There is a clear need for broad-spectrum cholinesterase reactivators (active against a multitude of organophosphorus ester enzyme inhibitors) with a higher efficacy than pralidoxime. The purpose of the study was to quantify in vivo the extent of oxime-conferred protection, using methyl-paraoxon [dimethyl p-nitrophenyl phosphate; (methyl-POX)] as a cholinesterase inhibitor. There were seven groups of six rats in each cycle of the experiment. Group 1 (G1) received 2 micromol methyl-POX ( approximately LD(50)), the other groups (G2-7) received 2 micromol methyl-POX + one of the six reactivators. The animals were monitored for 48 h and the time of mortality was recorded. The procedure was repeated six times. All substances were applied i.p. The experiments were repeated using 3 and 5 micromol methyl-POX. Mortality data were compared and hazards ratios (relative risks) ranked using the Cox proportional hazards model with methyl-POX dose and group (reactivator) as time-independent covariables. The relative risk of death estimated by Cox analysis (95% CI) in oxime-treated animals when compared with untreated animals, adjusted for methyl-POX dose (high/low) was K-27, 0.58 (0.42-0.80); K-48, 0.60 (0.43-0.83); trimedoxime, 0.76 (0.55-1.04); pralidoxime, 0.88 (0.65-1.20); obidoxime, 0.93 (0.68-1.26); HI-6, 0.96 (0.71-1.31). Only K-27 and K-48 provided statistically significant protection in rats exposed to methyl-POX. Despite the lower inhibitory potency (higher IC(50)) of methyl-POX compared with POX (ratio 4:1), the ability of oxime reactivators to protect from methyl-POX induced mortality was reduced compared with protection from POX (ethyl-analog).
ESTHER : Petroianu_2007_J.Appl.Toxicol_27_453
PubMedSearch : Petroianu_2007_J.Appl.Toxicol_27_453
PubMedID: 17304644

Title : Inhibition of blood cholinesterases following intoxication with VX and its derivatives - Bajgar_2007_J.Appl.Toxicol_27_458
Author(s) : Bajgar J , Kuca K , Fusek J , Karasova J , Kassa J , Cabal J , Jun D , Blaha V
Ref : J Appl Toxicol , 27 :458 , 2007
Abstract : Nerve agents can be divided into G-agents (sarin, soman, tabun, cyclosarin etc.) and V-agents. The studies dealing with V-agents (O-alkyl S-2-dialkylaminoethyl methyl phosphonothiolates) are limited to one or two representatives only (VX, Russian VX). Anticholinesterase properties of 11 V-agents were studied in rats in vivo. Following intoxication with these agents in doses of 1 x LD(50) (intramuscular administration), activities of cholinesterases in the blood were continuously monitored and half-lives (t(0.5)) of inhibition were determined. These values varied from 3 min (VX and some other agents) to 10-14 min (derivatives substituted on the phosphorus head by O-ethyl- or O-isopropyl-, and by dimethyl-, diethyl- and dibutyl- on the nitrogen). Acetylcholinesterase activities in selected parts of the brain and diaphragm (30 min after the intoxication) were also detected. A correlation between toxicities and rates of inhibition of the blood enzymes was demonstrated. A similar relationship between acetylcholinesterase inhibition in vitro (from literature data) and half-lives of the blood cholinesterases was also observed. Though the chemical similarity of V compounds is evident, marked differences were observed among different derivatives; however, all agents examined had high inhibition potency corresponding to their toxicities.
ESTHER : Bajgar_2007_J.Appl.Toxicol_27_458
PubMedSearch : Bajgar_2007_J.Appl.Toxicol_27_458
PubMedID: 17299830

Title : Comparison of reactivating and therapeutic efficacy of two salts of the oxime HI-6 against tabun, soman and cyclosarin in rats - Kassa_2007_Basic.Clin.Pharmacol.Toxicol_101_328
Author(s) : Kassa J , Jun D , Kuca K , Bajgar J
Ref : Basic Clin Pharmacol Toxicol , 101 :328 , 2007
Abstract : The reactivating and therapeutic efficacy of two salts of the oxime HI-6 (dichloride and dimethanesulphonate) against chosen nerve agents (tabun, soman and cyclosarin) was compared in rats. The potency of both salts of HI-6 to decrease the acute toxicity of tabun, soman and cyclosarin was similar in nerve agent-poisoned rats. While the potency of HI-6 dichloride and HI-6 dimethanesulphonate to counteract acute toxic effects of tabun is rather low, both salts of HI-6 were able to decrease the acute toxicity of soman two times and acute toxicity of cyclosarin more than three times. The therapeutic efficacy of both salts of the oxime HI-6 corresponds to their reactivating potency. While the reactivating efficacy of HI-6 dichloride as well as HI-6 dimethanesulphonate against tabun was negligible, their potency to reactivate soman-inhibited acetylcholinesterase and cyclosarin-inhibited acetylcholinesterase in peripheral (blood) and central (brain) compartment was relatively high. HI-6 dichloride showed a somewhat higher potency to reactivate tabun-inhibited acetylcholinesterase in brain, and soman-inhibited acetylcholinesterase in blood and brain than HI-6 dimethanesulphonate but the differences were not significant. Thus, the replacement of dichloride anion by dimethanesulphonate anion in the oxime HI-6 does not influence the therapeutic and reactivating efficacy of the oxime HI-6 against nerve agents. In addition, the higher solubility and stability of HI-6 dimethanesulphonate in comparison with HI-6 dichloride makes it possible to increase the dose and thus, the effectiveness of the oxime HI-6 in the antidotal treatment of acute nerve agent poisonings.
ESTHER : Kassa_2007_Basic.Clin.Pharmacol.Toxicol_101_328
PubMedSearch : Kassa_2007_Basic.Clin.Pharmacol.Toxicol_101_328
PubMedID: 17910616

Title : Comparison of effects of different antidotes on tabun-induced cognitive impairment in rats using water maze - Kunesova_2006_Acta.Medica.(Hradec.Kralove)_49_113
Author(s) : Kunesova G , Kassa J
Ref : Acta Medica (Hradec Kralove) , 49 :113 , 2006
Abstract : In the past, scientists focused on the development of antidotes (mainly anticholinergics in combination with reactivators of inhibited acetylcholinesterase-oximes) to increase the number of surviving nerve agent-intoxicated individuals. Recently, they are interested in antidotes able not only to protect nerve agent-poisoned men from lethal toxic effects but also to improve their life quality by improvement of their central cognitive functions. In our study, the water maze was used to measure spatial working learning and memory in the case of tabun-induced cognitive impairment in albino Wistar rats. Antidotal treatment consisted of atropine alone or a combination of atropine with an oxime (obidoxime, trimedoxime or oxime HI-6). Our results suggest that atropine alone is not sufficient as a treatment for saving cognitive functions impaired by tabun. On the other hand, the addition of oxime to atropine contributes to improvement of cognitive performance in tabun-poisoned rats regardless of type of oxime.
ESTHER : Kunesova_2006_Acta.Medica.(Hradec.Kralove)_49_113
PubMedSearch : Kunesova_2006_Acta.Medica.(Hradec.Kralove)_49_113
PubMedID: 16956120

Title : The Reactivating and Therapeutic Efficacy of Oximes to Counteract Russian VX Poisonings - Kassa_2006_Int.J.Toxicol_25_397
Author(s) : Kassa J , Jun D , Kuca K
Ref : Int J Toxicol , 25 :397 , 2006
Abstract : Russian VX (O-isobutyl-S-(2-diethylaminoethyl)methylphosphonothioate) is the structural analogue of VX agent. It differs from VX agent (O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate) by two alkyl groups. The potency of currently available oximes (pralidoxime, obidoxime, HI-6) to reactivate Russian VX-inhibited acetylcholinesterase and to eliminate Russian VX-induced acute toxic effects was evaluated using in vivo methods. In vivo determined percentage of reactivation of Russian VX-inhibited blood and brain acetylcholinesterase in poisoned rats shows that HI-6 seems to be the most efficacious reactivator of Russian VX-inhibited acetylcholinesterase among currently used oximes in the peripheral compartment, whereas no difference between reactivating efficacy of all tested oximes was observed in the central compartment. The oxime HI-6 was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in Russian VX-poisoned mice among all studied oximes. Thus, the oxime HI-6 seems to be the most suitable oxime for the antidotal treatment of acute poisonings with Russian VX as in the case of VX, sarin, cyclosarin, and soman poisonings.
ESTHER : Kassa_2006_Int.J.Toxicol_25_397
PubMedSearch : Kassa_2006_Int.J.Toxicol_25_397
PubMedID: 16940011

Title : Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: in vitro reactivation of red blood cell acetylcholinesterase inhibited by paraoxon - Petroianu_2006_J.Appl.Toxicol_26_64
Author(s) : Petroianu GA , Arafat K , Kuca K , Kassa J
Ref : J Appl Toxicol , 26 :64 , 2006
Abstract : Oximes are cholinesterase reactivators of use in poisoning with organophosphorus compounds. Pralidoxime (PRX) is used clinically as an adjunct to atropine in such exposure. Clinical experience with PRX (and other oximes) is, however, disappointing and routine use has been questioned. In addition it is known that oximes are not equally effective against all existing organophosphorus compounds. There is a clear demand for 'broad spectrum' cholinesterase reactivators with a higher efficacy than PRX. Over the years new reactivators of cholinesterase of potential clinical utility have been developed. Their chemical structures were derived from those of existing esterase reactivators, especially pralidoxime, obidoxime and HI-6. The purpose of the study was to quantify in vitro the extent of oxime (pralidoxime, K-27, K-33, K-48, methoxime and BI-6) conferred protection, using paraoxon as an inhibitor. Paraoxon (POX), the active metabolite of parathion (O,O-diethyl-O-p-nitro-phenyl phosphorothioate) is a non-neuropathic organophosphate. Red blood cell (RBC) acetylcholinesterase (AChE) activities in whole blood were measured photometrically in the presence of different POX concentrations and the IC50 was calculated. Determinations were repeated in the presence of increasing oxime concentrations. The IC50 of POX increases with the oxime concentration in a linear manner. The calculated IC50 values were plotted against the oxime concentrations to obtain an IC50 shift curve. The slope of the shift curve (tg alpha) was used to quantify the magnitude of the protective effect (nm IC50 increase per microm reactivator). Based on our determinations the new K series of reactivators is far superior to pralidoxime, methoxime and BI-6, K-27 being the outstanding compound with a tg alpha value of 3.7 (nm IC50 increase per microm reactivator) which is approximately 13 times the reactivator ability of PRX. In general there is an (expected) inverse relationship between the binding constant K and the slope of the IC50 shift curve (tg alpha) for all oximes examined. K-27 (the most protective substance judging by the tg alpha) has the lowest K value (highest affinity). In vivo testing of the new oximes as an organophosphate protective agent is necessary.
ESTHER : Petroianu_2006_J.Appl.Toxicol_26_64
PubMedSearch : Petroianu_2006_J.Appl.Toxicol_26_64
PubMedID: 16193529

Title : Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: survival in rats exposed to the organophosphate paraoxon - Petroianu_2006_J.Appl.Toxicol_26_262
Author(s) : Petroianu GA , Nurulain SM , Nagelkerke N , Al-Sultan MA , Kuca K , Kassa J
Ref : J Appl Toxicol , 26 :262 , 2006
Abstract : Oximes are cholinesterase reactivators used in organophosphorus poisoning. Clinical experience with pralidoxime (PRX) and other oximes is disappointing and their routine use has been questioned. In addition it is known that not all oximes are equally effective against all existing organophosphorus compounds. There is a demand for broad-spectrum reactivators with a higher efficacy than PRX. Based on our previous in vitro work the protection conferred by the various new oximes against inhibition by paraoxon as quantified by the IC(50) shift (nM increase in the IC(50) of the inhibitor per microM oxime present) is: 0.3 (PRX), 0.4 (methoxime; MMC-4), 1 (K-33), 1.2 (BI-6), 1.5 (K-48) and 3.7 (K-27). The purpose of the study was to quantify in vivo the extent of oxime-conferred protection, using paraoxon (POX) as a cholinesterase inhibitor and to test whether in vitro efficacy translates to protection from mortality. There were seven groups of six rats in each cycle of the experiment. Group 1 (G1) received 1 micromol POX (approximately LD(75)), the other groups (G2-G7) received 1 micromol POX + of one the six reactivators. The animals were monitored for 48 h and the time of mortality was recorded. The procedure was repeated five times (cycles). All substances were applied i.p. The experiments were repeated using 2, 3, 5 and 10 micromol POX. Mortality data were compared and hazards ratios (relative risks) ranked using the Cox proportional hazards model using POX dose and group (reactivator) as time-independent covariables. The relative risk of death estimated by Cox analysis (95% CI) in oxime treated animals when compared with untreated animals, adjusted for POX dose (high/low) was K-27: 0.26 (0.19-0.35); K-48: 0.34 (0.25-0.45); methoxime: 0.38 (0.29-0.50); BI-6: 0.53 (0.41-0.69); PRX: 0.70 (0.54-0.91); K-33: 0.82 (0.63-1.07). It is concluded that K-27 and K-48 are the most promising new oximes. The compounds with the best results in vitro also confer the best protection in vivo. Further testing using methyl- and propyl-organophosphates are needed.
ESTHER : Petroianu_2006_J.Appl.Toxicol_26_262
PubMedSearch : Petroianu_2006_J.Appl.Toxicol_26_262
PubMedID: 16583462

