Base de dados : MEDLINE
Pesquisa : D27.720.599 [Categoria DeCS]
Referências encontradas : 69 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 7 ir para página                  

  1 / 69 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27773692
[Au] Autor:Myhrer T; Aas P
[Ad] Endereço:Norwegian Defence Research Establishment (FFI), Protection and Societal Security Division, Kjeller, Norway.
[Ti] Título:Pretreatment and prophylaxis against nerve agent poisoning: Are undesirable behavioral side effects unavoidable?
[So] Source:Neurosci Biobehav Rev;71:657-670, 2016 12.
[Is] ISSN:1873-7528
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment (pyridostigmine) may cause some side effects in a small number of individuals. A comprehensive research on animals has been performed to clarify effects on behavior. The results from these studies are far from unambiguous, since pyridostigmine may produce adverse effects on behavior in animals in relatively high doses, but not in a consistent way. Other animal studies have examined the potential of drugs like physostigmine, galantamine, benactyzine, trihexyphenidyl, and procyclidine, but they all produce marked behavioral impairment at doses sufficient to contribute to protection against a convulsant dose of soman. Attempts have also been made to develop a combination of drugs capable of assuring full protection (prophylaxis) against nerve agents. However, common to all combinations is that they at anticonvulsant doses cause behavioral deficits. Therefore, the use of limited pretreatment doses may be performed without marked side effects followed by post-exposure therapy with a combination of drugs.
[Mh] Termos MeSH primário: Agentes Neurotóxicos/farmacologia
[Mh] Termos MeSH secundário: Animais
Benactizina
Inibidores da Colinesterase
Seres Humanos
Prociclidina
Soman
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Nerve Agents); 595EG71R3F (Benactyzine); 96-64-0 (Soman); C6QE1Q1TKR (Procyclidine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180124
[Lr] Data última revisão:
180124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


  2 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28743514
[Au] Autor:Herbert J; Thiermann H; Worek F; Wille T
[Ad] Endereço:Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
[Ti] Título:Precision cut lung slices as test system for candidate therapeutics in organophosphate poisoning.
[So] Source:Toxicology;389:94-100, 2017 08 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Standard therapeutic options in organophosphate (OP) poisoning are limited to the administration of atropine and oximes, a regimen often lacking in efficacy and applicability. Treatment alternatives are needed, preferably covering a broad spectrum of OP intoxications. Although recent research yielded several promising compounds, e.g. bioscavengers, modulators of the muscarinic acetylcholine (ACh) receptor or bispyridinium non-oximes, these substances still need further evaluation, especially regarding effects on the potentially lethal respiratory symptoms of OP poisoning. Aim of this study was the development of an applicable and easy method to test the therapeutic efficiency of such substances. For this purpose, airway responsiveness in viable precision cut lung slices (PCLS) from rats was analysed. We showed that ACh-induced airway contractions were spontaneously reversible in non-poisoned PCLS, whereas in OP poisoned PCLS, contractions were irreversible. This effect could be antagonized by addition of the standard therapeutic atropine, thereby presenting a clear indication for treatment efficiency. Now, candidate therapeutic compounds can be evaluated, based on their ability to counteract the irreversible airway contraction in OP poisoned PCLS.
[Mh] Termos MeSH primário: Antídotos/farmacologia
Atropina/farmacologia
Broncoconstrição/efeitos dos fármacos
Broncodilatadores/farmacologia
Descoberta de Drogas/métodos
Pulmão/efeitos dos fármacos
Antagonistas Muscarínicos/farmacologia
Contração Muscular/efeitos dos fármacos
Músculo Liso/efeitos dos fármacos
Agentes Neurotóxicos/toxicidade
Intoxicação por Organofosfatos/tratamento farmacológico
Organofosfatos/toxicidade
[Mh] Termos MeSH secundário: Acetilcolina/farmacologia
Animais
Relação Dose-Resposta a Droga
Pulmão/fisiopatologia
Masculino
Músculo Liso/fisiopatologia
Intoxicação por Organofosfatos/fisiopatologia
Ratos Wistar
Fatores de Tempo
Técnicas de Cultura de Tecidos
Sobrevivência de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidotes); 0 (Bronchodilator Agents); 0 (Muscarinic Antagonists); 0 (Nerve Agents); 0 (Organophosphates); 7C0697DR9I (Atropine); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


