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1.
Biochem J ; 450(1): 231-42, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23216060

RESUMO

In the present paper we show a comprehensive in vitro, ex vivo and in vivo study on hydrolytic detoxification of nerve agent and pesticide OPs (organophosphates) catalysed by purified hBChE (human butyrylcholinesterase) in combination with novel non-pyridinium oxime reactivators. We identified TAB2OH (2-trimethylammonio-6-hydroxybenzaldehyde oxime) as an efficient reactivator of OP-hBChE conjugates formed by the nerve agents VX and cyclosarin, and the pesticide paraoxon. It was also functional in reactivation of sarin- and tabun-inhibited hBChE. A 3-5-fold enhancement of in vitro reactivation of VX-, cyclosarin- and paraoxon-inhibited hBChE was observed when compared with the commonly used N-methylpyridinium aldoxime reactivator, 2PAM (2-pyridinealdoxime methiodide). Kinetic analysis showed that the enhancement resulted from improved molecular recognition of corresponding OP-hBChE conjugates by TAB2OH. The unique features of TAB2OH stem from an exocyclic quaternary nitrogen and a hydroxy group, both ortho to an oxime group on a benzene ring. pH-dependences reveal participation of the hydroxy group (pKa=7.6) forming an additional ionizing nucleophile to potentiate the oxime (pKa=10) at physiological pH. The TAB2OH protective indices in therapy of sarin- and paraoxon-exposed mice were enhanced by 30-60% when they were treated with a combination of TAB2OH and sub-stoichiometric hBChE. The results of the present study establish that oxime-assisted catalysis is feasible for OP bioscavenging.


Assuntos
Butirilcolinesterase/metabolismo , Substâncias para a Guerra Química/metabolismo , Organofosfatos/metabolismo , Oximas/química , Paraoxon/metabolismo , Sarina/metabolismo , Animais , Catálise , Substâncias para a Guerra Química/toxicidade , Feminino , Humanos , Concentração de Íons de Hidrogênio , Inativação Metabólica , Cinética , Camundongos , Camundongos Endogâmicos , Organofosfatos/toxicidade , Oximas/metabolismo , Paraoxon/toxicidade , Sarina/toxicidade
2.
J Biol Chem ; 287(15): 11798-809, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22343626

RESUMO

We present a systematic structural optimization of uncharged but ionizable N-substituted 2-hydroxyiminoacetamido alkylamine reactivators of phosphylated human acetylcholinesterase (hAChE) intended to catalyze the hydrolysis of organophosphate (OP)-inhibited hAChE in the CNS. Starting with the initial lead oxime RS41A identified in our earlier study and extending to the azepine analog RS194B, reactivation rates for OP-hAChE conjugates formed by sarin, cyclosarin, VX, paraoxon, and tabun are enhanced severalfold in vitro. To analyze the mechanism of intrinsic reactivation of the OP-AChE conjugate and penetration of the blood-brain barrier, the pH dependence of the oxime and amine ionizing groups of the compounds and their nucleophilic potential were examined by UV-visible spectroscopy, (1)H NMR, and oximolysis rates for acetylthiocholine and phosphoester hydrolysis. Oximolysis rates were compared in solution and on AChE conjugates and analyzed in terms of the ionization states for reactivation of the OP-conjugated AChE. In addition, toxicity and pharmacokinetic studies in mice show significantly improved CNS penetration and retention for RS194B when compared with RS41A. The enhanced intrinsic reactivity against the OP-AChE target combined with favorable pharmacokinetic properties resulted in great improvement of antidotal properties of RS194B compared with RS41A and the standard peripherally active oxime, 2-pyridinealdoxime methiodide. Improvement was particularly noticeable when pretreatment of mice with RS194B before OP exposure was combined with RS194B reactivation therapy after the OP insult.


