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[PMID]:28941624
[Au] Autor:Malfatti MA; Enright HA; Be NA; Kuhn EA; Hok S; McNerney MW; Lao V; Nguyen TH; Lightstone FC; Carpenter TS; Bennion BJ; Valdez CA
[Ad] Endereço:Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA; Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA. Electronic address: malfatti1@llnl.gov.
[Ti] Título:The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs.
[So] Source:Chem Biol Interact;277:159-167, 2017 Nov 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t of ∼1 h. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The C in the brain ranged between 0.03 and 0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.
[Mh] Termos MeSH primário: Acetamidas/farmacocinética
Reativadores da Colinesterase/farmacocinética
Oximas/farmacocinética
[Mh] Termos MeSH secundário: Acetamidas/administração & dosagem
Acetilcolinesterase/metabolismo
Animais
Barreira Hematoencefálica/metabolismo
Reativadores da Colinesterase/administração & dosagem
Cobaias
Rim/metabolismo
Masculino
Oximas/administração & dosagem
Oximas/metabolismo
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Cholinesterase Reactivators); 0 (Oximes); 0 (RS194B); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170925
[St] Status:MEDLINE


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[PMID]:28693885
[Au] Autor:Rosenberg YJ; Mao L; Jiang X; Lees J; Zhang L; Radic Z; Taylor P
[Ad] Endereço:PlantVax Inc, Rockville, MD 20850, USA. Electronic address: yjr@plantvax.com.
[Ti] Título:Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor.
[So] Source:Chem Biol Interact;274:50-57, 2017 Aug 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Organophosphate (OP) nerve agents and pesticides trigger a common mechanism of neurotoxicity resulting from critical targeting and inhibition of acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Therapeutic countermeasures have thus focused on either administering an oxime post-exposure, that can rapidly reactivate OP-inhibited AChE, or by preventing OP poisoning through administering pre-exposure treatments that scavenge OPs before they inhibit their physiological AChE targets. While several pyridinium aldoxime antidotes are currently approved, their utility is impaired due to their inability to cross the blood-brain barrier (BBB) efficiently. The present study utilized a macaque (Ma) model to demonstrate the efficacy of a novel zwitterionic and centrally acting oxime RS194B to reactivate sarin- and paraoxon-inhibited macaque AChE and butyrylcholinesterase (BChE) in vitro and to further assess the capacity of RS194B to effect a reversal of clinical symptoms following sarin inhalation in vivo. In vitro, oxime reactivation of MaAChE and MaBChE was shown to be comparable to their human orthologs, while the macaque studies indicated that IM administration of 62.5 mg/kg of RS194B and 0.28 mg/kg atropine after continuous exposure to 49.6 µg/kg sarin vapor, rapidly reactivated the inhibited AChE and BChE in blood and reversed both early and advanced clinical symptoms of sarin-induced toxicity following pulmonary exposure within 1 h. The rapid cessation of autonomic and central symptoms, including convulsions, observed in macaques bodes well for the use of RS194B as an intra- or post-exposure human treatment and validates the macaque model in generating efficacy and toxicology data required for approval under the FDA Animal rule.
[Mh] Termos MeSH primário: Acetamidas/farmacologia
Reativadores da Colinesterase/farmacologia
Oximas/farmacologia
[Mh] Termos MeSH secundário: Acetamidas/administração & dosagem
Acetamidas/química
Acetilcolinesterase/sangue
Acetilcolinesterase/química
Acetilcolinesterase/genética
Acetilcolinesterase/metabolismo
Animais
Butirilcolinesterase/sangue
Butirilcolinesterase/química
Butirilcolinesterase/genética
Butirilcolinesterase/metabolismo
Substâncias para a Guerra Química/toxicidade
Reativadores da Colinesterase/administração & dosagem
Reativadores da Colinesterase/química
Gases/química
Inalação
Macaca/metabolismo
Modelos Animais
Oximas/administração & dosagem
Oximas/química
Paraoxon/toxicidade
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
Sarina/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Chemical Warfare Agents); 0 (Cholinesterase Reactivators); 0 (Gases); 0 (Oximes); 0 (RS194B); 0 (Recombinant Proteins); B4XG72QGFM (Sarin); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase); Q9CX8P80JW (Paraoxon)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE


  3 / 1113 MEDLINE  
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[PMID]:28684009
[Au] Autor:Wei Z; Liu YQ; Wang SZ; Yao L; Nie HF; Wang YA; Liu XY; Zheng ZB; Li S
[Ad] Endereço:Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an 300071, China. Electronic address: weizhaobruce@163.com.
[Ti] Título:Conjugates of salicylaldoximes and peripheral site ligands: Novel efficient nonquaternary reactivators for nerve agent-inhibited acetylcholinesterase.
[So] Source:Bioorg Med Chem;25(16):4497-4505, 2017 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A new family of nonquaternary reactivators for nerve agent-inhibited human acetylcholinesterase (hAChE) were designed, synthesized and tested in this paper. It was found that salicylaldoximes were able to quickly cleave the P-S bond of organophosphate and avoid the reinhibition phenomenon in the reactivation process, but they lacked reactivating ability due to poor affinity for AChE. Based on a dual site binding strategy, different peripheral site ligands of AChE were introduced to achieve extra affinity. The in vitro reactivation experiments demonstrated that some of the yielding conjugates exhibited similar or even superior ability to reactivate sarin-, VX- or tabun-inhibited hAChE in comparison with the mono- and bis-pyridinium aldoximes currently used. Moreover, due to greatly improved lipophilicity, these nonquaternary conjugates hold promise for the development of efficient centrally activating reactivators.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Reativadores da Colinesterase/farmacologia
Oximas/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Inibidores da Colinesterase/farmacologia
Reativadores da Colinesterase/síntese química
Reativadores da Colinesterase/química
Relação Dose-Resposta a Droga
Seres Humanos
Ligantes
Estrutura Molecular
Oximas/síntese química
Oximas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Cholinesterase Reactivators); 0 (Ligands); 0 (Oximes); 2QTV2A0T5Q (salicylaldoxime); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE


  4 / 1113 MEDLINE  
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[PMID]:28569609
[Au] Autor:Gorecki L; Korabecny J; Musilek K; Nepovimova E; Malinak D; Kucera T; Dolezal R; Jun D; Soukup O; Kuca K
[Ad] Endereço:a Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences , University of Defence , Hradec Kralove , Czech Republic.
[Ti] Título:Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006-2016).
[So] Source:Expert Opin Ther Pat;27(9):971-985, 2017 Sep.
[Is] ISSN:1744-7674
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function. Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication. Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.
[Mh] Termos MeSH primário: Antídotos/farmacologia
Reativadores da Colinesterase/farmacologia
Intoxicação por Organofosfatos/tratamento farmacológico
[Mh] Termos MeSH secundário: Acetilcolinesterase/efeitos dos fármacos
Acetilcolinesterase/metabolismo
Animais
Substâncias para a Guerra Química/envenenamento
Inibidores da Colinesterase/envenenamento
Desenho de Drogas
Seres Humanos
Intoxicação por Organofosfatos/fisiopatologia
Compostos Organofosforados/antagonistas & inibidores
Compostos Organofosforados/toxicidade
Patentes como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antidotes); 0 (Chemical Warfare Agents); 0 (Cholinesterase Inhibitors); 0 (Cholinesterase Reactivators); 0 (Organophosphorus Compounds); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1080/13543776.2017.1338275


  5 / 1113 MEDLINE  
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[PMID]:28542985
[Au] Autor:Masson P; Nachon F
[Ad] Endereço:Neuropharmacology Laboratory, Kazan Federal University, Kazan, Russia.
[Ti] Título:Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning.
[So] Source:J Neurochem;142 Suppl 2:26-40, 2017 Aug.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for post-exposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre- and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Barreira Hematoencefálica/efeitos dos fármacos
Inibidores da Colinesterase/farmacologia
Reativadores da Colinesterase/metabolismo
Fármacos Neuroprotetores/farmacologia
Intoxicação por Organofosfatos/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Barreira Hematoencefálica/metabolismo
Reativadores da Colinesterase/farmacologia
Seres Humanos
Intoxicação por Organofosfatos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Cholinesterase Reactivators); 0 (Neuroprotective Agents); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14026