Title : The influence of oxime and anticholinergic drug selection on the potency of antidotal treatment to counteract acute toxic effects of tabun in mice - Kassa_2006_Neurotox.Res_9_59
Author(s) : Kassa J
Ref : Neurotox Res , 9 :59 , 2006
Abstract : The influence of newly developed oximes, K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide] and K048 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) butane dibromide], or currently used oximes (pralidoxime, obidoxime, trimedoxime, HI-6) and anticholinergic drugs (atropine, benactyzine) on the ability of antidotal treatment to eliminate tabun-induced acute toxic effects was studied in mice. The therapeutical efficacy of trimedoxime and both newly developed oximes (K027, K048) is significantly higher than the potency of pralidoxime (regardless of the choice of anticholinergic drug), obidoxime (in the case of its combination with atropine) and the oxime HI-6 (in the case of its combination with benactyzine). All studied oximes with the exception of pralidoxime and the oxime HI-6, when combined with benactyzine, appear to be more efficacious in the elimination of toxic effects of the lethal dose of tabun than their combination with atropine. The findings support the hypothesis that the choice of acetylcholinesterase reactivators as well as the anticholinergic drug selection are important for the effectiveness of an antidotal mixture in the case of antidotal treatment of tabun-induced acute poisonings.
ESTHER : Kassa_2006_Neurotox.Res_9_59
PubMedSearch : Kassa_2006_Neurotox.Res_9_59
PubMedID: 16464753

Title : A comparison of the efficacy of new asymmetric bispyridinium oximes (K027, K048) with currently available oximes against tabun by in vivo methods - Kassa_2006_J.Toxicol.Environ.Health.A_69_1875
Author(s) : Kassa J , Kuca K , Cabal J , Paar M
Ref : J Toxicol Environ Health A , 69 :1875 , 2006
Abstract : The potency of newly developed asymmetric bispyridinium oximes (K027, K048) in reactivating tabun-inhibited acetylcholinesterase (AChE) and in eliminating tabun-induced acute toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determined the percent of reactivation of tabun-inhibited blood and tissue AChE in poisoned rats and showed that the reactivating efficacy of both newly developed oximes is comparable with obidoxime and trimedoxime, the most efficacious known reactivators of tabun-inhibited AChE. These were also found to be sufficiently efficacious in the elimination of acute lethal toxic effects in tabun-poisoned rats. The oxime HI-6, relatively efficacious against soman, did not seem to be an adequately effective oxime in reactivation of tabun-inhibited AChE and in counteracting acute lethal effects of tabun. In addition, our results confirm that the efficacy of oximes in reactivating tabun-inhibited AChE in blood, diaphragm, and brain correlates with the potency of oximes in protecting rats poisoned with supralethal doses of tabun.
ESTHER : Kassa_2006_J.Toxicol.Environ.Health.A_69_1875
PubMedSearch : Kassa_2006_J.Toxicol.Environ.Health.A_69_1875
PubMedID: 16952906

Title : In vitro potency of H oximes (HI-6, HLo-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate nerve agent-inhibited rat brain acetylcholinesterase - Kuca_2006_J.Toxicol.Environ.Health.A_69_1431
Author(s) : Kuca K , Cabal J , Kassa J , Jun D , Hrabinova M
Ref : J Toxicol Environ Health A , 69 :1431 , 2006
Abstract : The efficacy of H oximes (HI-6, HLo-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate acetylcholinesterase inhibited by two nerve agents (tabun, VX agent) was tested in vitro. Both H oximes (HI-6, HLo-7) and the oxime BI-6 were found to be more efficacious reactivators of VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase was low and did not reach the reactivating efficacy of trimedoxime and obidoxime. Thus, none of these compounds can be considered to be a broad-spectrum reactivator of nerve agent-inhibited acetylcholinesterase in spite of high potency to reactivate acetylcholinesterase inhibited by some nerve agents. More than one oxime may be necessary for the antidotal treatment of nerve agent-exposed individuals.
ESTHER : Kuca_2006_J.Toxicol.Environ.Health.A_69_1431
PubMedSearch : Kuca_2006_J.Toxicol.Environ.Health.A_69_1431
PubMedID: 16766478

Title : A comparison of the potency of the oxime HLo-7 and currently used oximes (HI-6, pralidoxime, obidoxime) to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods - Kuca_2005_Acta.Medica.(Hradec.Kralove)_48_81
Author(s) : Kuca K , Cabal J , Kassa J , Jun D , Hrabinova M
Ref : Acta Medica (Hradec Kralove) , 48 :81 , 2005
Abstract : (1) The efficacy of the oxime HLo7 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 (HLo-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 HLo-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.
ESTHER : Kuca_2005_Acta.Medica.(Hradec.Kralove)_48_81
PubMedSearch : Kuca_2005_Acta.Medica.(Hradec.Kralove)_48_81
PubMedID: 16259317

Title : A comparison of the potency of newly developed oximes (K005, K027, K033, K048) and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate sarin-inhibited rat brain acetylcholinesterase by in vitro methods - Kuca_2005_J.Toxicol.Environ.Health.A_68_677
Author(s) : Kuca K , Cabal J , Kassa J
Ref : J Toxicol Environ Health A , 68 :677 , 2005
Abstract : The potency of newly developed and currently used oximes to reactivate sarin-inhibited acetylcholinesterase was evaluated using in vitro methods. A rat brain homogenate was used as a source of acetylcholinesterase. Significant differences in reactivation potency among all tested oximes were observed. Although the ability of newly developed oximes to reactivate sarin-inhibited acetylcholinesterase does not reach the reactivating potency of the oxime HI-6, the oxime K033 seems to be a more efficacious reactivator of sarin-inhibited acetylcholinesterase than other currently available oximes (pralidoxime, obidoxime) at concentrations (10(-5)-10(-4)M) corresponding to recommended doses in vivo. The results of our study also confirm that the reactivation potency of the tested reactivators depends on many factors, such as (1) the number of pyridinium rings, (2) the number of oxime groups and their position, and (3) the length and the shape of the linkage bridge between pyridinium rings.
ESTHER : Kuca_2005_J.Toxicol.Environ.Health.A_68_677
PubMedSearch : Kuca_2005_J.Toxicol.Environ.Health.A_68_677
PubMedID: 15901095

Title : New quaternary pyridine aldoximes as casual antidotes against nerve agents intoxications - Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_75
Author(s) : Kuca K , Bartosova L , Jun D , Patocka J , Cabal J , Kassa J , Kunesova G
Ref : Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub , 149 :75 , 2005
Abstract : In this work, the ability of four newly synthesized oximes--K005 (1,3-bis(2-hydroxyiminomethylpyridinium) propane dibromide), K027 (1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide), K033 (1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide) and K048 (1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide) to reactivate acetylcholinesterase (AChE, EC 3.1.1.7) inhibited by nerve agents is summarized. Reactivation potency of these compounds was tested using standard in vitro reactivation test. Tabun, sarin, cyclosarin and VX agent were used as appropriate testing nerve agents. Rat brain AChE was used as a source of the enzyme. Efficacies of new reactivators to reactivate tabun-, sarin-, cyclosarin- and VX-inhibited AChE were compared with the currently used AChE reactivators (pralidoxime, obidoxime and HI-6). Oxime K048 seems to be promising reactivator of tabun-inhibited AChE. Its reactivation potency is significantly higher than that of HI-6 and pralidoxime and comparable with the potency of obidoxime. The best reactivator of sarin-inhibited AChE seems to be oxime HI-6. None of the new AChE reactivators reached comparable reactivation potency. The same results were obtained for cyclosarin-inhibited AChE. However, oxime K033 is also potent reactivator of AChE inhibited by this nerve agent. In the case of VX inhibition, obidoxime and new oximes K027 and K048 seem to be the best AChE reactivators. None from the currently tested AChE reactivators is able to reactivate AChE inhibited by all nerve agents used and, therefore, the search for new potential broad spectrum AChE reactivators is needed.
ESTHER : Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_75
PubMedSearch : Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_75
PubMedID: 16170392

Title : In vitro reactivation potency of some acetylcholinesterase reactivators against sarin- and cyclosarin-induced inhibitions - Kuca_2005_J.Appl.Toxicol_25_296
Author(s) : Kuca K , Cabal J , Jun D , Kassa J , Bartosova L , Kunesova G
Ref : J Appl Toxicol , 25 :296 , 2005
Abstract : In our study, we have tested six acetylcholinesterase (AChE) reactivators (pralidoxime, obidoxime, HI-6, trimedoxime, BI-6 and Hlo-7) for reactivation of sarin- and cyclosarin-inhibited AChE using an in vitro reactivation test. We have used rat brain homogenate as the suitable source of enzyme. All oximes are able to reactivate sarin-inhibited AChE. On the other hand, only HI-6 is able to reactivate satisfactorily cyclosarin-inhibited AChE.
ESTHER : Kuca_2005_J.Appl.Toxicol_25_296
PubMedSearch : Kuca_2005_J.Appl.Toxicol_25_296
PubMedID: 16025528

Title : A comparison of the potency of trimedoxime and other currently available oximes to reactivate tabun-inhibited acetylcholinesterase and eliminate acute toxic effects of tabun - Kassa_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_419
Author(s) : Kassa J , Kuca K , Cabal J
Ref : Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub , 149 :419 , 2005
Abstract : Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates by its chemical structure and by the fact that tabun-inhibited acetylcholinesterase is extraordinarily difficult to reactivate. The potency of trimedoxime and other commonly used oximes (pralidoxime, obidoxime, the oxime HI-6) to reactivate tabun-inhibited acetylcholinesterase and to eliminate tabun-induced acute effects was evaluated using in vitro and in vivo methods. In vitro calculated kinetic parameters of reactivation of tabun-inhibited acetylcholinesterase from rat brain homogenate and in vivo determined percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats show that trimedoxime seems to be the most efficacious reactivator in the case of tabun poisonings. Trimedoxime was also found to be the most efficacious oxime in the elimination of acute lethal toxic effects in tabun-poisoned rats and mice. The oxime HI-6, so efficacious against soman, does not seem to be sufficiently effective oxime to reactivate tabun-inhibited acetylcholinesterase and to counteract acute lethal effects of tabun.
ESTHER : Kassa_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_419
PubMedSearch : Kassa_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_419
PubMedID: 16601802

Title : Comparison of the potency of newly developed and currently available oximes to reactivate nerve agent-inhibited acetylcholinesterase in vitro and in vivo - Kuca_2005_Chem.Biol.Interact_157-158_367
Author(s) : Kuca K , Bartosova L , Kassa J , Cabal J , Bajgar J , Kunesova G , Jun D
Ref : Chemico-Biological Interactions , 157-158 :367 , 2005
Abstract : Reactivation potency of three newly developed oximes K027, K033 and K048 was tested using standard in vitro and in vivo reactivation tests. K027 and K048 seem to be efficacious reactivators of tabun-inhibited acetylcholinesterase. K033 is sufficient reactivator of cyclosarin-inhibited AChE. However, its potency is poor compared with current "gold standard" oxime HI-6.
ESTHER : Kuca_2005_Chem.Biol.Interact_157-158_367
PubMedSearch : Kuca_2005_Chem.Biol.Interact_157-158_367
PubMedID: 16429489

Title : Strategy for the development of new acetylcholinesterase reactivators - antidotes used for treatment of nerve agent poisonings - Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_429
Author(s) : Kuca K , Cabal J , Jun D , Kassa J , Bartosova L , Kunesova G , Dohnal V
Ref : Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub , 149 :429 , 2005
Abstract : The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the formation of irreversibly inhibited acetylcholinesterase (AChE; EC 3.1.1.7) that could be followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic drug (atropine mostly) to counteract the accumulation of acetylcholine at muscarinic receptors and AChE reactivators (pralidoxime or obidoxime) to reactivate inhibited AChE. At the Department of Toxicology, the strategy of the development of new more potent AChE reactivators consists of several steps: description of the nerve agent intoxication mechanism on the molecular basis (molecular design), prediction of the biological active structure of AChE reactivators (artificial neural networks), their synthesis, in vitro evaluation of their potencies (potentiometric titration and Ellman's method), in vivo studies (therapeutic index, LD(50) of newly synthesized reactivators, reactivation in different tissues, neuroprotective efficacy).
ESTHER : Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_429
PubMedSearch : Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_429
PubMedID: 16601804

Title : Comparison of in vitro potency of oximes (pralidoxime, obidoxime, HI-6) to reactivate sarin-inhibited acetylcholinesterase in various parts of pig brain - Kuca_2005_J.Appl.Toxicol_25_271
Author(s) : Kuca K , Cabal J , Kassa J , Jun D , Hrabinova M
Ref : J Appl Toxicol , 25 :271 , 2005
Abstract : The potency of currently used oximes to reactivate sarin-inhibited acetylcholinesterase (AChE) in various parts of pig brain and whole pig brain was evaluated using in vitro methods. Significant differences in reactivation potency among all tested oximes were observed. At concentrations (10(-4) M) corresponding to recommended doses in vivo, the oxime HI-6 seems to be a more efficacious reactivator of sarin-inhibited AChE in whole pig brain as well as in cerebral hemispheres and cerebellum compared with the other oximes studied. Nevertheless, there are not any differences in the potency of oximes tested to reactivate sarin-inhibited AChE in medulla oblongata. Thus, the oxime HI-6 appears to be the most promising oxime among currently available oximes for the antidotal treatment of acute sarin poisoning, although it is not more efficacious than other currently used oximes in medulla oblongata, whose function is necessary for the vital functions of respiration and circulation.
ESTHER : Kuca_2005_J.Appl.Toxicol_25_271
PubMedSearch : Kuca_2005_J.Appl.Toxicol_25_271
PubMedID: 16021679

Title : Comparison of ability of some oximes to reactivate sarin-inhibited brain acetylcholinesterase from different species - Jun_2005_Chem.Biol.Interact_157-158_385
Author(s) : Jun D , Kuca K , Cabal J , Bartosova L , Kunesova G , Kassa J
Ref : Chemico-Biological Interactions , 157-158 :385 , 2005
Abstract : The aim of this work was the comparison of reactivation potency of four oxime acetylcholinesterase (AChE) reactivators (pralidoxime, HI-6, K027 and K033) on three resources of the enzyme (human, pig and rat brain homogenate) inhibited by nerve agent sarin. The results demonstrate remarkable differences in the reactivation of inhibited brain AChE, depending on the oxime and species
ESTHER : Jun_2005_Chem.Biol.Interact_157-158_385
PubMedSearch : Jun_2005_Chem.Biol.Interact_157-158_385
PubMedID: 16429518

Title : In vitro reactivation of sarin-inhibited brain acetylcholinesterase from different species by various oximes - Kuca_2005_J.Enzyme.Inhib.Med.Chem_20_227
Author(s) : Kuca K , Cabal J , Kassa J
Ref : J Enzyme Inhib Med Chem , 20 :227 , 2005
Abstract : In vitro as well as in vivo evaluation of the reactivating efficacy of various oximes against nerve agent-inhibited acetylcholinesterase has been usually done with the help of animal experiments. Nevertheless, previously published data indicate that the reactivation potency of oximes may be different in human and animal species, which may hamper the extrapolation of animal data to human data. Therefore, to better evaluate the efficacy of various oximes (pralidoxime, obidoxime, HI-6, K033) to reactivate brain acetylcholinesterase inhibited by sarin by in vitro methods, human, rat and pig brain acetylcholinesterase were used to calculate kinetic parameters for the reactivation. Our results show differences among the species, depending on the type of oxime, and indicate that data from animal experiments needs to be carefully evaluated before extrapolation to humans.
ESTHER : Kuca_2005_J.Enzyme.Inhib.Med.Chem_20_227
PubMedSearch : Kuca_2005_J.Enzyme.Inhib.Med.Chem_20_227
PubMedID: 16119192

Title : The influence of the time of antidotal treatment administration on its effectiveness against tabun-induced poisoning in mice - Kassa_2004_Acta.Medica.(Hradec.Kralove)_47_111
Author(s) : Kassa J
Ref : Acta Medica (Hradec Kralove) , 47 :111 , 2004
Abstract : 1. The influence of the time of administration of antidotal treatment consisting of anticholinergic drug (atropine) and oxime (pralidoxime, obidoxime, HI-6 or trimedoxime) on its effectiveness to eliminate tabun-induced lethal effects was studied in mice. 2. The therapeutic efficacy of antidotal treatment of tabun-induced acute poisoning depends on the time of its administration when obidoxime or the oxime HI-6 was used as an acetylcholinesterase reactivator. 3. Pralidoxime is practically ineffective to eliminate acute toxic effects of tabun regardless of the time of its administration. 4. Our results show that trimedoxime seems to be the most effective to eliminate lethal effects of tabun. In addition, its efficacy does not decrease when it is administered 5 min after tabun poisoning. 5. The findings support the hypothesis that trimedoxime appears to be the most suitable oxime to counteract acute toxicity of tabun because of its ability to eliminate lethal effects of tabun when it is injected 5 min after tabun challenge on the contrary to other oximes tested.
ESTHER : Kassa_2004_Acta.Medica.(Hradec.Kralove)_47_111
PubMedSearch : Kassa_2004_Acta.Medica.(Hradec.Kralove)_47_111
PubMedID: 15446360

Title : Assessment of the therapeutic and anticonvulsive efficacy of a drug combination consisting of trihexyphenidyle and HI-6 in soman-poisoned rats - Kassa_2004_Acta.Medica.(Hradec.Kralove)_47_171
Author(s) : Kassa J , Samnaliev I
Ref : Acta Medica (Hradec Kralove) , 47 :171 , 2004
Abstract : 1. The influence of two anticholinergic drugs (atropine, trihexyphenidyle) on the effectiveness of antidotal treatment to eliminate soman-induced lethal effects and convulsions was studied in rats. 2. The oxime HI-6 when combined with centrally acting anticholinergic drug trihexyphenidyle seems to be more efficacious in the elimination of acute toxic effects of soman than its combination with atropine. 3. The findings support the hypothesis that the choice of the anticholinergic drug is important for the effectiveness of antidotal mixture in the case of antidotal treatment of soman-induced acute poisoning.
ESTHER : Kassa_2004_Acta.Medica.(Hradec.Kralove)_47_171
PubMedSearch : Kassa_2004_Acta.Medica.(Hradec.Kralove)_47_171
PubMedID: 15568734

Title : Anticholinergic drugs--functional antidotes for the treatment of tabun intoxication - Krejcova_2004_Acta.Medica.(Hradec.Kralove)_47_13
Author(s) : Krejcova G , Kassa J
Ref : Acta Medica (Hradec Kralove) , 47 :13 , 2004
Abstract : 1. To study the influence of antidotes on tabun-induced neurotoxicity, the rats were injected intramuscularly with organophosphate tabun (LD50). The efficacy of choice antidotal treatment consisting of acetylcholinesterase reactivator obidoxime and one of four anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) was compared. 2. Testing of tabun-induced neurotoxicity progress was carried out using the method Functional observational battery. The experimental animals as well as controls were observed at 24 hours and 7 days following tabun or saline administration. 3. The results were compared to the condition of animals without anticholinergic drug (oxime alone) and control rats that received physiological solution instead of tabun and treatment. Antidotal treatment involving centrally acting anticholinergic drugs (benactyzine, biperiden, scopolamine) showed significantly higher neuroprotective efficacy compared to antidotal treatment containing atropine.
ESTHER : Krejcova_2004_Acta.Medica.(Hradec.Kralove)_47_13
PubMedSearch : Krejcova_2004_Acta.Medica.(Hradec.Kralove)_47_13
PubMedID: 15168875

Title : In vitro reactivation of acetylcholinesterase using the oxime K027 - Kuca_2004_Vet.Hum.Toxicol_46_15
Author(s) : Kuca K , Kassa J
Ref : Vet Hum Toxicol , 46 :15 , 2004
Abstract : The ability of a new bisquaternary oxime, K027 (1-[4-hydroxyiminomethylpyridinium]-3-[carbamoylpyridinium] propane dibromide), to reactivate the enzyme acetylcholinesterase (AChE) inhibited by the nerve agents Tabun, sarin and VX was evaluated. Its reactivation potency was compared to the AChE reactivators pralidoxime (2-PAM), obidoxime and HI-6; K027 seems a good reactivator of organophosphates-inhibited AChE. Its reactivation potency is lower compared to the other oximes for reactivation of sarin-inhibited AChE, but it is sufficient to significantly increase the activity of sarin-inhibited AChE. Its reactivation ability is comparable to obidoxime for reactivation of VX- and tabun-inhibited AChE and is higher than the reactivation potency of HI-6, for tabun-inhibited AChE. HI-6 is currently regarded the most promising reactivator of organophosphates-inhibited AChE.
ESTHER : Kuca_2004_Vet.Hum.Toxicol_46_15
PubMedSearch : Kuca_2004_Vet.Hum.Toxicol_46_15
PubMedID: 14748409

Title : Oximes-induced reactivation of rat brain acetylcholinesterase inhibited by VX agent - Kuca_2004_Hum.Exp.Toxicol_23_167
Author(s) : Kuca K , Kassa J
Ref : Hum Exp Toxicol , 23 :167 , 2004
Abstract : A comparison of one mono- and seven bisquaternary acetylcholinesterase (AChE) reactivators of acetylcholinesterase inhibited by VX agent was performed. As a source of the acetylcholinesterase, a rat brain homogenate was taken. There were significant differences in reactivation potency of all tested oximes. The oxime TO205 seems to be the most efficacious followed by TO046, HI-6, HS-6, K027, obidoxime, MMC and 2-PAM. In addition, the results of this study showed that the reactivation potency of the tested reactivators depends on many factors--such as the number of pyridinium rings, the number of oxime groups and their position, as well as the length and the shape of linkage bridge between two pyridinium rings.
ESTHER : Kuca_2004_Hum.Exp.Toxicol_23_167
PubMedSearch : Kuca_2004_Hum.Exp.Toxicol_23_167
PubMedID: 15171567

Title : [Effect of acetylcholinesterase reactivator dosage on its effectiveness in the treatment of tabun poisoning in mice] - Kassa_2004_Ceska.Slov.Farm_53_31
Author(s) : Kassa J
Ref : Ceska a Slovenska Farmacie , 53 :31 , 2004
Abstract : The therapeutic efficacy of selected reactivators of acetylcholinesterase (obidoxime, oxime HI-6, trimedoxime) against acute tabun poisoning in dependence on their dose was examined in experiments on male mice. A comparison of the values of the medium lethal dose (LD50) of tabun in the intoxication influenced by an antidote therapy consisting of atropin and some of the oximes tested revealed that in all three oximes under study their dose markedly influenced their effect. The highest efficacy was always achieved when oximes were administered in the maximal therapeutic dose (20% of LD50). It follows from the comparison of the efficacy of equieffective doses of the oximes tested that in all doses the acute lethal effects of tabun are most effectively eliminated by trimedoxime, and on the other hand, obidoxime seems to be least effective, though in the smallest dose tested (2% of LD50) the differences between the therapeutic efficacy of the individual oximes are not statistically significant. Oxime HI-6 is significantly more effective than obidoxime (in a dose corresponding to 20% of LD50), but it is less effective than trimedoxime (in a dose corresponding to 5% LD50). The achieved results have shown that oxime HI-6, so effective against soman, another nerve agent, is not the most advantageous reactivator of acetylcholinesterase for the therapy of acute tabun poisonings, though its efficacy is partly eliminated by its possible higher dosing in human medicine due to its lower toxicity for mammals. The most suitable reactivator of acetylcholinesterase for the elimination of acute lethal toxic effects of tabun seems to be trimedoxime. Obidoxime, which is the most widely used reactivator of acetylcholinesterase in the therapy of poisonings by nerve agents at present, is, like in the case of soman poisonings, a relatively least suitable oxime ensuring the survival in lethal tabun poisonings.
ESTHER : Kassa_2004_Ceska.Slov.Farm_53_31
PubMedSearch : Kassa_2004_Ceska.Slov.Farm_53_31
PubMedID: 15065394