Assuntos
Acetamidas/química , Antídotos/química , Reativadores da Colinesterase/química , Oximas/química , Acetamidas/farmacocinética , Acetamidas/toxicidade , Acetilcolinesterase , Animais , Antídotos/farmacocinética , Antídotos/toxicidade , Encéfalo/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacocinética , Reativadores da Colinesterase/toxicidade , Avaliação Pré-Clínica de Medicamentos/normas , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Dose Letal Mediana , Camundongos , Estrutura Molecular , Organofosfatos/química , Organofosfatos/toxicidade , Oximas/farmacocinética , Oximas/toxicidade , Ligação Proteica , Padrões de Referência , Relação Estrutura-Atividade , Distribuição Tecidual
3.
J Enzyme Inhib Med Chem ; 25(4): 531-6, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20235800

RESUMO

Organophosphorus compounds pose a potential threat to both military and civilian populations. Since post-exposure therapy has its limitations, our research was focused on the possibility of improving pretreatment in order to limit the toxic effects of tabun. We determined the protective index of various combinations of atropine, oximes (K074, K048, and TMB-4), and pyridostigmine given to mice before tabun intoxication. Although the tested oximes showed very good therapeutic efficacy in tabun-poisoned mice, the given pretreatments improved therapy against tabun poisoning. These regimens ensured survival of all animals up to 25.2 LD(50) of tabun. Our results indicate that even pretreatment with atropine alone is sufficiently effective in enhancing the survival of mice poisoned by multiple doses of tabun, if oxime therapy follows. K048 is our oxime of choice for future research, as it shows better protective and reactivating potency.


Assuntos
Atropina/farmacologia , Inibidores da Colinesterase/intoxicação , Intoxicação por Organofosfatos , Oximas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Atropina/uso terapêutico , Butanos/farmacologia , Butanos/uso terapêutico , Substâncias para a Guerra Química , Camundongos , Organofosfatos , Oximas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Compostos de Piridínio/farmacologia , Compostos de Piridínio/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento , Trimedoxima/farmacologia , Trimedoxima/uso terapêutico
4.
Acta Biochim Pol ; 55(1): 97-105, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18324340

RESUMO

This study aimed to evaluate the antidotal potency of tenocyclidine (TCP) that probably might protect acetylcholinesterase (AChE) in the case of organophosphate poisoning. TCP was tested alone as a pretreatment or in combination with atropine as a therapy in rats poisoned with (1/4) and (1/2) of LD(50) of soman. Possible genotoxic effects of TCP in white blood cells and brain tissue were also studied. Results were compared with previous findings on the adamantyl tenocyclidine derivative TAMORF. TCP given alone as pretreatment, 5 min before soman, seems to be superior in the protection of cholinesterase (ChE) catalytic activity in the plasma than in brain, especially after administration of the lower dose of soman. Plasma activities of the enzyme after a joint treatment with TCP and soman were significantly increased at 30 min (P<0.001) and 24 h (P=0.0043), as compared to soman alone. TCP and atropine, given as therapy, were more effective than TCP administered alone as a pretreatment. The above therapy significantly increased activities of the enzyme at 30 min (P=0.046) and 24 h (P<0.001), as compared to controls treated with (1/4) LD(50) of soman alone. Using the alkaline comet assay, acceptable genotoxicity of TCP was observed. However, the controversial role of TCP in brain protection of soman-poisoned rats should be studied further.


Assuntos
Piperidinas/farmacologia , Soman/intoxicação , Tiofenos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/metabolismo , Colinesterases/metabolismo , Ensaio Cometa , Leucócitos/metabolismo , Masculino , Modelos Químicos , Mutagênicos/farmacologia , Fenciclidina/análogos & derivados , Ratos , Ratos Wistar
5.
Chem Biol Interact ; 175(1-3): 413-6, 2008 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-18547553

RESUMO

Improving the efficacy of antidotal treatment of poisonings with nerve agents is still a challenge for the scientific community. This study investigated the interactions of four bispyridinium oximes with human erythrocyte acetylcholinesterase (AChE) and their effects on soman- and tabun-poisoned mice. Oximes HI-6 and TMB-4 were used for comparison. These oximes inhibited AchE with inhibitory potency (IC(50)) ranging from 0.02 to 1.0 mM. The best reactivating potency (%R) was obtained with K074, when AChE was inhibited by tabun. The protective potency (P(50)) of all oximes in human erythrocyte AChE inhibited by soman and tabun could not be determined. In tabun-poisoned mice very good antidotal efficacy was obtained with K027, K048, and K074, which makes them interesting for future investigation. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.


Assuntos
Substâncias para a Guerra Química/intoxicação , Reativadores Enzimáticos/farmacologia , Intoxicação por Organofosfatos , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Soman/intoxicação , Animais , Reativadores Enzimáticos/uso terapêutico , Humanos , Técnicas In Vitro , Dose Letal Mediana , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Organofosfatos , Oximas/uso terapêutico , Intoxicação/tratamento farmacológico , Compostos de Piridínio/uso terapêutico
6.
Chem Biol Interact ; 175(1-3): 173-9, 2008 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-18501341

RESUMO

One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime, found as the most effective reactivators, have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE. Three of our tested pyridinium oximes K027, K048, K074, along with TMB-4, were the most promising for AChE reactivation. Promising oximes were further tested in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. Herein, we showed that a promising treatment in tabun poisoning by selected oximes and atropine could be improved if oximes are also used in pretreatment. Since the reactivating efficacy of the oximes in vitro corresponded to their therapeutic efficacy in vivo, it seems that pharmacological effect of these oximes is indeed primarily related to the reactivation of tabun-phosphorylated AChE.


Assuntos
Acetilcolinesterase/metabolismo , Antídotos/uso terapêutico , Inibidores da Colinesterase/intoxicação , Reativadores Enzimáticos/uso terapêutico , Intoxicação por Organofosfatos , Oximas/uso terapêutico , Animais , Antídotos/química , Antídotos/farmacologia , Reativadores Enzimáticos/química , Reativadores Enzimáticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Organofosfatos , Oximas/química , Oximas/farmacologia , Fosforilação , Intoxicação/tratamento farmacológico
7.
Acta Biochim Pol ; 54(3): 583-93, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17713603

RESUMO

The function of acetylcholinesterase (AChE) is the rapid hydrolysis of the neurotransmitter acetylcholine (ACh), which is involved in the numerous cholinergic pathways in both the central and the peripheral nervous system. Therefore, AChE measurement is of high value for therapy management, especially during the course of intoxication with different chemicals or drugs that inhibit the enzyme. Pyridinium or bispyridinium aldoximes (oximes) are able to recover the activity of the inhibited enzyme. Since their adverse effects are not well elucidated, in this study the efficiency of HI-6 oxime in protection and/or reactivation of human erythrocyte AChE inhibited by the antineoplastic drug irinotecan as well as its cyto/genotoxicity in vitro were investigated. HI-6 was effective in protection of AChE and increased its activity up to 30%; the residual activity after irinotecan inhibition was 7%. Also, it reactivated the enzyme previously inhibited by 50% irinotecan (4.6 microg/ml) applied at 1/4 of the IC50 value. The tested concentrations of HI-6 exhibited acceptable genotoxicity towards white blood cells, as estimated by the alkaline comet assay, DNA diffusion assay and cytogenetic endpoints (structural chromosome aberrations and cytokinesis-block micronucleus assay). The results obtained warrant the further investigation of HI-6 in vivo, as well as its development for possible application in chemotherapy.


Assuntos
Acetilcolinesterase/metabolismo , Camptotecina/análogos & derivados , Compostos de Piridínio/farmacologia , Adulto , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Camptotecina/química , Camptotecina/farmacologia , Células Cultivadas , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Aberrações Cromossômicas/efeitos dos fármacos , Feminino , Humanos , Irinotecano , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Estrutura Molecular , Oximas , Compostos de Piridínio/química
8.
Mol Nutr Food Res ; 51(9): 1147-51, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17688296

RESUMO

The aim of this study was to find out whether very low doses of nephrotoxic and hepatotoxic mycotoxins ochratoxin A (OTA) and fumonisin B1 (FB1) induce oxidative stress in rat kidney and liver and whether their effect is synergistic. Rats were treated orally with OTA (5 ng/kg b.w. and 50 microg/kg b.w.) and FB1 (200 ng/kg b.w. and 50 microg/kg b.w.), or their combinations. Malondialdehyde (MDA) and protein carbonyls (PCs) concentration in kidney was affected with lower dose of OTA than in liver (p<0.05). FB1 did not affect MDA and PCs concentrations in the liver, while in the kidney both FB1 doses increased MDA concentration (p<0.05). The combination of the lower doses of OTA+FB1 increased the MDA and PCs concentration both in the liver and the kidney, compared to controls and animals treated with respective doses of mycotoxins (p<0.05). The combinations of mycotoxins reduced the catalase activity only in the kidney when compared to controls (p<0.05). In contrast to the increased kidney concentrations of MDA and PCs even with very low doses of OTA and FB1, the activity of catalase and SOD does not change. Combinations of OTA+FB1 affected almost all parameters, which indicates their potential to produce oxidative damage.


Assuntos
Fumonisinas/toxicidade , Ocratoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Fumonisinas/administração & dosagem , Rim/química , Rim/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Malondialdeído/análise , Micotoxinas/toxicidade , Ocratoxinas/administração & dosagem , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar
9.
Food Chem Toxicol ; 45(12): 2488-98, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17673351

RESUMO

Literature data on carbofuran genotoxicity in vitro and in vivo are very scarce. There are few papers indicating that occupational exposure to this AChE inhibiting insecticide might be connected to increased risk of developing non-Hodgkin's lymphoma and lung cancer. Other authors showed its genotoxicity in vitro. We used comet and CBMN micronucleus assay combined with centromere probes to evaluate genome damage in lymphocytes of workers employed in carbofuran production. Also, the level of AChE activity in blood and plasma was measured. Only few workers exhibited AChE activity below 85%. Comet assay parameters were slightly but significantly elevated compared to control subjects, especially the long-tailed nuclei ratio. We found poor correlation between AChE activity and comet assay parameters, but significant effect of smoking and alcohol intake on the latest. In binucleated lymphocytes of workers significantly increased number of micronuclei, nuclear buds, and nucleoplasmic bridges was detected. Proportion of micronuclei with centromere, DAPI signal positive micronuclei was also elevated. Micronucleus assay parameters also appeared to be significantly influenced by duration of exposure to carbofuran. Together with published data on carbofuran's effect on health our results might indicate the need for further evaluations of its genotoxicity using a range of different cytogenetic techniques.


Assuntos
Acetilcolinesterase/metabolismo , Poluentes Ocupacionais do Ar/toxicidade , Carbofurano/toxicidade , Inseticidas/toxicidade , Linfócitos/metabolismo , Exposição Ocupacional , Acetilcolinesterase/sangue , Adulto , Estudos de Casos e Controles , Ensaio Cometa , Dano ao DNA , Monitoramento Ambiental , Feminino , Humanos , Masculino , Micronúcleos com Defeito Cromossômico
10.
Basic Clin Pharmacol Toxicol ; 100(6): 403-13, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17516995

RESUMO

Toxic effects of the antineoplastic drug irinotecan on human blood cells at concentrations of 9.0 microg/ml and 4.6 microg/ml were evaluated in vitro. Using the alkaline and neutral comet assay significantly increased levels of primary DNA damage in lymphocytes were detected. The induction of apoptosis/necrosis, as determined by a fluorescent assay, was also notably increased. Cytogenetic outcomes of the treatment were assessed by the analysis of structural chromosome aberrations and fluorescence in situ hybridization. A significantly higher incidence of chromatid breaks and complex quadriradials was observed. Painted chromosomes 1, 2 and 4 were equally involved in translocations, but only the chromosome 1 was involved in the formation of quadriradials. Sister chromatid exchange analysis was performed in parallel with the analysis of lymphocyte proliferation kinetics. The higher concentration of irinotecan caused almost seven-time increase, while the lower one caused a five-time increase of the basal sister chromatid exchange frequency, accompanied with significant lowering of the lymphocyte proliferation index. Using the cytokinesis-block micronucleus assay, a dose-dependent increase in micronucleus frequency along with the formation of nuclear buds and nucleoplasmic bridges was noticed. Inhibitory effects of irinotecan on enzyme acetylcholinesterase (AChE) were studied in erythrocytes. An IC(50) value of 5.0 x 10(-7) was established. Irinotecan was found to be strong inhibitor of the acetylcholine hydrolysis and to cause a continuous decrease of catalytic activity of AChE. The results obtained on a single donor may contribute to the understanding of irinotecan toxicity, but further in vitro and in vivo studies are essential in order to clarify remaining issues, especially on possible inter-individual variability in genotoxic responses to the drug.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Camptotecina/análogos & derivados , Eritrócitos/metabolismo , Linfócitos/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Biomarcadores , Camptotecina/toxicidade , Inibidores da Colinesterase , Cromossomos Humanos 1-3/genética , Cromossomos Humanos 4-5/genética , Ensaio Cometa , Análise Citogenética , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Irinotecano , Troca de Cromátide Irmã
11.
J Mol Neurosci ; 30(1-2): 113-4, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17192653

RESUMO

The progressive inhibition of acetylcholinesterase (AChE [EC 3.1.1.7]) by organophosphates (OPs), such as the nerve agents tabun and soman, is due to phosphorylation of the active center serine characterized by the formation of conjugates and inactivation of this essential enzyme involved in neurotransmission. Presently, a combination of an antimuscarinic agent, e.g., atropine, and an AChE reactivator, oxime, is used for the treatment of organophosphorus compound poisoning. The increased concern about terrorist use of nerve agents prompted us to search for new, more effective oximes against tabun and soman poisoning. We investigated the interactions of five bispyridinium oximes with human erythrocyte AChE and their effects on tabun- and soman-poisoned mice.


Assuntos
Acetilcolinesterase/metabolismo , Antídotos/farmacologia , Organofosfatos/toxicidade , Oximas/farmacologia , Compostos de Piridínio/farmacologia , Acetilcolinesterase/sangue , Animais , Inibidores da Colinesterase/toxicidade , Eritrócitos/enzimologia , Humanos , Camundongos , Soman/toxicidade
12.
Toxicology ; 219(1-3): 85-96, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16332406

RESUMO

The increased concern about terrorist use of nerve agents prompted us to search for new more effective oximes against tabun and soman poisoning. We investigated the interactions of five bispyridinium oximes: K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], K033 [1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide], TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)] with human erythrocyte acetylcholinesterase (AChE; E.C. 3.1.1.7) and their effects on tabun- and soman-poisoned mice. All the oximes reversibly inhibited AChE, and the enzyme-oxime dissociation constants were between 17 and 180 microM. Tabun-inhibited AChE was completely reactivated by TMB-4, K027 and K048, with the overall reactivation rate constants of 306, 376 and 673 min(-1)M(-1), respectively. The reactivation of tabun-inhibited AChE by K033 reached 50% after 24h, while HI-6 failed to reactivate any AChE at all. Soman-inhibited AChE was resistant to reactivation by 1mM oximes. All studied oximes protected AChE from phosphorylation with both soman and tabun. In vivo experiments showed that the studied oximes were relatively toxic to mice; K033 was the most toxic (LD50=33.4 mg/kg), while K027 was the least toxic (LD50=672.8 mg/kg). The best antidotal efficacy was obtained with K048, K027 and TMB-4 for tabun poisoning, and HI-6 for soman poisoning. Moreover, all tested oximes showed no cytotoxic effect on several cell lines in concentrations up to 0.8mM. The potency of the oximes K048 and K027 to protect mice from five-fold LD50 of tabun and their low toxicity make these compounds leading in the therapy of tabun poisoning. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.


Assuntos
Acetilcolinesterase/metabolismo , Substâncias para a Guerra Química/intoxicação , Inibidores da Colinesterase/intoxicação , Reativadores da Colinesterase/farmacologia , Intoxicação por Organofosfatos , Organofosfatos/antagonistas & inibidores , Oximas/síntese química , Oximas/farmacologia , Compostos de Piridínio/síntese química , Compostos de Piridínio/farmacologia , Soman/antagonistas & inibidores , Soman/intoxicação , Algoritmos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Reativadores da Colinesterase/uso terapêutico , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oximas/uso terapêutico , Fosforilação , Compostos de Piridínio/uso terapêutico
13.
Toxicology ; 228(1): 41-50, 2006 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-16982122

RESUMO

Oximes K033 [1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide] and K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide] were tested as pretreatment drugs in tabun-poisoned mice followed by treatment with atropine plus K033, K048, K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)]. Oxime doses of 25% or 5% of its LD(50) were used for pretreatment 15 min before tabun-poisoning and for treatment 1 min after tabun administration to mice. The best therapeutic effect was obtained when oxime K048 (25% of its LD(50)) was used in both pretreatment and treatment with atropine. This regiment insured survival of all tested animals after the application of 10 LD(50) of tabun. In addition, since butyrylcholinesterase (BChE; EC 3.1.1.8) is considered an endogenous bioscavenger of anticholinesterase compounds and its interactions with oximes could be masked by AChE interactions, we evaluated kinetic parameters for interactions of tested oximes with native and tabun-inhibited human plasma BChE and compared them with results obtained previously for human erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7). Progressive inhibition of BChE by tabun was slightly faster than that of AChE. The reactivation of tabun-inhibited BChE by oximes was very slow, and BChE binding affinity for oximes was lower than AChE's. Therefore, BChE could scavenge tabun prior to AChE inhibition, but fast oxime-assisted reactivation of tabun-inhibited AChE or protection of AChE by oxime against inhibition with tabun would not be obstructed by interaction between BChE and oximes.


Assuntos
Antídotos/farmacologia , Substâncias para a Guerra Química/intoxicação , Intoxicação por Organofosfatos , Oximas/farmacologia , Intoxicação/prevenção & controle , Compostos de Piridínio/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Animais , Atropina/farmacologia , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Quimioterapia Combinada , Eritrócitos/enzimologia , Humanos , Dose Letal Mediana , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Organofosfatos
14.
Toxicol In Vitro ; 20(8): 1455-64, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16942853

RESUMO

Tenocyclidine-TCP showing a broad spectrum of pharmacological activity including antidotal effect in organophosphorus compounds poisoning, radioprotective and anticancer effects. We investigated in vitro interactions of TCP and its adamantane derivative--TAMORF with human erythrocyte acetylcholinesterase (AChE). Moreover, their genotoxicity and radioprotective activity on human white blood cells were studied using the alkaline comet assay, viability testing and the analysis of the structural chromosome aberrations. The tested compounds were found to be weak inhibitors of AChE, for TCP IC(50)=1 x 10(-5)M and for TAMORF IC(50)>1 x 10(-3)M, without reactivating and protective effects on AChE inhibited by soman. Results suggest that TCP modified by the replacement of the cyclohexyl ring with an adamantly ring and piperidine with morpholine group (TAMORF) have lower toxicity. Both compounds possess low cytotoxicity and radioprotective activity, but TAMORF also shows cell growth inhibitory effects. To clarify differences in their biological efficiency observed in vitro and in vivo, additional analyses are necessary. Since TAMORF was found to significantly inhibit cell growth and proliferation in vitro, it is reasonably to consider it as a source molecule promising for further modifications and development of more potent substances with antitumor properties rather then radioprotector or antidote in organophosphorus poisoning.


Assuntos
Adamantano/análogos & derivados , Reativadores da Colinesterase/farmacologia , Morfolinas/farmacologia , Piperidinas/farmacologia , Tiofenos/farmacologia , Adamantano/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Aberrações Cromossômicas/efeitos dos fármacos , Ensaio Cometa , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Raios gama , Humanos , Técnicas In Vitro , Dose Letal Mediana , Leucócitos/efeitos dos fármacos , Leucócitos/efeitos da radiação , Linfócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Fenciclidina/análogos & derivados , Protetores contra Radiação/farmacologia , Soman/antagonistas & inibidores , Soman/toxicidade , Relação Estrutura-Atividade , Azul Tripano
15.
Basic Clin Pharmacol Toxicol ; 99(1): 17-21, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16867165

RESUMO

Acetylcholinesterase (AChE; EC 3.1.1.7.) is an extremely active enzyme necessary for terminating the action of acetylcholine in cholinergic synapses. The aim of this study was to evaluate the efficacy of four mono-pyridinium compounds 1-phenacylpyridinium chloride (I), 1-phenacyl-2-methylpyiridinium chloride (II), 1-benzoylethylpyridinium chloride (III), and 1-benzoylethylpyridinium-4-aldoxime chloride (IV) in the therapy of soman poisoning. Their effect was compared with HI-6 and TMB-4 oximes. The inhibitory potency (IC50) of compounds as well as reactivating (%R) and protective potency (P50) with respect to soman-inhibited AChE were determined for each of the compounds. Their acute intraperitoneal toxicity (LD50 with 95% confidence limits) was tested in mice and observed for 24 hr. The therapeutic effect was expressed as the protective index and as the therapeutic dose. The tested compounds were found to be reversible inhibitors of AChE. In vivo results show that the tested compounds are relatively toxic (their LD50 was from 74.9 to 210.0 mg/kg body weight). The best antidotal efficacy was obtained with compound II, which had the highest affinity for AChE (IC50 was 1.9 x 10(-5) mol l(-1)) and seems to be an adequate antidote in soman poisoning (its protective index and therapeutic dose were 2.8 and 2, respectively). Our results indicate that its antidotal effect is related to the reactivation or protection of AChE. The type of the substituent in the pyridinium ring generally has a significant influence on toxicity in vitro and in vivo, and on the antidotal efficacy of all new tested compounds.


Assuntos
Antídotos/farmacologia , Substâncias para a Guerra Química/intoxicação , Inibidores da Colinesterase/intoxicação , Compostos de Piridínio/farmacologia , Soman/antagonistas & inibidores , Soman/intoxicação , Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Animais , Reativadores da Colinesterase/farmacologia , Reativadores da Colinesterase/uso terapêutico , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Humanos , Técnicas In Vitro , Dose Letal Mediana , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oximas/farmacologia , Fosforilação , Compostos de Piridínio/química , Relação Estrutura-Atividade
16.
Acta Pharm ; 55(2): 177-85, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16179131

RESUMO

The paper describes the effect of glucocorticoid dexamethasone (DM) given intraperitoneally on the catalytic activity of butyrylcholinesterase (BuChE) measured in plasma, liver and white adipose tissue of rats of both sexes. Effects of DM on the concentration of plasma lipids and lipoproteins were also tested. Rats were given multiple (2 and 4) pharmacological doses (0.4 and 3.0 mg kg(-1) body mass) of DM. All animals were sacrificed 48 hours after the last dose. Administration of DM significantly decreased the catalytic activity of BuChE in plasma and liver of all treated groups regardless of sex. BuChE catalytic activity in white adipose tissue differed depending on the dose and frequency of administration. In contrast to liver where both doses caused significant BuChE inhibition, the lower DM dose did not inhibit BuChE activity in adipose tissue, and the inhibition achieved by the higher dose was not as strong as in liver. This result corroborates an earlier hypothesis that BuChE is also synthesized in the adipose tissue. DM significantly increased plasma concentrations of triglycerides, total cholesterol and high-density lipoprotein (HDL) cholesterol and decreased the low-density lipoprotein (LDL) cholesterol concentration. Neither positive correlation between BuChE and triglycerides nor negative correlation between BuChE and HDL was found. Changes in lipid profile during DM treatment were not sex- and time-dependent.


Assuntos
Anti-Inflamatórios/farmacologia , Butirilcolinesterase/sangue , Dexametasona/farmacologia , Lipídeos/sangue , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , HDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Lipoproteínas/sangue , Masculino , Ratos , Ratos Wistar , Triglicerídeos/sangue
17.
Arh Hig Rada Toksikol ; 66(2): 129-34, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26110474

RESUMO

The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD50) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD50=21.4 mg kg-1) to mice, while monoxime K027 was the least toxic (LD50=672.8 mg kg-1). With the exception of K033, all of the tested K-oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication.


Assuntos
Antídotos/uso terapêutico , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/uso terapêutico , Oximas/farmacologia , Oximas/uso terapêutico , Paraoxon/toxicidade , Animais , Masculino , Camundongos
18.
Arh Hig Rada Toksikol ; 55(4): 243-8, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15584550

RESUMO

The aim of our study was to find whether ochratoxin A (OTA) induces the apoptosis and/or necrosis of kidney tissue in rats. In the first experiment, the highest number of apoptotic cells was found in rats sacrificed one day after OTA administration (1.00 mg/kg b.w., i.p.). The number of apoptotic cells reduced gradually and they were not seen nine days after OTA administration. A possible dose-dependence of histological changes was checked in kidney tissue of rats given 0.25, 0.50 or 1.00 mg of OTA/kg b.w., i.p. three times a week for four weeks. The number of apoptotic cells showed a clear dose-dependence, but necrosis was absent even at the highest doses. The time-dependent appearance of lesions related to OTA administration was checked by administering 0.50 mg OTA/kg body weight to rats, and sacrificing them one day after 1, 3, 6, and 9 doses/administrations, or 6 and 21 day after 12 doses/administrations. Long-term administration is associated with continued and increased apoptosis without necrosis, suggestive of OTA's role in the pathogenesis of progressive renal atrophy.


Assuntos
Apoptose/efeitos dos fármacos , Carcinógenos/toxicidade , Rim/efeitos dos fármacos , Ocratoxinas/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Rim/patologia , Ratos , Ratos Wistar
19.
Arh Hig Rada Toksikol ; 53(4): 275-81, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12828128

RESUMO

This paper describes the effects of dichlorvos (DDVP) on butyrylcholinesterase (BuChE) activity with possible consequences for lipid and lipoprotein metabolism in rats. The rats of both sexes were given a single and multiple doses of DDVP (8.0 mg/kg body weight) with two-day intervals between administrations, ensuring the continuous inhibition of BuChE activity without lethal outcome. BuChE activity was measured in plasma, liver, and white and brown adipose tissue. The recovery of BuChE activity was observed only in white adipose tissue of female rats 10 days after treatment. Our results show that DDVP significantly decreases BuChE activity in female and male rat plasma (40-60%; P < 0.05), and significantly increases triglycerides (60-600%; P < 0.05) and total cholesterol (35-75%; P < 0.05). In contrast to the increased HDL-cholesterol (20-30%; P < 0.05), LDL-cholesterol decreased (30-40%; P < 0.05). The decrease of BuChE activity and the changes in concentrations of lipids and lipoproteins were observed throughout the experiment. Our results contribute to the hypothesis that BuChE may play a role in lipid and lipoprotein metabolism.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Diclorvós/farmacologia , Metabolismo dos Lipídeos , Animais , Feminino , Masculino , Ratos , Ratos Wistar
20.
Arh Hig Rada Toksikol ; 53(3): 185-90, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12557470

RESUMO

The paper describes the catalytic activity of butyrylcholinesterase (BuChE) measured in plasma, liver, white adipose tissue, heart, and brain of rats intraperitoneally administered a single non-lethal dose of cycloheximide (2.0 mg/kg body weight; CHM). The BuChE assay was performed on rats of both sexes either administered CHM or saline (controls), and killed 2, 3, 4, 5, 10 days later. A significant decrease of BuChE catalytic activity was observed in all tested tissues except plasma. In animals of both sexes, the lowest BuChE catalytic activity was found in the liver (2-6%), while it was higher in white adipose tissue, heart, and brain. However, the respective values remained significantly different from controls (33-67%, 49-62%, and 14-71% in males, and 24-82%, 72-86%, and 33-67% in females). Since there was no effect of CHM on BuChE catalytic activity in plasma, the data suggest that CHM inhibits the synthesis of BuChE rather than its active site.


Assuntos
Antifúngicos/farmacologia , Butirilcolinesterase/metabolismo , Cicloeximida/farmacologia , Inibidores Enzimáticos/farmacologia , Animais , Feminino , Masculino , Ratos , Ratos Wistar
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