  6 / 1113 MEDLINE  
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[PMID]:28343895
[Au] Autor:Karasova JZ; Kvetina J; Tacheci I; Radochova V; Musilek K; Kuca K; Bures J
[Ad] Endereço:Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital, Hradec Kralove, Czech Republic. Electronic address: zdarova.jana@gmail.com.
[Ti] Título:Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs.
[So] Source:Toxicol Lett;273:20-25, 2017 May 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Standard treatment of organophosphorus compounds (OPs) poisoning includes administration of an anti-muscarinic (atropine), anticonvulsive (diazepam) and acetylcholinesterase reactivator (oxime). From a wide group of newly synthesized oximes, oxime K027 and oxime K203 seem to be perspective compounds in some specific OPs intoxication. The available in vitro and in vivo preclinical data indicate that both oximes may be considered for potential human use. The main aim of this study was to establish plasmatic concentration curves of both oximes after intramuscular (i.m.) and intragastric (i.g.) application with subsequent pharmacokinetic analysis and study distribution after (i.m.) application on a non-rodent animal model (experimental pigs; 1500mg/animal). According to the results, both oximes had similar C (K027: 106±19µg/mL and K203: 111±8µg/mL) in T 19±5min, respectively, in 22±3min. Bioavailability of oxime K027 calculated as AUC (8389±1024minµg/mL) was halved compared to oxime K203 (16938±795minµg/mL). The highest concentration from peripheral tissues was found in the kidney and lung, but the brain concentrations stay very low, the plasma/brain ratio being approximately 1%. The applied doses were derived from the recommendation where it is possible to use three autoinjectors to save human life. The results provide us with knowledge about the pharmacokinetics and distribution of these new oximes and may help us to better estimate the human pharmacokinetic profile.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Reativadores da Colinesterase/farmacocinética
Oximas/farmacocinética
Compostos de Piridínio/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Área Sob a Curva
Reativadores da Colinesterase/administração & dosagem
Reativadores da Colinesterase/sangue
Cromatografia Líquida de Alta Pressão
Feminino
Injeções Intramusculares
Especificidade de Órgãos
Oximas/administração & dosagem
Oximas/sangue
Compostos de Piridínio/administração & dosagem
Compostos de Piridínio/sangue
Sus scrofa
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene); 0 (1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide); 0 (Cholinesterase Reactivators); 0 (Oximes); 0 (Pyridinium Compounds); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170328
[St] Status:MEDLINE


  7 / 1113 MEDLINE  
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[PMID]:28296779
[Au] Autor:Bao HX; Tong PJ; Li CX; Du J; Chen BY; Huang ZH; Wang Y
[Ad] Endereço:aFirst Clinical Medical College of Zhejiang Chinese Medical University bZhejiang Provincial Hospital of TCM cDepartment of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College dDepartment of Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou eInstitute of Neuroscience and Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou fDepartment of Transfusion, Lishui People's Hospital, Lishui, Zhejiang, China.
[Ti] Título:Efficacy of fresh packed red blood transfusion in organophosphate poisoning.
[So] Source:Medicine (Baltimore);96(11):e6375, 2017 Mar.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mortality rate caused by organophosphate (OP) poisoning is still high, even the standard treatment such as atropine and oxime improves a lot. To search for alternative therapies, this study was aimed to investigate the effects of packed red blood cell (RBC) transfusion in acute OP poisoning, and compare the therapeutic effects of RBCs at different storage times.Patients diagnosed with OP poisoning were included in this prospective study. Fresh RBCs (packed RBCs stored less than 10 days) and longer-storage RBCs (stored more than 10 days but less than 35 days) were randomly transfused or not into OP poisoning patients. Cholinesterase (ChE) levels in blood, atropine usage and durations, pralidoxime durations were measured.We found that both fresh and longer-storage RBCs (200-400 mL) significantly increased blood ChE levels 6 hours after transfusion, shortened the duration for ChE recovery and length of hospital stay, and reduced the usage of atropine and pralidoxime. In addition, fresh RBCs demonstrated stronger therapeutic effects than longer-storage RBCs.Packed RBCs might be an alternative approach in patients with OP poisoning, especially during early stages.
[Mh] Termos MeSH primário: Transfusão de Eritrócitos/métodos
Intoxicação por Organofosfatos/terapia
[Mh] Termos MeSH secundário: Doença Aguda
Atropina/uso terapêutico
Reativadores da Colinesterase/uso terapêutico
Colinesterases/sangue
Feminino
Lavagem Gástrica
Seres Humanos
Masculino
Intoxicação por Organofosfatos/tratamento farmacológico
Compostos de Pralidoxima/uso terapêutico
Estudos Prospectivos
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Cholinesterase Reactivators); 0 (Pralidoxime Compounds); 7C0697DR9I (Atropine); EC 3.1.1.8 (Cholinesterases); P7MU9UTP52 (pralidoxime)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170410
[Lr] Data última revisão:
170410
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000006375


  8 / 1113 MEDLINE  
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[PMID]:28106328
[Au] Autor:Driant T; Nachon F; Ollivier C; Renard PY; Derat E
[Ad] Endereço:Sorbonne Universités, UPMC UNIV Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place Jussieu, 75252, Paris Cedex 05, France.
[Ti] Título:On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach.
[So] Source:Chembiochem;18(7):666-675, 2017 Apr 04.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Acetylcholinesterase (AChE), an enzyme of the serine hydrolase superfamily, is a mediator of signal transmission at cholinergic synapses by catalyzing acetylcholine cleavage into acetate and choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds (like VX). Covalent inhibition of AChE does not revert spontaneously. Known reactivator compounds have limited action in restoring catalytic activity. QM/MM simulations of VX-inhibited AChE reactivation by pralidoxime (2-PAM), a classical reactivator, were performed. These afforded a broad view of the effect of protonation states of active-site residues, and provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM for both protonation states of Glu202 showed that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Because the active site of serine hydrolases is highly conserved, this work provides new insights on the interplay between the catalytic triad residues and this glutamate, newly identified as protonatable.
[Mh] Termos MeSH primário: Acetilcolinesterase/química
Reativadores da Colinesterase/química
[Mh] Termos MeSH secundário: Domínio Catalítico
Inibidores da Colinesterase/química
Simulação por Computador
Ácido Glutâmico/química
Histidina/química
Modelos Químicos
Estrutura Molecular
Organofosfatos/química
Compostos Organotiofosforados/química
Compostos de Pralidoxima/química
Prótons
Teoria Quântica
Serina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Cholinesterase Reactivators); 0 (Organophosphates); 0 (Organothiophosphorus Compounds); 0 (Pralidoxime Compounds); 0 (Protons); 3KX376GY7L (Glutamic Acid); 452VLY9402 (Serine); 4QD397987E (Histidine); 9A4381183B (VX); EC 3.1.1.7 (Acetylcholinesterase); P7MU9UTP52 (pralidoxime); S45M750QSH (tabun)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201600646


  9 / 1113 MEDLINE  
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[PMID]:28043192
[Au] Autor:Kassa J; Misik J; Hatlapatkova J; Zdarova Karasova J
[Ad] Endereço:a Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences , University of Defense , Hradec Kralove , Czech Republic.
[Ti] Título: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.
[So] Source:Toxicol Mech Methods;27(3):236-243, 2017 Mar.
[Is] ISSN:1537-6524
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo: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 (FOB). The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (130 µg/kg i.m.; 80% of LD value) were evaluated. Tabun-induced neurotoxicity was monitored by FOB at 2 h 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 h. 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.
[Mh] Termos MeSH primário: Reativadores da Colinesterase/uso terapêutico
Fármacos Neuroprotetores/uso terapêutico
Síndromes Neurotóxicas/prevenção & controle
Organofosfatos/toxicidade
Oximas/uso terapêutico
Compostos de Piridínio/uso terapêutico
Trimedoxima/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Reativadores da Colinesterase/química
Masculino
Estrutura Molecular
Fármacos Neuroprotetores/química
Síndromes Neurotóxicas/etiologia
Oximas/química
Compostos de Piridínio/química
Ratos Wistar
Trimedoxima/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene); 0 (Cholinesterase Reactivators); 0 (K920 compound); 0 (K923 compound); 0 (Neuroprotective Agents); 0 (Organophosphates); 0 (Oximes); 0 (Pyridinium Compounds); 56-97-3 (Trimedoxime); S45M750QSH (tabun)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170104
[St] Status:MEDLINE
[do] DOI:10.1080/15376516.2016.1275907


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[PMID]:27358236
[Au] Autor:Wille T; von der Wellen J; Thiermann H; Worek F
[Ad] Endereço:Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937, Munich, Germany. timowille@bundeswehr.org.
[Ti] Título:Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6.
[So] Source:Arch Toxicol;91(3):1309-1318, 2017 Mar.
[Is] ISSN:1432-0738
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Despite six decades of extensive research in medical countermeasures against nerve agent poisoning, a broad spectrum acetylcholinesterase (AChE) reactivator is not yet available. One current approach is directed toward synthesizing oximes with high affinity and reactivatability toward butyrylcholinesterase (BChE) in plasma to generate an effective pseudocatalytic scavenger. An interim solution could be the administration of external AChE or BChE from blood products to augment pseudocatalytic scavenging with slower but clinically approved oximes to decrease nerve agent concentrations in the body. We here semiquantitatively investigate the ability of obidoxime and HI-6 to decrease the inhibitory activity of VX with human AChE and BChE from whole blood, erythrocyte membranes, erythrocytes, plasma, clinically available fresh frozen plasma and packed red blood cells. The main findings are that whole blood showed a VX concentration-dependent decrease in inhibitory activity with HI-6 being more potent than obidoxime. Using erythrocytes and erythrocyte membranes again, HI-6 was more potent compared to obidoxime. With freshly prepared plasma, obidoxime and HI-6 showed comparable results for the decrease in VX. The use of the clinically available blood products revealed that packed red blood cells showed similar kinetics as fresh erythrocytes. Fresh frozen plasma resulted in a slower and incomplete decrease in inhibitory plasma compared to freshly prepared plasma. In conclusion, the administration of blood products in combination with available oximes augments pseudocatalytic scavenging and might be useful to decrease the body load of persistent, highly toxic nerve agents.
[Mh] Termos MeSH primário: Inibidores da Colinesterase/toxicidade
Cloreto de Obidoxima/farmacologia
Compostos Organotiofosforados/toxicidade
Oximas/farmacologia
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/sangue
Acetilcolinesterase/metabolismo
Sítios de Ligação
Coleta de Amostras Sanguíneas
Butirilcolinesterase/sangue
Butirilcolinesterase/metabolismo
Substâncias para a Guerra Química/toxicidade
Reativadores da Colinesterase/farmacologia
Membrana Eritrocítica/efeitos dos fármacos
Eritrócitos/efeitos dos fármacos
Eritrócitos/metabolismo
Congelamento
Seres Humanos
Inativação Metabólica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemical Warfare Agents); 0 (Cholinesterase Inhibitors); 0 (Cholinesterase Reactivators); 0 (Organothiophosphorus Compounds); 0 (Oximes); 0 (Pyridinium Compounds); 3HXR312Z9M (Obidoxime Chloride); 9A4381183B (VX); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase); HUV88P6SJS (asoxime chloride)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160701
[St] Status:MEDLINE
[do] DOI:10.1007/s00204-016-1776-x



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