  3 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28983034
[Au] Autor:Connolly CN
[Ad] Endereço:School of Medicine and Centre for Environmental Change and Human Resilience (CECHR) University of Dundee, Scotland DD1 9SY, UK. c.n.connolly@dundee.ac.uk.
[Ti] Título:Nerve agents in honey.
[So] Source:Science;358(6359):38-39, 2017 10 06.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Mel
Agentes Neurotóxicos
[Mh] Termos MeSH secundário: Antibacterianos
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Nerve Agents)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE
[do] DOI:10.1126/science.aao6000


  4 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28892361
[Au] Autor:Dafferner AJ; Schopfer LM; Xiao G; Cashman JR; Yerramalla U; Johnson RC; Blake TA; Lockridge O
[Ad] Endereço:Eppley Institute, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
[Ti] Título:Immunopurification of Acetylcholinesterase from Red Blood Cells for Detection of Nerve Agent Exposure.
[So] Source:Chem Res Toxicol;30(10):1897-1910, 2017 Oct 16.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nerve agents and organophosphorus pesticides make a covalent bond with the active site serine of acetylcholinesterase (AChE), resulting in inhibition of AChE activity and toxic symptoms. AChE in red blood cells (RBCs) serves as a surrogate for AChE in the nervous system. Mass spectrometry analysis of adducts on RBC AChE could provide evidence of exposure. Our goal was to develop a method of immunopurifying human RBC AChE in quantities adequate for detecting exposure by mass spectrometry. For this purpose, we immobilized 3 commercially available anti-human acetylcholinesterase monoclonal antibodies (AE-1, AE-2, and HR2) plus 3 new monoclonal antibodies. The monoclonal antibodies were characterized for binding affinity, epitope mapping by pairing analysis, and nucleotide and amino acid sequences. AChE was solubilized from frozen RBCs with 1% (v/v) Triton X-100. A 16 mL sample containing 5.8 µg of RBC AChE was treated with a quantity of soman model compound that inhibited 50% of the AChE activity. Native and soman-inhibited RBC AChE samples were immunopurified on antibody-Sepharose beads. The immunopurified RBC AChE was digested with pepsin and analyzed by liquid chromatography tandem mass spectrometry on a 6600 Triple-TOF mass spectrometer. The aged soman-modified PheGlyGluSerAlaGlyAlaAlaSer (FGESAGAAS) peptide was detected using a targeted analysis method. It was concluded that all 6 monoclonal antibodies could be used to immunopurify RBC AChE and that exposure to nerve agents could be detected as adducts on the active site serine of RBC AChE.
[Mh] Termos MeSH primário: Acetilcolinesterase/isolamento & purificação
Eritrócitos/enzimologia
Imunoprecipitação
Agentes Neurotóxicos/análise
[Mh] Termos MeSH secundário: Acetilcolinesterase/imunologia
Acetilcolinesterase/metabolismo
Seres Humanos
Espectrometria de Massas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Agents); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00209