Title : Pharmacological Prophylaxis and Antidotal Treatment of Acute Tabun Poisoning - Kassa_2004_Mil.Med.Sci.Lett_73_107
Author(s) : Kassa J , Kunesova G , Vachek J , Kuca K , Cabal J
Ref : Military Medical Science Letters , 73 :107 , 2004
Abstract : Male NMRI mice were used to test the influence of orally administered prophylactic mean PANPAL on acute toxic effects of tabun and to compare its efficacy with the commonly used pyridostigmine by means of protective ratio evaluation. The effect of antidotal treatment of acute tabun poisoning which depends on the choice of anticholinergic drug or the addition of anticonvulsive drug was compared in the same way. Then the reactivating efficacy of selected oximes was tested on Wistar rats using evaluation of the percentage of tabun-inhibited acetylchollinesterase reactivation in blood, the diaphragm and in the brain of poisoned rats 30 minutes after poisoning and antidotal treatment. We also used the rats to test the influence of pharmacological prophylaxis and the choice of a suitable reactivator for tabun-induced neurotoxic symptoms with the help of functional observatory battery.The results confirm that obidoxime seems to be the most suitable acetylcholinesterase reactivator while the oxime HI-6, which is very effective against soman, is practically ineffective against tabun. Trimedoxim also appears to be a prospective acetylcholinesterase reactivator for the antidotal treatment of tabun poisoning. In order to achieve the sufficient effectiveness of antidotal treatment of acute tabun poisonings, the commonly used anticholinergic drug atropine should be replaced by a cholinolytic drug with pronounced central effects (biperiden, benactyzine, scopolamine). If atropine is used for the antidotal treatment of tabun poisoning, the addition of an anticonvulsive drug such as diazepam is suitable. If PANPAL is administered in case of tabun exposure threat, the resistance of the exposed organism as well as the efficacy of postexposure antidotal treatment are significantly increased. Unlike PANPAL, pyridostigmine is not practically effective against acute toxic effects of tabun.
ESTHER : Kassa_2004_Mil.Med.Sci.Lett_73_107
PubMedSearch : Kassa_2004_Mil.Med.Sci.Lett_73_107
PubMedID:

Title : The Effect of Repeated Antidotal Treatment on Tabun-Induced Toxicity in Mice - Kassa_2004_Mil.Med.Sci.Lett_73_142
Author(s) : Kassa J
Ref : Military Medical Science Letters , 73 :142 , 2004
Abstract : Male NMRI mice were used to test the effect of single or repeated antidotal treatment with various oximes (pralidoxime, obidoxime, trimedoxime, the oxime HI-6) in combination with an anticholinergic drug atropine on the acute toxicity of organophosphorus tabun compound with the help of evaluating medial lethal (LD50) dose at a 24-hour survival of tabun-poisoned experimental animals.If some of the tested oximes in combination with atropine were administered repeatedly during acute tabun intoxication, a slight increase in the LD50 value was observed compared to a single administration when pralidoxime or obidoxime was used as an acetylcholinesterase reactivator. This means that the repeated administration of observed antidotal mixtures does not bring a significant improvement in the efficacy of antidotal treatment of acute tabun poisoning. The comparison of the therapeutic effects of tested oximes shows that trimedoxime seems to be the most suitable oxime for decreasing the acute tabun toxicity.The results confirm that no currently used oxime is sufficiently effective for eliminating acute tabun toxicity. Trimedoxime appears to be a prospective acetylcholinesterase reactivator for the antidotal treatment of tabun poisoning. The repeated administration of antidotes during acute tabun poisoning does not show a significant increase in the therapeutical efficacy of antidotal treatment of acute tabun poisoning
ESTHER : Kassa_2004_Mil.Med.Sci.Lett_73_142
PubMedSearch : Kassa_2004_Mil.Med.Sci.Lett_73_142
PubMedID:

Title : A comparison of the efficacy of a bispyridinium oxime--1,4-bis-(2-hydroxyiminomethylpyridinium) butane dibromide and currently used oximes to reactivate sarin, tabun or cyclosarin-inhibited acetylcholinesterase by in vitro methods - Kuca_2004_Pharmazie_59_795
Author(s) : Kuca K , Cabal J , Kassa J
Ref : Pharmazie , 59 :795 , 2004
Abstract : The efficacy of a bispyridinium oxime 1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide, called K033, and of currently used oximes (pralidoxime, obidoxime, oxime HI-6), to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun cyclosarin) was tested by in vitro methods. The new oxime K033 was found to be a more efficacious reactivator of sarin or cyclosarin-inhibited acetylcholinesterase than pralidoxime and obidoxime but it did not reach the efficacy of oxime HI-6 in the case of the inhibition of acetylcholinesterase by sarin or cyclosarin. On the other hand, oxime K033 was more efficacious than oxime HI-6 in reactivating tabun-inhibited acetylcholinesterase. Thus, oxime K033 seems to be a relatively efficacious broad spectrum acetylcholinesterase reactivator and, therefore, could be useful if no information about the type of nerve agent used was available.
ESTHER : Kuca_2004_Pharmazie_59_795
PubMedSearch : Kuca_2004_Pharmazie_59_795
PubMedID: 15544060

Title : Biochemical effects of low level exposure to soman vapour - Bajgar_2004_Cent.Eur.J.Public.Health_12 Suppl_S4
Author(s) : Bajgar J , Sevelova L , Krejcova G , Fusek J , Vachek J , Kassa J , Herink J , De Jong LP , Benschop H
Ref : Central European Journal of Public Health , 12 Suppl :S4 , 2004
Abstract : The aim of this study was to demonstrate changes in acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities, tyrosine aminotransferase activity (TAT) and plasma corticosterone level, neuroexcitability and behavior following 24 hours and 4 weeks of soman sublethal inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the concentration of soman) 24 h and 4 weeks after the exposure. Similar decrease in AChE activity in different brain parts was observed. One of stressogenic parameters (TAT) was changed after 24 h exposure only. 4 weeks after the exposure, these parameters (corticosterone and TAT) were in the range of normal values. Behaviour of experimental animals was changed 24 h after the exposure persisting 4 weeks after the exposure as well as neuroexcitability.
ESTHER : Bajgar_2004_Cent.Eur.J.Public.Health_12 Suppl_S4
PubMedSearch : Bajgar_2004_Cent.Eur.J.Public.Health_12 Suppl_S4
PubMedID: 15141961

Title : Biochemical and behavioral effects of soman vapors in low concentrations - Bajgar_2004_Inhal.Toxicol_16_497
Author(s) : Bajgar J , Sevelova L , Krejcova G , Fusek J , Vachek J , Kassa J , Herink J , De Jong LP , Benschop HP
Ref : Inhal Toxicol , 16 :497 , 2004
Abstract : Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be concluded that exposure to nerve agents leading to acute effects or chronic exposure to nerve agents may lead to delayed and persistent adverse effects. The aim of this study was to demonstrate changes in AChE and butyrylcholinesterase (BuChE) activities, stressogenic markers (i.e., tyrosine aminotransferase [TAT] activity, and plasma corticosterone level), and neuroexcitability and behavior 24 h and 4 wk following a single soman inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the dose of soman) 24 h and 4 wk after the exposure. A similar decrease in AChE activity in different brain parts was observed. One of the stressogenic parameters, TAT, was changed 24 h after exposure only. Behavior of experimental animals was changed 24 h after the exposure, and 4 behavioral parameters persisted 4 wk after the exposure. Neuroexcitability was increased at 24 h after the exposure and had become about normal 4 wk after the exposure. Summarizing, long-term effects (4 wk) were observed after inhalation exposure of guinea pigs to sublethal concentrations of soman.
ESTHER : Bajgar_2004_Inhal.Toxicol_16_497
PubMedSearch : Bajgar_2004_Inhal.Toxicol_16_497
PubMedID: 15204741

Title : Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase - Cabal_2004_Basic.Clin.Pharmacol.Toxicol_95_81
Author(s) : Cabal J , Kuca K , Kassa J
Ref : Basic Clin Pharmacol Toxicol , 95 :81 , 2004
Abstract : The efficacy of various oximes to reactivate acetylcholinesterase phosphorylated by tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) was tested by in vitro and in vivo methods. The oximes commonly used for the treatment of acute poisonings with highly toxic organophosphates appeared to be almost ineffective (HI-6, pralidoxime, methoxime) or just slightly effective (obidoxime) against tabun. On the other hand, trimedoxime seemed to be a significantly more efficacious reactivator than the others in the case of tabun poisonings. In vitro, the concentration of trimedoxime corresponding to 1.0 mmol/l was able to reach 50% reactivation of tabun-inhibited brain acetylcholinesterase. Higher reactivating potency of trimedoxime in comparison with the other commonly used oximes was demonstrated by in vivo method, too. In addition, other structural analogues of trimedoxime were found to be efficacious in counteracting tabun-induced acetylcholinesterase inhibition although not as efficacious as trimedoxime itself. Some effective acetylcholinesterase reactivators were characterised by dissociation constant of enzyme-reactivator complex as well as enzyme-inhibitor-reactivator complex and by rate constant of reactivation.
ESTHER : Cabal_2004_Basic.Clin.Pharmacol.Toxicol_95_81
PubMedSearch : Cabal_2004_Basic.Clin.Pharmacol.Toxicol_95_81
PubMedID: 15379785

Title : Neuroprotective effects of currently used antidotes in tabun-poisoned rats - Kassa_2003_Pharmacol.Toxicol_92_258
Author(s) : Kassa J , Krejeova G
Ref : Pharmacol Toxicol , 92 :258 , 2003
Abstract : The neuroprotective effects of antidotes (atropine, pralidoxime/atropine, obidoxime/atropine and HI-6/atropine mixtures) on rats poisoned with tabun at a lethal dose (220 microg/kg intramuscularly; 100% of LD50 value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 hr and 7 days after tabun challenge. The results indicate that atropine alone is not able to protect the rats from the lethal effects of tabun. Three non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine alone died within 24 hr. On the other hand, atropine combined with all tested oximes allows all tabun-poisoned rats to survive at least 7 days following tabun challenge. Obidoxime combined with atropine seems to be the most effective antidotal treatment for the elimination of tabun-induced neurotoxicity in the case of lethal poisoning among tested antidotal mixtures. The antidotal mixture consisting of atropine and HI-6 is significantly less effective than the combination of atropine with obidoxime in the elimination of tabun-induced neurotoxicity in rats at 24 hr following tabun challenge. Pralidoxime in combination with atropine appears to be practically ineffective to decrease tabun-induced neurotoxicity at 24 hours as well as 7 days following tabun poisoning. Due to its neuroprotective effects, obidoxime seems to be the most effective and most suitable oxime for the antidotal treatment of acute tabun exposure among currently used oximes. Thus, the replacement of obidoxime by a more effective acetylcholinesterase reactivator for soman poisoning, the oxime HI-6, can to a small extent diminish the neuroprotective efficacy of antidotal treatment in the case of acute tabun poisonings.
ESTHER : Kassa_2003_Pharmacol.Toxicol_92_258
PubMedSearch : Kassa_2003_Pharmacol.Toxicol_92_258
PubMedID: 12787257

Title : A comparison of the neuroprotective efficacy of pharmacological pretreatment and antidotal treatment in soman-poisoned rats - Kassa_2003_Acta.Medica.(Hradec.Kralove)_46_101
Author(s) : Kassa J , Krejcova G , Samnaliev I
Ref : Acta Medica (Hradec Kralove) , 46 :101 , 2003
Abstract : 1. To study the influence of pharmacological pretreatment (PANPAL or pyridostigmine combined with biperiden) and antidotal treatment (the oxime HI-6 plus atropine) on soman-induced neurotoxicity, male albino rats were poisoned with a lethal dose of soman (54 (g/kg i.m.; 100% of LD50 value) and observed at 24 hours and 7 days following soman challenge. The neurotoxicity of soman was evaluated using a Functional observational battery and an automatic measurement of motor activity. 2. Pharmacological pretreatment as well as antidotal treatment were able to eliminate some of soman-induced neurotoxic effects observed at 24 hours following soman poisoning. The combination of pharmacological pretreatment (PANPAL or pyridostigmine combined with biperiden) and antidotal treatment was found to be more effective in the elimination of soman-induced neurotoxicity in rats at 24 hours following soman challenge in comparison with the administration of pharmacological pretreatment or antidotal treatment alone. To compare both pharmacological pretreatments, the combination of pyridostigmine with biperiden seems to be more efficacious to eliminate soman-induced signs of neurotoxicity than PANPAL. 3. At 7 days following soman poisoning, the combination of pharmacological pretreatment involving pyridostigmine and biperiden with antidotal treatment was only able to completely eliminate soman-induced neurotoxic signs. 4. Thus, our findings confirm that the combination of pharmacological pretreatment and antidotal treatment is able not only to protect the experimental animals from the lethal effects of soman but also to eliminate most soman-induced signs of neurotoxicity in poisoned rats. The pharmacological pretreatment containing pyridostigmine and biperiden appears to be more efficacious to eliminate soman-induced neurotoxic sings than PANPAL.
ESTHER : Kassa_2003_Acta.Medica.(Hradec.Kralove)_46_101
PubMedSearch : Kassa_2003_Acta.Medica.(Hradec.Kralove)_46_101
PubMedID: 14677718

Title : A comparison of the ability of a new bispyridinium oxime--1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods - Kuca_2003_J.Enzyme.Inhib.Med.Chem_18_529
Author(s) : Kuca K , Kassa J
Ref : J Enzyme Inhib Med Chem , 18 :529 , 2003
Abstract : 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.
ESTHER : Kuca_2003_J.Enzyme.Inhib.Med.Chem_18_529
PubMedSearch : Kuca_2003_J.Enzyme.Inhib.Med.Chem_18_529
PubMedID: 15008517

Title : Synthesis of a new reactivator of tabun-inhibited acetylcholinesterase - Kuca_2003_Bioorg.Med.Chem.Lett_13_3545
Author(s) : Kuca K , Bielavsky J , Cabal J , Kassa J
Ref : Bioorganic & Medicinal Chemistry Lett , 13 :3545 , 2003
Abstract : Synthesis of a new asymmetric bisquaternary reactivator of tabun-inhibited acetylcholinesterase-1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide is described. Reactivation potency of this oxime is compared to the currently used reactivators-pralidoxime, obidoxime and H-oxime HI-6.
ESTHER : Kuca_2003_Bioorg.Med.Chem.Lett_13_3545
PubMedSearch : Kuca_2003_Bioorg.Med.Chem.Lett_13_3545
PubMedID: 14505667

Title : The influence of oxime selection on the efficacy of antidotal treatment of soman-poisoned rats - Kassa_2002_Acta.Medica.(Hradec.Kralove)_45_19
Author(s) : Kassa J , Fusek J
Ref : Acta Medica (Hradec Kralove) , 45 :19 , 2002
Abstract : 1. The influence of some acetylcholinesterase reactivators (HI-6, obidoxime, pralidoxime) on the efficacy of antidotal treatment to eliminate soman-induced disturbance of respiration and circulation and to protect experimental animals poisoned with supralethal dose of soman (1.5 x LD50) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2. Obidoxime or pralidoxime in combination with atropine were insufficient to enable soman-poisoned rats to survive for 2 hours when given 1 minute after the administration of soman. 3. On the other hand, the ability of the oxime HI-6 in combination with atropine to prevent soman-induced alteration of respiration and circulation was significantly higher. Some rats treated with HI-6 in combination with atropine were fully protected against the lethal toxic effects of soman within 2 hours following soman administration. 4. Our findings confirm that the oxime HI-6 seems to be a much more suitable and efficacious acetylcholinesterase reactivator for the antidotal treatment of severe acute soman-induced poisoning than currently used obidoxime or pralidoxime.
ESTHER : Kassa_2002_Acta.Medica.(Hradec.Kralove)_45_19
PubMedSearch : Kassa_2002_Acta.Medica.(Hradec.Kralove)_45_19
PubMedID: 12143107

Title : The influence of anticholinergic drug and oxime selection on the effectiveness of antidotal treatment against tabun-induced poisoning in mice - Kassa_2002_Acta.Medica.(Hradec.Kralove)_45_75
Author(s) : Kassa J
Ref : Acta Medica (Hradec Kralove) , 45 :75 , 2002
Abstract : 1. The influence of oximes (pralidoxime, obidoxime, HI-6) and anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) on the effectiveness of antidotal treatment to eliminate tabun-induced lethal effects was studied in mice. 2. Obidoxime seems to be the most efficacious oxime for the elimination of tabun-induced lethal effects in mice, although the difference in the efficacy of obidoxime and HI-6 is not significant when they are combined with atropine. 3. Obidoxime and HI-6 when combined with centrally acting anticholinergic drugs (benactyzine, biperiden and scopolamine) seem to be more efficacious in the elimination of toxic effects of the lethal dose of tabun than their combination with atropine. 4. The findings support the hypothesis that the choice of acetylcholinesterase reactivators as well as the anticholinergic drug selection are important for the effectiveness of antidotal mixture in the case of antidotal treatment of tabun-induced acute poisoning.
ESTHER : Kassa_2002_Acta.Medica.(Hradec.Kralove)_45_75
PubMedSearch : Kassa_2002_Acta.Medica.(Hradec.Kralove)_45_75
PubMedID: 12325456

Title : Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents - Kassa_2002_J.Toxicol.Clin.Toxicol_40_803
Author(s) : Kassa J
Ref : J Toxicol Clinical Toxicology , 40 :803 , 2002
Abstract : The cholinesterase-inhibiting organophosphorus compounds referred to as nerve agents (soman, sarin, tabun, GF agent, and VX) are particularly toxic and are considered to be among the most dangerous chemical warfare agents. Included in antidotal medical countermeasures are oximes to reactivate the inhibited cholinesterase. Much experimental work has been done to better understand the properties of the oxime antidotal candidates including the currently available pralidoxime and obidoxime, the H oximes HI-6 and Hlo-7, and methoxime. There is no single, broad-spectrum oxime suitablefor the antidotal treatment of poisoning with all organophosphorus agents. If more than one oxime is available, the choice depends primarily on the identity of the responsible organophosphorus compound. The H oximes appear to be very promising antidotes against nerve agents because they are able to protect experimental animals from toxic effects and improve survival of animals poisoned with supralethal doses. They appear more effective against nerve agent poisoning than the currently used oximes pralidoxime and obidoxime, especially in the case of soman poisoning. On the other hand, pralidoxime and especially obidoxime seem sufficiently effective to treat poisonings with organophosphorus insecticides that have relatively less toxicity than nerve agents.
ESTHER : Kassa_2002_J.Toxicol.Clin.Toxicol_40_803
PubMedSearch : Kassa_2002_J.Toxicol.Clin.Toxicol_40_803
PubMedID: 12475193

Title : The influence of anticholinergic drug selection on the effectiveness of oximes against soman-induced supralethal poisoning in mice - Kassa_2001_Acta.Medica_44_77
Author(s) : Kassa J
Ref : Acta Medica , 44 :77 , 2001
Abstract : 1. The influence of anticholinergic drugs (atropine, benactyzine, biperiden) on the efficacy of monopyridinium and bispyridinium oximes (HI-6, BI-6, obidoxime, pralidoxime, methoxime) on soman-induced supralethal poisoning was studied in mice. 2. While methoxime combined with benactyzine or biperiden seems to be more efficacious in the elimination of toxic effects of supralethal dose of soman than its combination with atropine, the efficacy of the other oximes studied against soman-induced toxic effects is not significantly influenced by the anticholinergic drug selection. 3. On the other hand, there are big differences in the effectiveness of oximes tested as to their ability to eliminate toxic effects of soman at supralethal doses. 4. The findings support the fact that the choice of acetylcholinesterase reactivator is more important than the anticholinergic drug selection for the effectiveness of antidotal mixture in the case of prophylactic administration of antidotes.
ESTHER : Kassa_2001_Acta.Medica_44_77
PubMedSearch : Kassa_2001_Acta.Medica_44_77
PubMedID: 11488139

Title : Vliv diazepamu na schopnost antidotni terapie eliminovat akutni letalni ucinek somanu u mysi - Kassa_2001_Cas.Lek.Cesk_140_497
Author(s) : Kassa J
Ref : Casopis Lekaru Ceskych , 140 :497 , 2001
Abstract : BACKGROUND The currently used antidotal treatment of intoxication with nerve agents, consisting of an anticholinergic drug and an acetylcholinesterase reactivator, is often completed with the anticonvulsive drug diazepam to prevent poisoned organisms from centrally mediated seizures and subsequent tonic-clonic convulsions. The aim of this study was to find out whether the complementation of the antidotal treatment with diazepam can influence antidotal treatment-induced elimination of acute lethal effects of the chosen nerve agent--soman. METHODS AND RESULTS: In experiments on mice, the values of medium lethal dose of soman in the case of 24 h surviving of soman-exposed mice, treated with the basic antidotes involving various types of anticholinergic drugs and acetylcholinesterase reactivators, were evaluated and compared to the values of medium lethal dose of soman in mice treated with antidotes completed with diazepam. Our findings confirm that diazepam is able to enhance the efficacy of basic antidotal treatment to eliminate acute lethal effects of soman if atropin is used as anticholinergic drug. On the other hand, no ability of diazepam to enhance soman-induced lethal effects was demonstrated if an anticholinergic drug with central effects such as benactyzine, biperiden or scopolamin was used. The ability of diazepam to influence the efficacy of antidotes to eliminate soman-induced acute lethal effects was only observed in the case of using the oxime HI-6 as acetycholinesterase reactivator.
CONCLUSIONS: The most perspective antidotal mixture against soman, consisting of the oxime HI-6 and atropine, should be complemented by diazepam no only because of the prevention of poisoned organisms from centrally mediated seizures and subsequent tonic-clonic convulsions but also because of the increase in the ability of antidotal treatment to eliminate soman-induced acute lethal effects.
ESTHER : Kassa_2001_Cas.Lek.Cesk_140_497
PubMedSearch : Kassa_2001_Cas.Lek.Cesk_140_497
PubMedID: 11678028

Title : [Effect of diazepam on antidote therapy of lethal toxic effects of soman in rats] - Kassa_2001_Ceska.Slov.Farm_50_254
Author(s) : Kassa J
Ref : Ceska a Slovenska Farmacie , 50 :254 , 2001
Abstract : Experiments on male rats examined the effect of a basic antidotal therapy consisting of various types of anticholinergic substances and reactivators of acetylcholinesterase on the lethal effects of the highly toxic organophosphorous compound soman by means of determination of the medium lethal dose of soman in 24-hour survival of experimental animals. The efficacy of the basic antidotal therapy of acute intoxications by soman evaluated in this way was compared with the effect of an antidotal therapy enriched with diazepam, a drug with anticonvulsive action. The obtained results show that addition of diazepam to the basic antidotal therapy increases the ability of the antidotal therapy to eliminate acute lethal effects of soman if it includes atropine as an anticholinergic agent regardless of the employed type of acetylcholinesterase reactivator. In the case of employment of anticholinergic agents with prevailing central effects, such as benactyzine, biperiden, or scopolamine, the addition of diazepam will not significantly influence the therapeutic efficacy of the antidotal therapy regardless of the selected aetylcholinesterase reactivator. At the same time, the addition of diazepam to the antidotal therapy does not change the difference in the efficacy of the antidotal therapy in dependence on the selected anticholinergic agent or acetylcholinesterase reactivator. At present the most common combination of antidotes against soman, consisting of obidoxime and atropine, as well as a prospective combination containing oxime HI-6 and atropine should be supplemented with diazepam not only to prevent centrally induced seizures and tonic-clonic convulsions but also to increase the ability of such antidotal therapy to eliminate acute lethal toxicity of soman.
ESTHER : Kassa_2001_Ceska.Slov.Farm_50_254
PubMedSearch : Kassa_2001_Ceska.Slov.Farm_50_254
PubMedID: 11579693

Title : The long-term influence of low-level sarin exposure on behavioral and neurophysiological functions in rats - Kassa_2001_Acta.Medica_44_21
Author(s) : Kassa J , Koupilova M , Herink J , Vachek J
Ref : Acta Medica , 44 :21 , 2001
Abstract : 1. Long term effects of low doses of highly toxic organophosphorus agent sarin on behavioral and neurophysiological functions were studied in rats exposed to sarin by inhalation. The toxic effects of sarin were monitored using a functional observational battery (FOB), an automatic measurement of motor activity and a test of excitability of central nervous system at 3, 6 and 12 months following sarin exposure. 2. The results indicate that sarin at symptomatic as well as asymptomatic doses (level 2 and 3) is able to induce some neurotoxic effects (a decrease in activity and mobility, an alteration of gait, an increase in stereotyped behavior) including an increase in the excitability of central nervous system (an increase in convulsive activity following the administration of pentamethylenetetrazole) in rats at 3 months following inhalation exposure. Some sings of increased excitability were also observed in sarin-exposed rats following 6 or 12 months (an increase in exploratory activity, body temperature and a hindlimb grip strength at 6 months following exposure to sarin at asymptomatic doses, an increase in tail-pinch response at 12 months following exposure to sarin at symptomatic doses). 3. Therefore, nerve agents such as sarin seem to be harmful not only at high, clinically symptomatic doses but also at low, clinically asymptomatic doses because of long term manifestation of alteration of neurophysiological functions in sarin-exposed rats without disruption of cholinergic nervous system.
ESTHER : Kassa_2001_Acta.Medica_44_21
PubMedSearch : Kassa_2001_Acta.Medica_44_21
PubMedID: 11367887

Title : Neuroprotective effects of currently used antidotes in soman-poisoned rats - Kassa_2000_Pharmacol.Biochem.Behav_67_663
Author(s) : Kassa J , Koupilova M
Ref : Pharmacol Biochem Behav , 67 :663 , 2000
Abstract : The neuroprotective effects of antidotes (atropine, obidoxime, obidoxime/atropine mixture) on rats poisoned with soman at a sublethal dose (54 microg/kg, im, 80% of LD(50) value) were studied. The soman-induced neurotoxicity was monitored using a functional observational battery (FOB) and an automatic measurement of motor activity. The neurotoxicity of soman was monitored at 24 h and 7 days following soman challenge. The results indicate that obidoxime alone is not able to protect the rats from the lethal effects of soman. Three soman-poisoned rats treated with obidoxime alone died within 24 h. On the other hand, atropine alone or combined with obidoxime allows all soman-poisoned rats to survive within 7 days following soman challenge. Atropine alone and combined with obidoxime seems to be relatively effective antidotal treatment for the elimination of soman-induced neurotoxicity in the case of sublethal poisonings, although the antidotal mixture is significantly less effective than atropine alone because obidoxime can counteract the beneficial effects of atropine. Obidoxime appears to be practically ineffective to diminish soman-induced neurotoxicity. The neuroprotective effects of antidotal mixture consisting of atropine and obidoxime depend on the antimuscarinic effects of atropine only. Thus, the replacement of obidoxime by more effective acetylcholinesterase (AChE) reactivators is necessary to increase the neuroprotective efficacy of antidotal treatment in the case of soman poisonings.
ESTHER : Kassa_2000_Pharmacol.Biochem.Behav_67_663
PubMedSearch : Kassa_2000_Pharmacol.Biochem.Behav_67_663
PubMedID: 11164099

Title : [Importance of reactivation of fosdrin-inhibited acetylcholinesterase in the brain and diaphragm for the in vivo therapeutic effect of oximes in rats poisoned with fosdrin] - Kassa_2000_Cas.Lek.Cesk_139_237
Author(s) : Kassa J
Ref : Casopis Lekaru Ceskych , 139 :237 , 2000
Abstract : BACKGROUND: The composition of the causal antidotal therapy of subjects, poisoned with organophosphorus insecticides, has not been satisfactorily solved till now in spite of the knowledge of the basic mechanism of action of these toxic substances. The purpose of this study is to evaluate which of currently used or perspective acetylcholinesterase reactivators seems to be the most efficacious to protect poisoned subjects. METHODS AND RESULTS: In experiments on white laboratory rats, the reactivating efficacy of selected acetylcholinesterase reactivators (oximes), administered at equimolar doses, was evaluated in target tissue of toxic effects of organophosphorus insecticides (diaphragm, brain) and compared with their therapeutic efficacy in the case of prophylactic administration with the help of the evaluation of mean efficacy dose of oximes, possible to protect rats exposed to supralethal dose of organophosphorus insecticide fosdrin for 24 hours. Our findings confirm that there are not statistically significant differences in reactivating and therapeutic efficacy of oximes tested against fosdrin in rats.
CONCLUSIONS: The perspective acetylcholinesterase reactivators (H oximes) seem to be as suitable as currently used oximes for the therapy of acute poisonings with organophosphorus insecticides although they are not significantly more efficacious than currently used oximes as in the case of the treatment of poisoning with highly toxic organophosphorus compounds.
ESTHER : Kassa_2000_Cas.Lek.Cesk_139_237
PubMedSearch : Kassa_2000_Cas.Lek.Cesk_139_237
PubMedID: 10916212

Title : A comparison of the efficacy of acetylcholinesterase reactivators against cyclohexyl methylphosphonofluoridate (GF agent) by in vitro and in vivo methods - Kassa_1999_Pharmacol.Toxicol_84_41
Author(s) : Kassa J , Cabal J
Ref : Pharmacol Toxicol , 84 :41 , 1999
Abstract : The purpose of this study was to compare the therapeutic efficacy of a new acetylcholinesterase reactivator, designated BI-6 (1-(2-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium )-2-butene dibromide), with presently used oximes (pralidoxime, obidoxime, methoxime) and H-oximes (HI-6, HLo-7) by in vitro and in vivo methods. In vitro, methoxime seems to be the most efficacious reactivator of GF agent-inhibited acetylcholinesterase because the phosphorylation of acetylcholinesterase by GF agent markedly increases its affinity for the enzyme. The oxime BI-6 is more efficacious than other presently used oximes (pralidoxime, obidoxime) but its reactivating efficacy does not reach the efficacy of H-oximes tested. On the other hand, obidoxime and pralidoxime appear to be very poor reactivators of GF agent-inhibited acetylcholinesterase because the phosphonylation of acetylcholinesterase by GF agent markedly decreases their affinity to the enzyme. In vivo, H oximes (HI-6, HLo-7) are the most efficacious antidotes for the treatment of acute poisoning with GF agent in rats while the presently used oximes such as pralidoxime and obidoxime are practically ineffective. BI-6 and methoxime are more efficacious than pralidoxime and obidoxime, nevertheless their therapeutic efficacy does not reach the efficacy of H oximes. Our results show that the ability of oximes to reactivate GF agent-inhibited acetylcholinesterase in vitro usually corresponds to their therapeutic effects against GF agent in vivo.
ESTHER : Kassa_1999_Pharmacol.Toxicol_84_41
PubMedSearch : Kassa_1999_Pharmacol.Toxicol_84_41
PubMedID: 9974189

Title : A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with currently available oximes and H oximes against soman by in vitro and in vivo methods - Kassa_1999_Toxicology_132_111
Author(s) : Kassa J , Cabal J
Ref : Toxicology , 132 :111 , 1999
Abstract : The reactivating and therapeutic efficacy of a new acetylcholinesterase reactivator, designated BI-6(1-/2-hydroxyiminomethylpyridinium/-4-/carbamoylpyridinium+ ++/-2-butene dibromide), against the organophosphate soman was compared with oximes at present used (pralidoxime, obidoxime, methoxime) and H oximes (HI-6, HL-7) using in vitro and in vivo methods. H oximes HI-6 and HL-7 seem to be the most efficacious acetylcholinesterase reactivators against soman according to the evaluation of their reactivating and therapeutic efficacy in vitro as well as in vivo. The new oxime BI-6 is not as effective as the H oximes against soman, nevertheless it is significantly more effective against soman than the currently available oximes, pralidoxime, obidoxime and methoxime, which failed to protect rats poisoned with supralethal doses of soman. Our results confirm that the reactivating efficacy of oximes evaluated by the methods in vitro closely correlates not only with the potency of oximes in vivo in reactivating soman-inhibited acetylcholinesterase but also with the ability to protect rats poisoned with supralethal doses of soman.
ESTHER : Kassa_1999_Toxicology_132_111
PubMedSearch : Kassa_1999_Toxicology_132_111
PubMedID: 10433374

Title : Neuroprotective effects of antidotes in soman-poisoned rats - Kassa_1999_Acta.Medica.(Hradec.Kralove)_42_127
Author(s) : Kassa J , Koupilova M
Ref : Acta Medica (Hradec Kralove) , 42 :127 , 1999
Abstract : 1. The neuroprotective effects of antidotes (atropine, obidoxime/atropine mixture, HI-6/atropine mixture) on rats poisoned with soman at a sublethal dose (48 micrograms/kg i.m.; 60% of LD50 value) were studied. The neurotoxicity was monitored using a functional observational battery (FOB) and an automatic measurement of motor activity. The neurotoxicity of soman was monitored at 24 h and 7 d following soman poisoning. 2. The results indicate that atropine alone and the oxime HI-6 in combination with atropine seem to be effective antidotal treatment for the elimination of soman-induced neurotoxicity in the case of sublethal poisonings. 3. On the other hand, the combination of obidoxime with atropine appears to be practically ineffective in diminishing neurotoxic soman-induced symptoms. 4. Dealing with neuroprotective effects of antidotes, the oxime HI-6 in combination with atropine seems to be more suitable antidotal mixture than obidoxime in combination with atropine even in the case of sublethal poisoning with nerve agents.
ESTHER : Kassa_1999_Acta.Medica.(Hradec.Kralove)_42_127
PubMedSearch : Kassa_1999_Acta.Medica.(Hradec.Kralove)_42_127
PubMedID: 10812679

Title : A comparison of the efficacy of new monopyridinium oximes with the oxime HI-6 against mevinphos in mice - Kassa_1999_Acta.Medica_42_9
Author(s) : Kassa J , Bielavsky J
Ref : Acta Medica , 42 :9 , 1999
Abstract : 1. The therapeutic efficacy of three new monopyridinium oximes (2,4-PAEtM, 2,5-PAEtM, 2,5-PAAM) and the bispyridinium oxime HI-6 was evaluated in combination with benactyzine against acute poisoning with the organophosphorus insecticide mevinphos in mice. 2. When mice were treated two min after mevinphos poisoning, no significant differences in the therapeutic effectiveness of tested oximes were observed. They increased the 24h LD50 values of mevinphos about three times in comparison with non-treated intoxicated animals. 3. On the other hand, there were significant differences in their therapeutic efficacy when they were administered 30 sec following mevinphos challenge. The monopyridinium oxime 2,5-PAEtM seems to be the most efficacious against mevinphos toxicity. 4. Use of new monopyridinium oxime 2,5-PAEtM appears to be the improvement in the antidotal treatment of poisoning with organophosphorus insecticide mevinphos in comparison with HI-6.
ESTHER : Kassa_1999_Acta.Medica_42_9
PubMedSearch : Kassa_1999_Acta.Medica_42_9
PubMedID: 10566173

Title : [Comparison of the reactivating effect of BI-6, a new asymmetrical bispyridinium oxime, with oxime HI-6 and obidoxime on soman-inhibited acetylcholinesterase in the diaphragm and various parts of the brain in rats] - Kassa_1999_Cas.Lek.Cesk_138_532
Author(s) : Kassa J , Bajgar J
Ref : Casopis Lekaru Ceskych , 138 :532 , 1999
Abstract : BACKGROUND Acute poisoning with the highly toxic organophosphorus agent, soman, is not treated satisfactorily even by the most modern antidotes. METHODS AND RESULTS: In experiments on rats, the reactivating effect of a new asymmetric bispyridinium oxime BI-6 was compared with widely used oximes HI-6 and obidoxime by investigating the changes of soman-inhibited acetylcholinesterase activity in the diaphragm and various parts of the brain in rats up to three hours following soman challenge. Our findings confirm that the new oxime BI-6 is a more effective reactivator of soman-inhibited acetylcholinesterase than obidoxime but not as effective as the oxime HI-6 especially in the peripheral compartment.
CONCLUSIONS: The new oxime BI-6 is not as effective as HI-6 which seems to have definite advantages over other oximes in the treatment of soman poisoning.
ESTHER : Kassa_1999_Cas.Lek.Cesk_138_532
PubMedSearch : Kassa_1999_Cas.Lek.Cesk_138_532
PubMedID: 10566233

Title : [Comparison of the effects of BI-6, a new asymmetric bipyridine oxime, with HI-6 oxime and obidoxime in combination with atropine on soman and fosdrine toxicity in mice] - Kassa_1999_Ceska.Slov.Farm_48_44
Author(s) : Kassa J
Ref : Ceska a Slovenska Farmacie , 48 :44 , 1999
Abstract : The therapeutic efficacy of the new asymmetric bispyridinium oxime BI-6 against acute toxicity of the highly toxic organophosphate soman and the organophosphorus insecticide fosdrin by means of affecting the LD50 values of these noxiores substances was compared with the effect of the hitherto most perspective oxime HI-6 and the classic obidoxime always in combination with the identical dose of atropine. At the equimolar level the effect of oxime BI-6 against fosdrin completely equals the effects of both oximes HI-6 and obidoxime. The effect of oxime BI-6 against soman is even more marked than the effect of HI-6 but this difference is not statistically significant. On the other hand, at the equi-effective level, the effect of oxime BI-6 against soman is statistically significantly lower than the effect of HI-6, and against fosdrin it is even lower than the effect of both remaining oximes. The effects of the new oxime BI-6 equal, or slightly exceed the therapeutic effect of HI-6 but at the equimolar level only. At the equi-effective level which respects the toxicity of the oxime and is therefore more important for practical use, it is a therapeutically weaker reactivator of acetylcholinesterase than HI-6.
ESTHER : Kassa_1999_Ceska.Slov.Farm_48_44
PubMedSearch : Kassa_1999_Ceska.Slov.Farm_48_44
PubMedID: 10376416

Title : A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with presently used oximes and H oximes against sarin by in vitro and in vivo methods - Kassa_1999_Hum.Toxicol_18_560
Author(s) : Kassa J , Cabal J
Ref : Hum Toxicol , 18 :560 , 1999
Abstract : 1. The reactivating and therapeutic efficacy of a new acetylcholinesterase reactivator, designated BI-6 (1-/2-hydroxyiminomethylpyridinium/-4-/carbamoylpyridinium/- 2-butene dibromide), against organophosphate sarin was compared with presently used oximes (pralidoxime, obidoxime, methoxime) and H oximes (HI-6, HL-7) by in vitro and in vivo methods. 2. Our results confirm that the new oxime BI-6 is a significantly more efficacious acetylcholinesterase reactivator than currently available pralidoxime and obidoxime but not as effective as H oximes (HI-6, HL-7) in vitro as well as in vivo. In addition, the oxime BI-6 is able to protect supralethal sarin poisoned rats at human-relevant doses. 3. Our data also suggest that the potency of oximes tested to reactivate sarin-inhibited acetylcholinesterase in vitro closely corresponds to their reactivating efficacy in vivo and their ability to protect rats poisoned with supralethal doses of sarin.
ESTHER : Kassa_1999_Hum.Toxicol_18_560
PubMedSearch : Kassa_1999_Hum.Toxicol_18_560
PubMedID: 10523870

Title : A comparison of the efficacy of new asymmetric bispyridinium oxime BI-6 with other oximes (obidoxime, HI-6) against soman in rats - Kassa_1998_Hum.Exp.Toxicol_17_331
Author(s) : Kassa J
Ref : Hum Exp Toxicol , 17 :331 , 1998
Abstract : 1. The influence of three oximes (obidoxime, HI-6 and the new asymmetric bispyridinium oxime BI-6) in combination with atropine on soman-induced cholinergic and stressogenic effects in rats was studied. 2. The oxime BI-6 produced significantly higher reactivation of soman-inhibited blood and diaphragm cholinesterases than obidoxime. On the other hand, its reactivating effect was not so high as the effect of the oxime HI-6. 3. There were not significant differences in the reactivation of soman-inhibited brain acetylcholinesterase among all three oximes tested. 4. The influence of the oxime BI-6 on soman-induced stressogenic effects was greater than the antistressogenic effects of HI-6 or obidoxime at 1 h or 3 h following soman poisoning. 5 These findings confirm that the oxime BI-6 has no definite advantages over HI-6 in the antidotal treatment of soman poisoning but BI-6 is significantly more effective in rats than obidoxime, one of the oximes presently in use.
ESTHER : Kassa_1998_Hum.Exp.Toxicol_17_331
PubMedSearch : Kassa_1998_Hum.Exp.Toxicol_17_331
PubMedID: 9688357

Title : The positive influence of a cholinergic-anticholinergic pretreatment and antidotal treatment on rats poisoned with supralethal doses of soman - Kassa_1998_Toxicology_128_1
Author(s) : Kassa J , Fusek J
Ref : Toxicology , 128 :1 , 1998
Abstract : The influence of pretreatment with the drug mixture (pyridostigmine, benactyzine and trihexyphenidyle), and antidotal treatment (the oxime HI-6 in combination with benactyzine) on respiration, circulation and survival of experimental animals poisoned with supralethal doses of soman (2 x LD50) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. Untreated soman poisoning caused rapid respiratory depression, progressive bradycardia and a short-term increase in the mean arterial pressure, followed immediately by hypotension. The poisoned rats died on average within 10 min from respiratory and circulatory insufficiency. A cholinergic-anticholinergic pretreatment alone partially prevented changes in monitored physiological variables, caused by soman, but only for a few minutes; post-poisoning treatment with antidotes, also alone, had similar effects. The rats died on average within 30 min from respiratory and circulatory failure. When rats were pretreated by the drug mixture and treated by antidotes, respiration as well as circulation were completely restored and the rats survived at least 120 min following soman challenge. The results of the investigation suggest that cholinergic-anticholinergic pretreatment seems able to enhance the efficacy of antidotal treatment in restoring respiratory and circulatory changes induced by soman.
ESTHER : Kassa_1998_Toxicology_128_1
PubMedSearch : Kassa_1998_Toxicology_128_1
PubMedID: 9704900

Title : Changes of acetylcholinesterase activity in various parts of brain following nontreated and treated soman poisoning in rats - Kassa_1998_Mol.Chem.Neuropathol_33_175
Author(s) : Kassa J , Bajgar J
Ref : Molecular & Chemical Neuropathology , 33 :175 , 1998
Abstract : Changes of acetylcholinesterase (AChE) activity in various parts of the brain (frontal cortex, medulla oblongata, pons Varoli, cerebellum, hypothalamus, and hippocampus), following im sublethal non-treated and treated soman poisoning were studied. As a treatment, two antidotal mixtures containing atropine and either obidoxime or oxime HI-6 were used. This antidotal treatment was administered im for 30 s following soman intoxication. The AChE activities in the various brain tissues were evaluated at 1 and 3 h following soman administration. As expected, the highly toxic organophosphorus compound, soman, markedly inhibited AChE activity in all the brain sections at both time intervals. Both oximes had little influence on soman-induced AChE inhibition, but only the HI-6 mixture was able to reactivate soman-inhibited AChE significantly in some of the brain parts (frontal cortex, pons Varoli, hypothalamus). In the brain, the effect of HI-6 against soman-induced AChE inhibition is higher in comparison with obidoxime, but not quite satisfactory. Despite its limited effectiveness in the brain, HI-6 seems to be the most effective oxime yet found against soman poisoning because of its high reactivating effect in the peripheral compartment and other beneficial effects.
ESTHER : Kassa_1998_Mol.Chem.Neuropathol_33_175
PubMedSearch : Kassa_1998_Mol.Chem.Neuropathol_33_175
PubMedID: 9642671

Title : [The effect of pharmacologic prophylaxis with Panpal on acetylcholinesterase activity in the diaphragm and various parts of the brain in rats during treated and untreated Soman poisoning] - Kassa_1998_Cas.Lek.Cesk_137_299
Author(s) : Kassa J
Ref : Casopis Lekaru Ceskych , 137 :299 , 1998
Abstract : The pharmacological prophylaxis protecting the organism against organophosphorus compounds could increase the effect of antidotal treatment of poisoning with organophosphates. METHODS AND RESULTS: The influence of the pharmacological prophylaxis with Panpal (pyridostigmine in combination with benaetyzine and trihexyphenidyle) on acetylcholinesterase activity in diaphragm and various parts of brain at 1 and 3 h following non-treated and treated (the oxime HI-6 in combination with atropine) soman poisoning was tested on male rats. While Panpal did not significantly influence the acetylcholinesterase activity in brain following non-treated as well as treated soman poisoning. Panpal increased so many-induced acetylcholinesterase inhibition following non-treated poisoning and decreased the reactivating effect of the oxime HI-6 following treated soman poisoning in diaphragm. CONCLUSIONS: Our data confirm the importance of the combination of reversible acetylcholinesterase inhibitor pyridostigmine with anticholinergic drugs in the pharmacological prophylaxis of soman poisoning because of the elimination of consequences of pyridostigmine-induced increasing in acetylcholinesterase inhibition in the peripheral compartment.
ESTHER : Kassa_1998_Cas.Lek.Cesk_137_299
PubMedSearch : Kassa_1998_Cas.Lek.Cesk_137_299
PubMedID: 9650360

Title : A comparison of the therapeutic efficacy of conventional and modern oximes against supralethal doses of highly toxic organophosphates in mice - Kassa_1998_Acta.Medica_41_19
Author(s) : Kassa J
Ref : Acta Medica , 41 :19 , 1998
Abstract : 1. The therapeutic efficacy of various oximes (pralidoxime, obidoxime, methoxime, HI-6, HL-7, BI-6) against supralethal nerve agent poisoning (soman, sarin, cyclosin) in mice was tested. 2. New oxime BI-6, synthesized in our laboratory, is significantly more efficacious than conventional oximes but a little less efficacious than other H-oximes (HI-6, HL-7). 3. H-oximes (HI-6, HL-7) seem to be the most efficacious reactivators of nerve agent-inhibited acetylcholinesterase for antidotal treatment of supralethal nerve agent poisoning in mice.
ESTHER : Kassa_1998_Acta.Medica_41_19
PubMedSearch : Kassa_1998_Acta.Medica_41_19
PubMedID: 9588068

Title : Effect of Panpal pretreatment and antidotal treatment (HI-6 plus benactyzine) on respiratory and circulatory function in soman-poisoned rats - Kassa_1997_Hum.Exp.Toxicol_16_563
Author(s) : Kassa J , Fusek J
Ref : Hum Exp Toxicol , 16 :563 , 1997
Abstract : 1 The effect of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated Panpal, and antidotal treatment (the oxime HI-6 plus benactyzine) in soman poisoning was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2 Soman poisoning caused a high decrease in respiratory rate as well as minute respiratory volume and an increase in mean arterial pressure from 30-120 min following soman challenge. Soman at sublethal dose also significantly inhibited acetylcholinesterase activity in diaphragm and various brain parts. 3 Panpal pretreatment as well as antidotal treatment were effective in improving the respiratory and circulatory function disturbed by soman without the ability to increase significantly soman-inhibited acetylcholinesterase activity in all brain parts studied. 4 The efficacy of combined Panpal pretreatment and antidotal treatment against sublethal soman poisoning was not different from the efficacy of Panpal pretreatment or antidotal treatment alone. 5 The results of this investigation suggest that Panpal pretreatment as well as antidotal treatment are able to restore respiratory and circulatory function in soman-poisoned rats without significant reactivation of brain acetylcholinesterase.
ESTHER : Kassa_1997_Hum.Exp.Toxicol_16_563
PubMedSearch : Kassa_1997_Hum.Exp.Toxicol_16_563
PubMedID: 9363473

Title : Importance of cholinolytic drug selection for the efficacy of HI-6 against soman in rats - Kassa_1997_Toxicology_116_147
Author(s) : Kassa J
Ref : Toxicology , 116 :147 , 1997
Abstract : The influence of cholinolytic drugs (atropine, benactyzine, biperiden) on the efficacy of the oxime HI-6 (1-[[[(4-aminocarbonyl)pyridinio]methoxy ]methyl]-2-[hydroxyimino)methyl]pyridinium dichloride monohydrate) on soman-induced anticholinesterase and stressogenic effects was studied in rats. Soman-induced acetylcholinesterase inhibition in blood and diaphragm and the stressogenic effects of soman, i.e. an increase in plasma corticosterone level and liver tyrosine aminotransferase activity, were more significantly diminished by HI-6 in combination with benactyzine or biperiden in comparison with HI-6 plus atropine. These findings support a hypothesis that benactyzine as well as biperiden can increase the efficacy of the oxime HI-6 in comparison with atropine. They demonstrate the importance of cholinolytic drug selection in the treatment of soman poisoning in rats. Ltd.
ESTHER : Kassa_1997_Toxicology_116_147
PubMedSearch : Kassa_1997_Toxicology_116_147
PubMedID: 9020515

Title : [The effect of parasympatholytics on the therapeutic effectiveness of the oxime HI-6 against organophosphorus compounds (Soman, substance VX, Fosdrin) in mice] - Kassa_1997_Cas.Lek.Cesk_136_124
Author(s) : Kassa J , Vachek J
Ref : Casopis Lekaru Ceskych , 136 :124 , 1997
Abstract : BACKGROUND Causal antidotal therapy of acute intoxications with organophosphorus compounds involving administration of the parasympatholytic and cholineesterase reactivator (oxime) has not been resolved so far satisfactorily despite knowledge of the basic mechanism of action of these noxious substances. METHODS AND RESULTS: In experiments on mice the therapeutic effect of parasympatholytics atropine, benactyzine and biperidene (Akineton) combined with oxime HI-6 on the toxicity of highly toxic organophosphates soman and substance VX and the organophosphorus insecticide phosdrine was compared as regards their influence on the LD50 of these noxious substances during 24-hour survival of experimental animals. Two levels of antidotes were tested. These findings confirm that the LD50 value of untreated intoxication with all three organophosphorus compounds is most increased by oxime HI-6 combined with benactyzine regardless of the antidote dosage.
CONCLUSIONS: Oxime HI-6 is the most effective against highly toxic organophosphates and organophosphorus insecticides when combined with the centrally acting parasympatholytic benactyzine.
ESTHER : Kassa_1997_Cas.Lek.Cesk_136_124
PubMedSearch : Kassa_1997_Cas.Lek.Cesk_136_124
PubMedID: 9221183

Title : The efficacy of monopyridinium (2-PAAM, 2-PAEM) and bispyridinium (obidoxime, HI-6) oximes against mevinphos in mice - Kassa_1997_Pharmacol.Toxicol_81_144
Author(s) : Kassa J , Bielavsky J
Ref : Pharmacol Toxicol , 81 :144 , 1997
Abstract : The efficacy of two new monopyridinium oximes (2-PAAM, 2-PAEM) and two bispyridinium oximes (obidoxime. HI-6) was tested in combination with atropine sulphate against acute poisoning with the organophosphorus insecticide mevinphos in mice. When mice were treated two min. after mevinphos poisoning, no significant differences in the therapeutic effect of tested oximes were observed. The oximes increased the 24 hr LD50 values of mevinphos about two times in comparison with the 24 hr LD50 values of mevinphos in mice protected with atropine sulphate alone and more than three times in comparison with non-treated intoxicated animals. On the other hand, both monopyridinium oximes were significantly more efficacious than HI-6 and as efficacious as obidoxime when they were administered 30 sec. after mevinphos poisoning. Both monopyridinium oximes and obidoxime increased the 24 hr values of mevinphos almost three times in comparison with the 24 hr values of mevinphos in mice protected with atropine sulphate alone and about twenty-five times in comparison with non-treated intoxicated animals, while the oxime HI-6 less than two times in comparison with the 24 hr values of mevinphos in mice protected with atropine sulphate alone and about fifteen times in comparison with non-treated intoxicated animals. Use of new monopyridinium oximes seems to be the improvement in the antidotal treatment of poisoning with organophosphorous insecticide mevinphos in comparison with HI-6 but not in comparison with obidoxime when oximes are used in equimolar doses.
ESTHER : Kassa_1997_Pharmacol.Toxicol_81_144
PubMedSearch : Kassa_1997_Pharmacol.Toxicol_81_144
PubMedID: 9335072

Title : Therapeutic efficacy of obidoxime or HI-6 with atropine against intoxication with some nerve agents in mice - Kassa_1996_Acta.Medica.(Hradec.Kralove)_39_27
Author(s) : Kassa J , Bajgar J
Ref : Acta Medica (Hradec Kralove) , 39 :27 , 1996
Abstract : 1 The toxicity of pinacolyl methylphosphonofluoridate (soman, GD), cyclohexyl methylphosphonofluoridate (cyclohe xylsarin, GF) and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV) and the therapeutic efficacy of two oximes (obidoxime and HI-6) in combination with atropine against mentioned nerve agents were evaluated in mice. 2 The 24-h i.m. LD50 of GD was 101 micrograms/kg (99.5-104.0), LD50 of GF was 170 micrograms/kg (151.0-190.0 and LD50 of GV was 25.2 micrograms/kg (23.0-27.7). 3 The efficacy of two oximes, obidoxime (15 and 30 mg/kg) or HI-6 (15 and 30 mg/kg) in combination with atropine (21 mg/kg) was tested. HI-6 was significantly more effective in reducing mortality than obidoxime following poisoning with all three nerve agents. 4 Higher doses of both oximes showed significantly more effective therapeutic efficacy against all nerve agents studied.
ESTHER : Kassa_1996_Acta.Medica.(Hradec.Kralove)_39_27
PubMedSearch : Kassa_1996_Acta.Medica.(Hradec.Kralove)_39_27
PubMedID: 9106387

Title : [Comparison of the effect of HI-6 oxime and its derivatives in combination with benactyzine on cholinergic and stress effects of soman in rats]. [Czech] - Kassa_1996_Ceska.Slov.Farm_45_149
Author(s) : Kassa J
Ref : Ceska a Slovenska Farmacie , 45 :149 , 1996
Abstract : In male rat experiments, the therapeutic effect of oxime HI-6 and its derivatives (HI-6 ester and amide) in combination with benactyzine on the cholinergic and stressogenic effects of a sublethal dose of soman was compared. Cholinergic effects were investigated by monitoring the changes in the activity of cholinesterases in the whole blood, brain and diaphragm, stressogenic effects by monitoring the changes in the level of corticosterone in the plasma and the activity of tyrosine aminotransferase in the liver. The monitoring of the changes in the selected parameters of cholinergic and stressogenic effects of soman has demonstrated that neither of the derivatives of oxime HI-6 under study achieves its therapeutic effect and thus seems to be a suitable substitute of oxime HI-6 for the therapy of acute intoxications with the organophosphate soman, which are difficult to treat.
ESTHER : Kassa_1996_Ceska.Slov.Farm_45_149
PubMedSearch : Kassa_1996_Ceska.Slov.Farm_45_149
PubMedID: 8696692

Title : [Comparison of the therapeutic effectiveness of selected cholinesterase reactivators with atropine in acute fosdrine poisoning in mice] - Kassa_1996_Ceska.Slov.Farm_45_31
Author(s) : Kassa J , Bajgar J
Ref : Ceska a Slovenska Farmacie , 45 :31 , 1996
Abstract : In experiments on male mice, the effect of the cholinesterase reactivators obidoxime, methoxime and HI-6 in combination with atropine sulfate on the acute intoxication with the organophosphorous insecticide fosdrine was tested in dependence on the period of administration of drugs after intoxication and on the dose of oxime by influencing the LD50 value in 48-hour survival of experimental animals. It has been demonstrated that the rate of the therapeutic intervention is a much more important factor influencing the effect of oximes than the dose of oximes. A shortening of the period of drug administration from 2 minutes to 30 seconds substantially increases the effects of all three oximes. A comparison of the effects of all three reactivators has shown that the oxime HI-6 is significantly more effective than the remaining two reactivators in the case of therapy of intoxication 30 seconds after the application of the noxa. In the therapy of intoxication 2 minutes after the exposure of experimental animals to fosdrine, the effect of the antidotal therapy was relatively low regardless of the selected oxime.
ESTHER : Kassa_1996_Ceska.Slov.Farm_45_31
PubMedSearch : Kassa_1996_Ceska.Slov.Farm_45_31
PubMedID: 8620316

Title : Comparison of efficacy of two oximes (HI-6 and obidoxime) in soman poisoning in rats - Kassa_1995_Toxicology_101_167
Author(s) : Kassa J
Ref : Toxicology , 101 :167 , 1995
Abstract : The action of HI-6 (1-[[[(4-aminocarbonyl)pyridiniol]methoxy]methyl]-2-[ (hydroxyimino)methyl] pyridinium dichloride monohydrate) and obidoxime on soman-induced anticholinesterase and stressogenic effects was studied in rats. HI-6 significantly affected acetylcholinesterase inhibition in erythrocytes, brain and diaphragm and practically eliminated the stressogenic effects of soman, i.e. an increase in plasma corticosterone level and liver tyrosine amino-transferase activity, while obidoxime, on the other hand, had very little influence on soman-induced inhibition of acetylcholinesterase activity and the stressogenic effects of soman. These findings support a hypothesis that the effects of HI-6 are not solely due to reactivation of the enzyme. They also demonstrate its importance in the treatment of soman poisoning in rats.
ESTHER : Kassa_1995_Toxicology_101_167
PubMedSearch : Kassa_1995_Toxicology_101_167
PubMedID: 7676463

Title : Comparison of the efficacy of HI-6 and obidoxime against cyclohexyl methylphosphonofluoridate (GF) in rats - Kassa_1995_Human.Exp.Toxicol_14_923
Author(s) : Kassa J , Bajgar J
Ref : Hum Exp Toxicol , 14 :923 , 1995
Abstract : 1. The efficacy of HI-6 and obidoxime in combination with atropine on cyclohexyl methylphosphonofluoridate (GF)-induced cholinergic and stressogenic effects in rats was studied. 2. HI-6 sufficiently reactivated cholinesterase activity in blood as well as acetylcholinesterase activity in brain and diaphragm following GF intoxication, and practically eliminated stressogenic effects of GF (an increase in plasma corticosterone level and liver tyrosine aminotransferase activity). 3. Obidoxime had practically no effect on enzyme activity or stressogenic effects of GF agent. 4. These findings confirm that HI-6 has definite advantages over obidoxime in the treatment of intoxication with GF.
ESTHER : Kassa_1995_Human.Exp.Toxicol_14_923
PubMedSearch : Kassa_1995_Human.Exp.Toxicol_14_923
PubMedID: 8588955

Title : [Comparison of the effect of selected cholinesterase reactivators combined with atropine on soman and fosdrin toxicity in mice] - Kassa_1995_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove.Suppl_38_63
Author(s) : Kassa J
Ref : Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl , 38 :63 , 1995
Abstract : The efficacy of cholinesterase reactivators tetroxime, HI-6 and obidoxime in combination with atropine against highly toxic organophosphate soman as well as organophosphorus insecticide fosdrin was evaluated in male mice using median lethal dose (LD50) for 48 hours. Oxime HI-6 appears to be considerably more effective than tetroxime as well as obidoxime for the treatment of acute poisonings by soman or fosdrin, although the difference in effect is not significant in the case of poisoning by fosdrin. These findings suggest that HI-6 has definite advantage over obidoxime as well as tetroxime in the treatment of poisoning with not only highly toxic organophosphates but also organophoshorus insecticides.
ESTHER : Kassa_1995_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove.Suppl_38_63
PubMedSearch : Kassa_1995_Sb.Ved.Pr.Lek.Fak.Karlovy.Univerzity.Hradci.Kralove.Suppl_38_63
PubMedID: 9441373

Title : [Comparison of the effect of selected anticholinergic agents on cholinergic and noncholinergic effects of GV substances during acute poisoning in rats]. [Czech] - Kassa_1994_Ceska.Slov.Farm_43_222
Author(s) : Kassa J , Bajgar J
Ref : Ceska a Slovenska Farmacie , 43 :222 , 1994
Abstract : In experiments on male rats, the effect of selected cholinolytic agents (atropine, benactyzine, G 3063) in combination with the reactivator of cholinesterases HI-6 on the cholinergic and non-cholinergic effects of GV substance in the course of acute sublethal intoxication was compared. The cholinergic affects of GV substance were examined by means of the changes in the activity of cholinesterases in whole blood, the CNS, diaphragm and liver, the noncholinergic stressogenic effects by means of the changes in the level of corticosterone in plasma and the activity of tyrosine amino transferase in the liver. It follows from the changes in the activity of cholinesterases that the cholinergic effects of GV substance are least influenced by atropine, whereas benactyzine and G 3063 exert an approximately similar effect. The difference in the effect is evident especially in the 24th hour of intoxication. Similarly stressogenic effects of GV substance are least influenced by an antidotal combination of atropine and HI-6. It means that the centrally acting cholinolytic agents benactyzine and G 3063 are more advantageous for the therapy of GV substance poisonings than the peripherally acting atropine.
ESTHER : Kassa_1994_Ceska.Slov.Farm_43_222
PubMedSearch : Kassa_1994_Ceska.Slov.Farm_43_222
PubMedID: 7982005

Title : [Use of peritoneal dialysis as a therapeutic method in poisoning by Neguvon] - Kassa_1990_Cesk.Farm_39_7
Author(s) : Kassa J
Ref : Ceska Farmacie , 39 :7 , 1990
Abstract : In experiments on female rats the effect of peritoneal dialysis with variously diluted human plasma in peroral poisoning with the organophosphorous insecticide Neguvon, in which inhibition of blood acetylcholinesterase occurs, was examined. Out of the three protein plasma concentrations tested (7 g/l, 70 g/l and 140 g/l), the highest increase in the activity of the inhibited acetylcholinesterase in the blood was induced with the concentration of 70 g/l. A closer examination of the effect of the individual components of the dialysate for Neguvon poisoning revealed that approximately 60% of the effect of treatment is due to albumin, 40% to butyrylcholinesterase in the administered plasma. The comparison of the inhibition of butyrylcholinesterase in the plasma, which was administered as the dialysate, with Neguvon in vitro and in vivo shows that the inhibition of butyrylcholinesterase in the dialysate in vivo is produced by about 35% of the Neguvon dose, administered to experimental animals, and that therefore the actual dose of Neguvon, which induced the poisoning, was decreased to two thirds. This is in agreement with the fact that the LD50 value in treated rats after single-dose administration of the dialysate is more than two times higher than in untreated rats.
ESTHER : Kassa_1990_Cesk.Farm_39_7
PubMedSearch : Kassa_1990_Cesk.Farm_39_7
PubMedID: 2379248