  5 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28712549
[Au] Autor:Weissberg A; Madmon M; Elgarisi M; Dagan S
[Ad] Endereço:Department of Analytical Chemistry, Israel Institute for Biological Research (IIBR), P.O.B. 19, Ness Ziona, Israel. Electronic address: aviwe@iibr.gov.il.
[Ti] Título:Determination of trace amounts of G-type nerve agents in aqueous samples utilizing "in vial" instantaneous derivatization and liquid chromatography-tandem mass spectrometry.
[So] Source:J Chromatogr A;1512:71-77, 2017 Aug 25.
[Is] ISSN:1873-3778
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A methodology for sensitive determination of sarin (GB), soman (GD) and cyclosarin (GF) chemical warfare agents in aqueous media was developed. The method incorporates direct derivatization with 2-[(dimethylamino)methyl]phenol (2-DMAMP), a commercially available, water-soluble reagent, followed by LC-ESI-MS/MS analysis in the positive ion mode. Five derivatization agents were characterized for their MS/MS fragmentation pattern, and their reaction time, temperature and derivatization-reagent amount were optimized. The developed derivatization reaction is simple, fast (1min) and proceeds at ambient temperature. Sample preparation consists of only the addition of the reagent directly into an injection vial prior to LC-ESI(+)-MS/MS analysis. All 2-DMAMP derivatives were stable for at least 48h and had unique tandem mass spectra characterized by common product ions at m/z 230 and 185. Compared with conventional GC-MS or LC-MS methods, simplicity, better sensitivity and informative MS/MS spectra were achieved by this method. Limits of detection (LODs), identification (LOIs), and quantification (LOQs) were determined in tap water and found to be 1pg/ml, 4pg/ml and 4pg/ml respectively. The proposed methodology is appropriate for routine evaluation of contaminated water supplies and has the advantage of a simultaneous analysis of both derivatized G-nerve agents and their intact hydrolysis products within a single LC-MS analysis.
[Mh] Termos MeSH primário: Substâncias para a Guerra Química/química
Cromatografia Líquida/métodos
Agentes Neurotóxicos/química
Espectrometria de Massas em Tandem/métodos
Poluentes Químicos da Água/química
[Mh] Termos MeSH secundário: Cromatografia Gasosa-Espectrometria de Massas
Hidrólise
Limite de Detecção
Sarina/química
Soman/química
Espectrometria de Massas em Tandem/instrumentação
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemical Warfare Agents); 0 (Nerve Agents); 0 (Water Pollutants, Chemical); 96-64-0 (Soman); B4XG72QGFM (Sarin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE


  6 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28531843
[Au] Autor:Baygildiev T; Zatirakha A; Rodin I; Braun A; Stavrianidi A; Koryagina N; Rybalchenko I; Shpigun O
[Ad] Endereço:Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, GSP-1, Moscow 119991, Russia.
[Ti] Título:Rapid IC-MS/MS determination of methylphosphonic acid in urine of rats exposed to organophosphorus nerve agents.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1058:32-39, 2017 Jul 15.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A direct approach for the determination of a specific hydrolysis product of organophosphorus nerve agents such as methylphosphonic acid (MPA) in urine by ion chromatography and tandem mass spectrometry (IC-MS/MS) has been developed. The first advantage of the proposed approach is a rapid and simple sample preparation, which does not require a large sample volume, complicated and laborious preconcentration and derivatization steps, and takes less than 7min per sample. The second advantage is the fast and selective IC determination of MPA carried out on a noncommercial anion exchanger based on a poly(styrene-co-divinylbenzene) (PS-DVB) substrate with a high degree of crosslinking and a covalently-bonded branched functional layer, which enables complete resolution of MPA from major urine matrix components and allows one to overcome matrix effects. Hyphenation of IC with tandem mass spectrometry results in highly sensitive and reliable MPA determination with the lowest detection limit (4ngmL ) reported so far for HPLC determination of MPA in urine. The proposed approach is successfully applied for the analysis of urine from rats exposed to nonlethal doses of organophosphorus nerve agents such as sarin, soman, and VR in up to 13days after initial exposure, which shows the possibility to verify the nerve agent exposure after a long period of time.
[Mh] Termos MeSH primário: Agentes Neurotóxicos/metabolismo
Compostos Organofosforados/urina
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Animais
Limite de Detecção
Modelos Lineares
Compostos Organofosforados/metabolismo
Compostos Organotiofosforados/administração & dosagem
Compostos Organotiofosforados/metabolismo
Ratos
Reprodutibilidade dos Testes
Sarina/administração & dosagem
Sarina/metabolismo
Soman/administração & dosagem
Soman/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Agents); 0 (Organophosphorus Compounds); 0 (Organothiophosphorus Compounds); 0 (S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate); 329W4YM10Z (methylphosphonic acid); 96-64-0 (Soman); B4XG72QGFM (Sarin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE


  7 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28434709
[Au] Autor:Seto Y; Tachikawa M; Kanamori-Kataoka M; Sasamoto K; Ochiai N
[Ad] Endereço:National Research Institute of Police Science, Kashiwa, Chiba 277-0882, Japan. Electronic address: seto@nrips.go.jp.
[Ti] Título:Target analysis of tert-butyldimethylsilyl derivatives of nerve agent hydrolysis products by selectable one-dimensional or two-dimensional gas chromatography-mass spectrometry.
[So] Source:J Chromatogr A;1501:99-106, 2017 Jun 09.
[Is] ISSN:1873-3778
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A target analysis method for the sensitive and discriminative determination of the nerve agent hydrolysis products alkyl methylphosphonic acids as their tert-butyldimethylsilyl (TBDMS) derivatives was developed using a combination of selectable one- and two-dimensional ( D/ D) GC-MS, and applied to the analysis of samples with significant interfering matrices. After sample drying, the alkylmethylphosphonic acids and methylphosphonic acid (MPA) were converted to TBDMS derivatives by addition of N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide with heating, and subjected to D/ D GC-MS. The apparatus consisted of an initial low thermal mass DB-5 column and a second DB-17 column together with an electron ionization quadrupole mass spectrometer, offering simple and flexible switching between one- and two-dimensional GC-MS analysis in a single GC-MS system. Using D/ D GC-MS, analytes that do not co-elute with matrix components can be separated using D GC mode alone. Only those parts of the chromatogram that are negatively affected by the co-elution of matrix components need to be transferred and separated with D GC. Quantitation can be performed by a combination of both separations and mass spectrometric detection. The TBDMS derivatives of ethyl-, isopropyl-, isobutyl-, pinacolyl-, and cyclohexyl-MPA (cHMPA) and MPA itself were well separated within 3min and determined in D GC-MS mode with detection limits of around 10ng/ml of reaction mixture (except for the cHMPA derivative, whose mass spectrum contained noisy background peaks). In D-GC-MS mode, where each 0.04min elution window from the D GC was subjected to heart-cut (H/C) and transferred to the second column after back-flushing the first column, the peak for the cHMPA TBDMS derivative was isolated and afforded a clean mass spectrum within 6min. The recoveries of all the derivatives on D GC from D GC were estimated to be over 66%, and the detection limits were around 10ng/ml of reaction mixture. In the presence of urine extract, the target compounds were not detected as separated peaks in D GC-MS mode (except for isobutyl-MPA), and quantification based on extracted ion monitoring could not be achieved. However, D GC-MS of the H/C fractions of the target derivatives gave single peaks with well-defined mass spectra, and the recoveries of the derivatives were over 70% except for cHMPA (31% at 1.25µg/ml). Phosphonic acids could be detected at less than 60ng/ml. Sulfuric acid and phosphoric acid also negatively affected the determination of alkyl methylphosphonic acid TBDMS derivatives in D GC-MS, and the MPA-TBDMS-derivative peak was completely obscured by the large sulfuric-acid-derivative peak. However, under D/ D GC-MS conditions, baseline separation of the MPA derivative and sulfuric acid derivative was achieved, enabling highly sensitive MPA detection at 20ng/ml.
[Mh] Termos MeSH primário: Cromatografia Gasosa-Espectrometria de Massas/métodos
Agentes Neurotóxicos/química
Compostos Organofosforados/química
[Mh] Termos MeSH secundário: Cromatografia Gasosa-Espectrometria de Massas/instrumentação
Seres Humanos
Hidrólise
Estrutura Molecular
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Agents); 0 (Organophosphorus Compounds); 329W4YM10Z (methylphosphonic acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE


  8 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28267914
[Au] Autor:Carmany D; Walz AJ; Hsu FL; Benton B; Burnett D; Gibbons J; Noort D; Glaros T; Sekowski JW
[Ad] Endereço:Excet, Inc. , 6225 Brandon Avenue, Suite 360, Springfield, Virginia 22150, United States.
[Ti] Título:Activity Based Protein Profiling Leads to Identification of Novel Protein Targets for Nerve Agent VX.
[So] Source:Chem Res Toxicol;30(4):1076-1084, 2017 Apr 17.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects. These are important for establishing a comprehensive understanding of the toxic mechanisms of OP nerve agents. To identify novel proteins that interact with VX, and that may give insight into these other mechanisms, we used activity-based protein profiling (ABPP) employing a novel VX-probe on lysates from rat heart, liver, kidney, diaphragm, and brain tissue. By making use of a biotin linked VX-probe, proteins covalently bound by the probe were isolated and enriched using streptavidin beads. The proteins were then digested, labeled with isobarically distinct tandem mass tag (TMT) labels, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative analysis identified 132 bound proteins, with many proteins found in multiple tissues. As with previously published ABPP OP work, monoacylglycerol lipase associated proteins and fatty acid amide hydrolase (FAAH) were shown to be targets of VX. In addition to these two and other predicted neurotransmitter-related proteins, a number of proteins involved with energy metabolism were identified. Four of these enzymes, mitochondrial isocitrate dehydrogenase 2 (IDH2), isocitrate dehydrogenase 3 (IDH3), malate dehydrogenase (MDH), and succinyl CoA (SCS) ligase, were assayed for VX inhibition. Only IDH2 NADP+ activity was shown to be inhibited directly. This result is consistent with other work reporting animals exposed to OP compounds exhibit reduced IDH activity. Though clearly a secondary mechanism for toxicity, this is the first time VX has been shown to directly interfere with energy metabolism. Taken together, the ABPP work described here suggests the discovery of novel protein-agent interactions, which could be useful for the development of novel diagnostics or potential adjuvant therapeutics.
[Mh] Termos MeSH primário: Agentes Neurotóxicos/química
Compostos Organotiofosforados/química
Proteínas/química
[Mh] Termos MeSH secundário: Amidoidrolases/química
Amidoidrolases/metabolismo
Animais
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Cromatografia Líquida de Alta Pressão
Coração/efeitos dos fármacos
Isocitrato Desidrogenase/química
Isocitrato Desidrogenase/metabolismo
Rim/efeitos dos fármacos
Rim/metabolismo
Fígado/efeitos dos fármacos
Fígado/metabolismo
Malato Desidrogenase/química
Malato Desidrogenase/metabolismo
Masculino
Agentes Neurotóxicos/toxicidade
Compostos Organotiofosforados/toxicidade
Peptídeos/análise
Isoformas de Proteínas/química
Isoformas de Proteínas/metabolismo
Proteínas/metabolismo
Ratos
Ratos Sprague-Dawley
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Agents); 0 (Organothiophosphorus Compounds); 0 (Peptides); 0 (Protein Isoforms); 0 (Proteins); 9A4381183B (VX); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.41 (Isocitrate Dehydrogenase); EC 3.5.- (Amidohydrolases); EC 3.5.1.- (fatty-acid amide hydrolase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170426
[Lr] Data última revisão:
170426
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.6b00438


  9 / 69 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28179194
[Au] Autor:Thors L; Lindberg S; Johansson S; Koch B; Koch M; Hägglund L; Bucht A
[Ad] Endereço:Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden. Electronic address: lina.thors@foi.se.
[Ti] Título:RSDL decontamination of human skin contaminated with the nerve agent VX.
[So] Source:Toxicol Lett;269:47-54, 2017 Mar 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dermal exposure to low volatile organophosphorus compounds (OPC) may lead to penetration through the skin and uptake in the blood circulation. Skin decontamination of toxic OPCs, such as pesticides and chemical warfare nerve agents, might therefore be crucial for mitigating the systemic toxicity following dermal exposure. Reactive skin decontamination lotion (RSDL) has been shown to reduce toxic effects in animals dermally exposed to the nerve agent VX. In the present study, an in vitro flow-through diffusion cell was utilized to evaluate the efficacy of RSDL for decontamination of VX exposed to human epidermis. In particular, the impact of timing in the initiation of decontamination and agent dilution in water was studied. The impact of the lipophilic properties of VX in the RSDL decontamination was additionally addressed by comparing chemical degradation in RSDL and decontamination efficacy between the VX and the hydrophilic OPC triethyl phosphonoacetate (TEPA). The epidermal membrane was exposed to 20, 75 or 90% OPC diluted in deionized water and the decontamination was initiated 5, 10, 30, 60 or 120min post-exposure. Early decontamination of VX with RSDL, initiated 5-10min after skin exposure, was very effective. Delayed decontamination initiated 30-60min post-exposure was less effective but still the amount of penetrated agent was significantly reduced, while further delayed start of decontamination to 120min resulted in very low efficacy. Comparing RSDL decontamination of VX with that of TEPA showed that the decontamination efficacy at high agent concentrations was higher for VX. The degradation mechanism of VX and TEPA during decontamination was dissected by P NMR spectroscopy of the OPCs following reactions with RSDL and its three nucleophile components. The degradation rate was clearly associated with the high pH of the specific solution investigated; i.e. increased pH resulted in a more rapid degradation. In addition, the solubility of the OPC in RSDL also influenced the degradation rate since the degradation of VX was significantly faster when the NMR analysis was performed in the organic solvent acetonitrile compared to water. In conclusion, we have applied the in vitro flow-through diffusion cell for evaluation of skin decontamination procedures of human epidermis exposed to OPCs. It was demonstrated that early decontamination is crucial for efficient mitigation of epidermal penetration of VX and that almost complete removal of the nerve agent from the skin surface is possible. Our data also indicate that the pH of RSDL together with the solubility of OPC in RSDL are of primary importance for the decontamination efficacy.
[Mh] Termos MeSH primário: Descontaminação/métodos
Agentes Neurotóxicos/toxicidade
Compostos Organotiofosforados/toxicidade
Pele/efeitos dos fármacos
[Mh] Termos MeSH secundário: Administração Cutânea
Seres Humanos
Concentração de Íons de Hidrogênio
Espectroscopia de Ressonância Magnética
Compostos Organofosforados/toxicidade
Ácido Fosfonoacéticos/análogos & derivados
Ácido Fosfonoacéticos/toxicidade
Pele/metabolismo
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nerve Agents); 0 (Organophosphorus Compounds); 0 (Organothiophosphorus Compounds); 867-13-0 (triethyl phosphonoacetate); 9A4381183B (VX); N919E46723 (Phosphonoacetic Acid)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170321
[Lr] Data última revisão:
170321
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE


  10 / 69 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28159998
[Au] Autor:Goldsmith M; Aggarwal N; Ashani Y; Jubran H; Greisen PJ; Ovchinnikov S; Leader H; Baker D; Sussman JL; Goldenzweig A; Fleishman SJ; Tawfik DS
[Ad] Endereço:Department of Biomolecular Sciences, Weizmann Institute of Science, 234 Herzel St, Rehovot 7610001, Israel.
[Ti] Título:Overcoming an optimization plateau in the directed evolution of highly efficient nerve agent bioscavengers.
[So] Source:Protein Eng Des Sel;30(4):333-345, 2017 Apr 01.
[Is] ISSN:1741-0134
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Improving an enzyme's initially low catalytic efficiency with a new target substrate by an order of magnitude or two may require only a few rounds of mutagenesis and screening or selection. However, subsequent rounds of optimization tend to yield decreasing degrees of improvement (diminishing returns) eventually leading to an optimization plateau. We aimed to optimize the catalytic efficiency of bacterial phosphotriesterase (PTE) toward V-type nerve agents. Previously, we improved the catalytic efficiency of wild-type PTE toward the nerve agent VX by 500-fold, to a catalytic efficiency (kcat/KM) of 5 × 106 M-1 min-1. However, effective in vivo detoxification demands an enzyme with a catalytic efficiency of >107 M-1 min-1. Here, following eight additional rounds of directed evolution and the computational design of a stabilized variant, we evolved PTE variants that detoxify VX with a kcat/KM ≥ 5 × 107 M-1 min-1 and Russian VX (RVX) with a kcat/KM ≥ 107 M-1 min-1. These final 10-fold improvements were the most time consuming and laborious, as most libraries yielded either minor or no improvements. Stabilizing the evolving enzyme, and avoiding tradeoffs in activity with different substrates, enabled us to obtain further improvements beyond the optimization plateau and evolve PTE variants that were overall improved by >5000-fold with VX and by >17 000-fold with RVX. The resulting variants also hydrolyze G-type nerve agents with high efficiency (GA, GB at kcat/KM > 5 × 107 M-1 min-1) and can thus serve as candidates for broad-spectrum nerve-agent prophylaxis and post-exposure therapy using low enzyme doses.
[Mh] Termos MeSH primário: Proteínas de Bactérias
Evolução Molecular Direcionada/métodos
Agentes Neurotóxicos/química
Diester Fosfórico Hidrolases
[Mh] Termos MeSH secundário: Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Diester Fosfórico Hidrolases/química
Diester Fosfórico Hidrolases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Nerve Agents); EC 3.1.4.- (Phosphoric Diester Hydrolases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170205
[St] Status:MEDLINE
[do] DOI:10.1093/protein/gzx003



página 1 de 7 ir para página                  
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde