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1.
Biochem Biophys Res Commun ; 599: 127-133, 2022 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-35180472

RESUMO

Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposure attenuated neutrophil recruitment to the lungs in mice suffering from experimental polymicrobial abdominal sepsis. We found that isoflurane attenuated one of major neutrophil chemoattractants LTB4 mediated response via its receptor BLT1 in neutrophils. Furthermore, we have shown that isoflurane directly bound to BLT1 by a competition assay using newly developed labeled BLT1 antagonist, suggesting that isoflurane would be a BLT1 antagonist.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Isoflurano/farmacologia , Sepse/complicações , Anestésicos Inalatórios/farmacologia , Animais , Quimiotaxia/efeitos dos fármacos , Modelos Animais de Doenças , Eicosanoides/metabolismo , Isoflurano/química , Isoflurano/metabolismo , Leucotrieno B4/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Receptores do Leucotrieno B4/antagonistas & inibidores , Receptores do Leucotrieno B4/química , Receptores do Leucotrieno B4/metabolismo , Sepse/fisiopatologia
2.
J Clin Monit Comput ; 36(3): 725-733, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33914229

RESUMO

Flow sensors are often sensitive to the presence of volatile anesthetics. However, this sensitivity provides a unique opportunity to combine flow sensors of differing technological principles as an alternative to measuring volatile anesthetic gas concentration, particularly for austere settings. To determine the feasibility of flow sensor fusion for volatile anesthetic concentrations monitoring, eight flow sensors were tested with isoflurane, sevoflurane, and desflurane, ranging in concentrations from 0-4.5%, 0-3.5%, and 0-18%, respectively. Pairs of flow sensors were fit to the volatile anesthetic gas concentration with a leave-one-out cross-validation method to reduce the likelihood of overfitting. Bland-Altman was used for the final evaluation of sensor pair performance. Several sensor pairs yielded limits of agreement comparable to the rated accuracy of a commercial infrared spectrometer. The ultrasonic and orifice-plate flowmeters yielded the most combinations of viable sensor pairs for all three volatile anesthetic gases. Conclusion: Measuring volatile anesthetic gases using flow sensor fusion is a feasible low-cost, low-maintenance alternative to infrared spectroscopy. In this study, testing was done under steady-state conditions in 100% oxygen. Further testing is necessary to ensure sensor fusion performance under conditions that are more reflective of the clinical use case.


Assuntos
Anestésicos Inalatórios , Isoflurano , Éteres Metílicos , Humanos , Isoflurano/química , Sevoflurano
3.
Biochem Biophys Res Commun ; 557: 254-260, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33894411

RESUMO

Isoflurane and sevoflurane are volatile anesthetics (VA) widely used in clinical practice to provide general anesthesia. We and others have previously shown that VAs have immunomodulatory effects and may have a significant impact on the progression of disease states. Flagellin is a component of Gram negative bacteria and plays a significant role in the pathophysiology of bacterial pneumonia through its binding to Toll-like Receptor 5 (TLR5). Our results showed that VAs, not an intravenous anesthetic, significantly attenuated the activation of TLR5 and the release of the neutrophil chemoattractant IL-8 from lung epithelial cells. Furthermore, flagellin-induced lung injury was significantly attenuated by VAs by inhibiting neutrophil migration to the bronchoalveolar space. The lungs of cystic fibrosis (CF) patients are highly colonized by Pseudomonas aeruginosa, which causes inflammation. The retrospective study of oxygenation in patients with CF who had received VA versus intravenous anesthesia suggested that VAs might have the protective effect for gas exchange. To understand the interaction between VAs and TLR5, a docking simulation was performed, which indicated that isoflurane and sevoflurane docked into the binding interphase between TLR5 and flagellin.


Assuntos
Anestésicos Inalatórios/farmacologia , Fibrose Cística/microbiologia , Células Epiteliais/efeitos dos fármacos , Flagelina/toxicidade , Inflamação/prevenção & controle , Pulmão/efeitos dos fármacos , Infecções por Pseudomonas/tratamento farmacológico , Receptor 5 Toll-Like/metabolismo , Anestésicos Inalatórios/química , Animais , Linhagem Celular Tumoral , Fibrose Cística/complicações , Células Epiteliais/metabolismo , Feminino , Flagelina/química , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-8/metabolismo , Isoflurano/química , Isoflurano/farmacologia , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/imunologia , Estudos Retrospectivos , Sevoflurano/química , Sevoflurano/farmacologia , Receptor 5 Toll-Like/química , Receptor 5 Toll-Like/genética
4.
FASEB J ; 34(11): 14645-14654, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32901993

RESUMO

Toll like receptors (TLRs) are critical receptors to respond to danger signals, and their functions are relevant in the perioperative period. We previously reported that volatile anesthetics directly bound to TLR2 and TLR4 and attenuated their functions. Given that TLR9 can respond to mitochondrial DNA, a danger signal that is released upon tissue injury, we examined the role of anesthetics on TLR9 function. Our reporter assay showed that volatile anesthetics isoflurane and sevoflurane increased the activation of TLR9, while propofol attenuated it. TLR9 activation occurs via its dimerization. The dimerization is facilitated by unmethylated cytosine-phosphate-guanine (CpG) DNA as well as DNA containing cytosine at the second position from 5'-end (5'-xCx DNA). Our structural analysis using photoactivable anesthetics and rigid docking simulation showed that isoflurane and sevoflurane bound to both TLR9 dimer interface and 5'-xCx DNA binding site. Propofol bound to the TLR9 antagonist binding site. This is the first illustration that anesthetics can affect the binding of nucleic acids to their receptor. This study sets the foundation for the effect of anesthetics on TLR9 and will pave the way for future studies to determine the significance of such interactions in the clinical setting.


Assuntos
Anestésicos Inalatórios/farmacologia , Isoflurano/farmacologia , Sevoflurano/farmacologia , Receptor Toll-Like 9/química , Anestésicos Inalatórios/química , Animais , Sítios de Ligação , Células HEK293 , Cavalos , Humanos , Isoflurano/química , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Multimerização Proteica , Sevoflurano/química , Receptor Toll-Like 9/metabolismo
5.
Electrophoresis ; 40(15): 1959-1965, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30900259

RESUMO

An enantioselective assay for the determination of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equine plasma based on capillary electrophoresis with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection is described. The assay is based on liquid/liquid extraction of the analytes at alkaline pH from 0.1 mL plasma followed by electrokinetic sample injection of the analytes from the extract across a buffer plug without chiral selector. Separation occurs cationically at normal polarity in a pH 3 phosphate buffer containing 0.16% (w/v) of highly sulfated γ-cyclodextrin. The developed assay is precise (intra- and interday RSD < 4% and < 7%, respectively), is capable to determine enantiomer levels of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in plasma down to 2.5 ng/mL, and was successfully applied to monitor enantiomer drug and metabolite levels in plasma of a pony that was anesthetized with racemic ketamine and isoflurane and received a bolus of racemic methadone and a bolus followed by constant rate infusion of racemic methadone. The data suggest that the assay is well suited for pharmacokinetic purposes.


Assuntos
Eletroforese Capilar/métodos , Isoflurano/farmacocinética , Ketamina/farmacocinética , Metadona , Pirrolidinas , Animais , Interações Medicamentosas , Cavalos , Isoflurano/sangue , Isoflurano/química , Ketamina/sangue , Ketamina/química , Metadona/sangue , Metadona/química , Metadona/farmacocinética , Pirrolidinas/sangue , Pirrolidinas/química , Pirrolidinas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estereoisomerismo
6.
Proc Natl Acad Sci U S A ; 113(48): 13762-13767, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27856739

RESUMO

Voltage-gated sodium channels (NaV) play an important role in general anesthesia. Electrophysiology measurements suggest that volatile anesthetics such as isoflurane inhibit NaV by stabilizing the inactivated state or altering the inactivation kinetics. Recent computational studies suggested the existence of multiple isoflurane binding sites in NaV, but experimental binding data are lacking. Here we use site-directed placement of 19F probes in NMR experiments to quantify isoflurane binding to the bacterial voltage-gated sodium channel NaChBac. 19F probes were introduced individually to S129 and L150 near the S4-S5 linker, L179 and S208 at the extracellular surface, T189 in the ion selectivity filter, and all phenylalanine residues. Quantitative analyses of 19F NMR saturation transfer difference (STD) spectroscopy showed a strong interaction of isoflurane with S129, T189, and S208; relatively weakly with L150; and almost undetectable with L179 and phenylalanine residues. An orientation preference was observed for isoflurane bound to T189 and S208, but not to S129 and L150. We conclude that isoflurane inhibits NaChBac by two distinct mechanisms: (i) as a channel blocker at the base of the selectivity filter, and (ii) as a modulator to restrict the pivot motion at the S4-S5 linker and at a critical hinge that controls the gating and inactivation motion of S6.


Assuntos
Flúor/química , Íons/química , Sódio/química , Canais de Sódio Disparados por Voltagem/química , Sítios de Ligação , Fenômenos Biofísicos , Ativação do Canal Iônico/genética , Isoflurano/química , Cinética , Espectroscopia de Ressonância Magnética , Sódio/metabolismo , Canais de Sódio Disparados por Voltagem/genética
7.
Proc Natl Acad Sci U S A ; 113(51): 14823-14828, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27911815

RESUMO

The prefrontal cortex (PFC) plays an important role in cognitive processes, including access to consciousness. The PFC receives significant cholinergic innervation and nicotinic acetylcholine receptors (nAChRs) contribute greatly to the effects of acetylcholine signaling. Using in vivo two-photon imaging of both awake and anesthetized mice, we recorded spontaneous, ongoing neuronal activity in layer II/III in the PFC of WT mice and mice deleted for different nAChR subunits. As in humans, this activity is characterized by synchronous ultraslow fluctuations and neuronal synchronicity is disrupted by light general anesthesia. Both the α7 and ß2 nAChR subunits play an important role in the generation of ultraslow fluctuations that occur to a different extent during quiet wakefulness and light general anesthesia. The ß2 subunit is specifically required for synchronized activity patterns. Furthermore, chronic application of mecamylamine, an antagonist of nAChRs, disrupts the generation of ultraslow fluctuations. Our findings provide new insight into the ongoing spontaneous activity in the awake and anesthetized state, and the role of cholinergic neurotransmission in the orchestration of cognitive functions.


Assuntos
Estado de Consciência/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores Colinérgicos/metabolismo , Receptores Nicotínicos/metabolismo , Acetilcolina/química , Anestesia Geral , Animais , Deleção de Genes , Isoflurano/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Fenótipo , Polimorfismo Genético , Transdução de Sinais/fisiologia , Transmissão Sináptica/efeitos dos fármacos
8.
J Occup Environ Hyg ; 16(4): 294-301, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852983

RESUMO

International guidelines recommend the use of ventilation systems in operating rooms to reduce the concentration of potentially hazardous substances such as anesthetic gases. The exhaust air grilles of these systems are typically located in the lower corners of the operating room and pick up two-thirds of the air volume, whereas the final third is taken from near the ceiling, which guarantees an optimal perfusion of the operating room with a sterile filtered air supply. However, this setup is also employed because anesthetic gases have a higher molecular weight than the components of air and should pool on the floor if movement is kept to a minimum and if a ventilation system with a unidirectional displacement flow is employed. However, this anticipated pooling of volatile anesthetics at the floor level has never been proven. Thus, we herein investigated the flow behaviors of isoflurane, sevoflurane, and carbon dioxide (for comparison) in a measuring chamber sized 2.46 × 1.85 × 5.40 m with a velocity of 0.3 m/sec and a degree of turbulence <20%. Gas concentrations were measured at 1,728 measuring positions throughout the measuring chamber, and the flow behaviors of isoflurane and sevoflurane were found to be similar, with an overlap of 90%. The largest spread of both gases was 55 cm at 5.4 m from the emission source. Interestingly, neither isoflurane nor sevoflurane was detected at floor level, but a continuous cone-like spreading was observed due to gravity. In contrast, carbon dioxide accumulated at floor level in the form of a gas cloud. Thus, floor level exhaust ventilation systems are likely unsuitable for the collection and removal of anesthetic gases from operating rooms.


Assuntos
Isoflurano/química , Salas Cirúrgicas , Sevoflurano/química , Movimentos do Ar , Poluentes Ocupacionais do Ar/química , Anestésicos Inalatórios/química , Dióxido de Carbono/química , Cinética , Ventilação
9.
J Biol Chem ; 292(23): 9480-9492, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28420728

RESUMO

General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand-gated ion channels. Although numerous studies have focused on pentameric ligand-gated ion channels, the details of anesthetic binding and channel modulation are still debated. A better understanding of the anesthetic mechanism of action is necessary for the development of safer and more efficacious drugs. Herein, we present a computational study identifying two anesthetic binding sites in the transmembrane domain of the Gloeobacter violaceus ligand-gated ion channel (GLIC) channel, characterize the putative binding pathway, and observe structural changes associated with channel function. Molecular simulations of desflurane reveal a binding pathway to GLIC via a membrane-embedded tunnel using an intrasubunit protein lumen as the conduit, an observation that explains the Meyer-Overton hypothesis, or why the lipophilicity of an anesthetic and its potency are generally proportional. Moreover, employing high concentrations of ligand led to the identification of a second transmembrane site (TM2) that inhibits dissociation of anesthetic from the TM1 site and is consistent with the high concentrations of anesthetics required to achieve clinical effects. Finally, asymmetric binding patterns of anesthetic to the channel were found to promote an iris-like conformational change that constricts and dehydrates the ion pore, creating a 13.5 kcal/mol barrier to ion translocation. Together with previous studies, the simulations presented herein demonstrate a novel anesthetic binding site in GLIC that is accessed through a membrane-embedded tunnel and interacts with a previously known site, resulting in conformational changes that produce a non-conductive state of the channel.


Assuntos
Anestésicos Inalatórios/química , Proteínas de Bactérias , Membrana Celular , Cianobactérias , Isoflurano/análogos & derivados , Canais Iônicos de Abertura Ativada por Ligante , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Membrana Celular/química , Membrana Celular/metabolismo , Cianobactérias/química , Cianobactérias/metabolismo , Desflurano , Transporte de Íons/fisiologia , Isoflurano/química , Canais Iônicos de Abertura Ativada por Ligante/química , Canais Iônicos de Abertura Ativada por Ligante/metabolismo
10.
Magn Reson Med ; 79(4): 2183-2189, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28833448

RESUMO

PURPOSE: To develop a chemical shift encoding (CSE) approach for fluorine-19 MRI of perfluorocarbons in the presence of multiple known fluorinated chemical species. THEORY AND METHODS: A multi-echo CSE technique is applied for spectral separation of the perfluorocarbon perfluoro-15-crown-5-ether (PFCE) and isoflurane (ISO) based on their chemical shifts at 4.7 T. Cramér-Rao lower bound analysis is used to identify echo combinations with optimal signal-to-noise performance. Signal contributions are fit with a multispectral fluorine signal model using a non-linear least squares estimation reconstruction directly from k-space data. This CSE approach is tested in fluorine-19 phantoms and in a mouse with a 2D and 3D spoiled gradient-echo acquisition using multiple echo times determined from Cramér-Rao lower bound analysis. RESULTS: Cramér-Rao lower bound analysis for PFCE and ISO separation shows signal-to-noise performance is maximized with a 0.33 ms echo separation. A linear behavior (R2 = 0.987) between PFCE signal and known relative PFCE volume is observed in CSE reconstructed images using a mixed PFCE/ISO phantom. Effective spatial and spectral separation of PFCE and ISO is shown in phantoms and in vivo. CONCLUSION: Feasibility of a gradient-echo CSE acquisition and image reconstruction approach with optimized noise performance is demonstrated through fluorine-19 MRI of PFCE with effective removal of ISO signal contributions. Magn Reson Med 79:2183-2189, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Assuntos
Imagem por Ressonância Magnética de Flúor-19 , Animais , Simulação por Computador , Meios de Contraste/química , Éteres de Coroa/química , Humanos , Processamento de Imagem Assistida por Computador/métodos , Isoflurano/química , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Estatísticos , Imagens de Fantasmas , Razão Sinal-Ruído
11.
Chemistry ; 23(33): 7871-7875, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28432702

RESUMO

The uptake of inhalation anesthetics by three topologically identical frameworks is described. The 3D network materials, which possess square channels of different dimensions, are formed from the relatively simple combination of ZnII centres and dianionic ligands that contain a phenolate and a carboxylate group at opposite ends. All three framework materials are able to adsorb N2 O, Xe and isoflurane. Whereas the framework with the widest channels is able to adsorb large quantities of the various guests from the gas phase, the frameworks with the narrower channels have superior binding enthalpies and exhibit higher levels of retention. The use of ligands in which substituents are bound to the aromatic rings of the bridging ligands offers great scope for tuning the adsorption properties of the framework materials.


Assuntos
Anestésicos Inalatórios/química , Estruturas Metalorgânicas/química , Polímeros/química , Adsorção , Isoflurano/química , Óxido Nitroso/química , Porosidade , Xenônio/química , Zinco/química
12.
FASEB J ; 30(8): 2915-25, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27170289

RESUMO

Isoflurane and propofol are known to depress cardiac contraction, but the molecular mechanisms involved are not known. In this study, we determined whether decreasing myofilament Ca(2+) responsiveness underlies anesthesia-induced depression of contraction and uncovered the molecular targets of isoflurane and propofol. Force and intracellular Ca(2+) ([Ca(2+)]i) were measured in rat trabeculae superfused with Krebs-Henseleit solution, with or without propofol or isoflurane. Photoaffinity labeling of myofilament proteins with meta-Azi-propofol (AziPm) and Azi-isoflurane (Azi-iso) and molecular docking were also used. Both propofol and isoflurane dose dependently depressed force from low doses (propofol, 27 ± 6 µM; isoflurane, 1.0 ± 0.1%) to moderate doses (propofol, 87 ± 4 µM; isoflurane, 3.0 ± 0.25%), without significant alteration [Ca(2+)]i During steady-state activations in both intact and skinned preparations, propofol and isoflurane depressed maximum Ca(2+)-activated force and increased the [Ca(2+)]i required for 50% of activation. Myofibrils photolabeled with AziPm and Azi-iso identified myosin, actin, and myosin light chain as targets of the anesthetics. Several adducted residues in those proteins were located in conformationally sensitive regions that underlie contractile function. Thus, propofol and isoflurane decrease force development by directly depressing myofilament Ca(2+) responsiveness and have binding sites in key regions for contraction in both actin and myosin.-Meng, T., Bu, W., Ren, X., Chen, X., Yu, J., Eckenhoff, R. G., Gao, W. D. Molecular mechanism of anesthetic-induced depression of myocardial contraction.


Assuntos
Anestésicos Inalatórios/farmacologia , Hipnóticos e Sedativos/farmacologia , Isoflurano/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miofibrilas/efeitos dos fármacos , Propofol/farmacologia , Anestésicos Inalatórios/química , ATPase de Ca(2+) e Mg(2+)/metabolismo , Cálcio/metabolismo , Cálcio/farmacologia , Corantes , Humanos , Hipnóticos e Sedativos/química , Isoflurano/química , Modelos Moleculares , Miosinas/química , Miosinas/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Propofol/química , Ligação Proteica , Conformação Proteica
13.
Nature ; 469(7330): 428-31, 2011 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-21248852

RESUMO

General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (γ-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.


Assuntos
Anestésicos Gerais/química , Anestésicos Gerais/metabolismo , Cianobactérias/química , Isoflurano/análogos & derivados , Canais Iônicos de Abertura Ativada por Ligante/química , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Propofol/química , Sítios de Ligação/genética , Cristalografia por Raios X , Desflurano , Fenômenos Eletrofisiológicos , Isoflurano/química , Isoflurano/metabolismo , Canais Iônicos de Abertura Ativada por Ligante/genética , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Propofol/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Prótons
14.
Anesth Analg ; 124(2): 473-479, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27632346

RESUMO

At room temperature, the vapor pressures of desflurane, isoflurane, and sevoflurane are well above the clinically useful range. We hypothesized that therapeutic concentrations of these agents could be achieved at temperatures below 0°C, but the vapor pressure-temperature relationship is unknown below 0. Second, we hypothesized that this relationship could be exploited to deliver therapeutic-range concentrations of anesthetic vapor. We therefore set out to determine the low temperature-vapor pressure relationships of each anesthetic agent, thereby identifying the saturated vapor concentration of each agent at any temperature below 0°C. To test our hypothesis, we measured the saturated vapor concentration at 1 atm of pressure for temperatures between -60 and 0°C, thus developing an empiric relationship for each agent. There was consistency in repeated experiments for all 3 agents. To test the empiric data, we constructed a digitally controlled thermoelectric anesthetic vaporizer, characterized the device, and used it to deliver anesthetic vapor to laboratory mice. We report, for the first time, the temperature-vapor pressure relationship at temperatures below 0°C for desflurane, isoflurane, and sevoflurane as well as the TMAC of these agents: the temperature at which the vapor pressure is equal to the minimum alveolar concentration. We describe the construction and limited validation of an anesthetic vaporizer prototype on the basis of this principle. We conclude that clinically relevant concentrations of volatile anesthetics may be achieved at low temperatures.


Assuntos
Anestésicos Inalatórios/química , Pressão de Vapor , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/metabolismo , Animais , Temperatura Baixa , Desflurano , Sistemas de Liberação de Medicamentos , Feminino , Isoflurano/análogos & derivados , Isoflurano/química , Éteres Metílicos/química , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/metabolismo , Sevoflurano , Temperatura
15.
Proc Natl Acad Sci U S A ; 111(24): 8949-54, 2014 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-24889633

RESUMO

Mammals navigate by means of a metric cognitive map. Insects, most notably bees and ants, are also impressive navigators. The question whether they, too, have a metric cognitive map is important to cognitive science and neuroscience. Experimentally captured and displaced bees often depart from the release site in the compass direction they were bent on before their capture, even though this no longer heads them toward their goal. When they discover their error, however, the bees set off more or less directly toward their goal. This ability to orient toward a goal from an arbitrary point in the familiar environment is evidence that they have an integrated metric map of the experienced environment. We report a test of an alternative hypothesis, which is that all the bees have in memory is a collection of snapshots that enable them to recognize different landmarks and, associated with each such snapshot, a sun-compass-referenced home vector derived from dead reckoning done before and after previous visits to the landmark. We show that a large shift in the sun-compass rapidly induced by general anesthesia does not alter the accuracy or speed of the homeward-oriented flight made after the bees discover the error in their initial postrelease flight. This result rules out the sun-referenced home-vector hypothesis, further strengthening the now extensive evidence for a metric cognitive map in bees.


Assuntos
Abelhas/fisiologia , Cognição , Comportamento de Retorno ao Território Vital/fisiologia , Anestésicos/química , Animais , Teorema de Bayes , Encéfalo/fisiologia , Ritmo Circadiano , Sinais (Psicologia) , Voo Animal , Isoflurano/química , Memória , Razão de Chances , Orientação , Comportamento Espacial , Luz Solar
16.
J Anesth ; 31(6): 911-914, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28831619

RESUMO

We investigated whether calcium chloride (CaCl2), a supplementary additive in carbon dioxide (CO2) absorbents, could affect carbon monoxide (CO) production caused by desflurane degradation, using a Japanese alkali-free CO2 absorbent Yabashi Lime®-f (YL-f), its CaCl2-free and 1% CaCl2-added derivatives, and other commercially available alkali-free absorbents with or without CaCl2. The reaction between 1 L of desflurane gas (3-10%) and 20 g of desiccated specimen was performed in an artificial closed-circuit anesthesia system for 3 min at 20 or 40 °C. The CO concentration was measured using a gas chromatograph equipped with a semiconductor sensor detector. The systems were validated by detecting dose-dependent CO production with an alkali hydroxide-containing CO2 absorbent, Sodasorb®. Compared with YL-f, the CaCl2-free derivative caused the production of significantly more CO, while the 1% CaCl2-added derivative caused the production of a comparable amount of CO. These phenomena were confirmed using commercially available absorbents AMSORB® PLUS, an alkali-free absorbent with CaCl2, and LoFloSorb™, an alkali-free absorbent without CaCl2. These results suggest that CaCl2 plays an important role in preventing CO generation caused by desflurane degradation with alkali hydroxide-free CO2 absorbents like YL-f.


Assuntos
Cloreto de Cálcio/química , Dióxido de Carbono/química , Monóxido de Carbono/química , Isoflurano/análogos & derivados , Álcalis/química , Anestesia com Circuito Fechado , Anestésicos Inalatórios/química , Anestésicos Inalatórios/metabolismo , Hidróxido de Cálcio/química , Desflurano , Hidróxidos/química , Isoflurano/química
17.
Anesth Analg ; 122(5): 1377-84, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26859875

RESUMO

BACKGROUND: Phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathway activation may promote neuronal survival via neuroprotection during inflammation after cerebral ischemia. In this study, we investigated whether IV pretreatment with emulsified isoflurane (EI) could decrease ischemic brain injury related to the PI3K/Akt pathway. METHODS: Male Sprague-Dawley rats received different doses of IV EI (1, 2, 4, or 8 mL/kg/h) or Intralipid (8 mL/kg/h) for 30 minutes (n = 6-12 per group), followed by middle cerebral artery occlusion (MCAO) for 100 minutes to induce transient focal ischemia. The neurologic score and infarct volume were measured 48 hours after MCAO. Immunostaining, Western blot analysis, and an enzyme-linked immunosorbent assay were used to assess EI effects on the cell inflammatory response, high-mobility group box-1 release, and phosphorylated Akt (expression. LY294002, a PI3K inhibitor, was also infused into the ventricular space before EI to determine the effect of EI. RESULTS: Four milliliters per kilogram per hour of EI reduced the infarct size (21.08 ± 11.24 vs 37.09 ± 10.46, P = 0.006), improved neurologic scores after MCAO (1.13 ± 0.48 vs 1.95 ± 0.65, P = 0.015), significantly reinforced neuronal survival (982.7 ± 364.4 vs 439.8 ± 278.4, P = 0.036), and inhibited CD68 macrophage/macroglial infiltration in the ischemic core (188.2 ± 49.1 vs 282 ± 49.4, P = 0.018) compared with the vehicle group. In the EI pretreatment group, the serum high-mobility group box-1 concentration (3.62 ± 0.72 vs 5.73 ± 0.65, P < 0.001) was decreased, and the cerebral phosphorylated Akt level (50.33 ± 4.73 vs 37.5 ± 3.11, P = 0.007) was increased at 48 hours, which was inhibited by LY294002 compared with the vehicle group (5.31 ± 0.72 vs 5.73 ± 0.65, P = 0.216; 43.00 ± 4.84 vs 37.5 ± 3.11, P = 0.091). CONCLUSIONS: These findings suggest that EI pretreatment protects against ischemic brain injury via the inhibition of cerebral inflammation and is associated with the PI3K-Akt pathway in rats with MCAO. This drug may be a novel therapeutic agent for patients after stroke.


Assuntos
Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/prevenção & controle , Ataque Isquêmico Transitório/prevenção & controle , Isoflurano/farmacologia , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Administração Intravenosa , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Encéfalo/enzimologia , Encéfalo/patologia , Química Farmacêutica , Citoproteção , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Emulsões , Proteína HMGB1/sangue , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Ataque Isquêmico Transitório/enzimologia , Ataque Isquêmico Transitório/patologia , Isoflurano/administração & dosagem , Isoflurano/química , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Fatores de Tempo
18.
Chirality ; 28(6): 445-52, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27103344

RESUMO

Chiroptical spectroscopy has evolved into a promising tool for chiral molecular structural determination in the last four decades. Determination of the absolute configurations (ACs) of bromochlorofluoromethane and [(2) H1 ,(2) H2 ,(2) H3 ]-neopentane demonstrated the enviable advantages of chiroptical spectroscopy. Furthermore, uncovering the errors in the ACs reported in the literature established a glimpse of what can be accomplished with the modern chiroptical spectroscopic methods. Despite these triumphs, it is important to exercise caution in the practice of chiroptical spectroscopic methods, because certain widely practiced approaches can lead to erroneous conclusions. Selected major accomplishments and special precautions needed for future applications are emphasized. Chirality 28:445-452, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Dicroísmo Circular/métodos , Modelos Moleculares , Análise Espectral Raman/métodos , Hidrocarbonetos Halogenados/química , Isoflurano/química , Estrutura Molecular , Pentanos/química , Teoria Quântica , Estereoisomerismo
19.
J Clin Monit Comput ; 30(6): 977-984, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26546363

RESUMO

The Analgesia/Nociception Index (ANI), a 0-100 non-invasive index calculated from heart rate variability, reflects the analgesia/nociception balance during general anesthesia. We hypothesized that dynamic variations of ANI (∆ANI) would provide better performance than static values to predict hemodynamic reactivity during desflurane/remifentanil general anesthesia. One hundred and twenty-eight patients undergoing ear-nose-throat or lower limb orthopedic surgery were analyzed in this prospective observational study. The ANI, heart rate and systolic blood pressure were recorded before induction, at skin incision, during procedure and at emergence from general anesthesia. Changes in these variables were recorded after 1 min for ANI (ANI1min) and 5 min for heart rate and systolic blood pressure. The dynamic variation of ANI at the different time points was defined as: ∆ANI = (ANI1min - ANI)/([ANI + ANI1min]/2). Receiver-operating characteristic (ROC) curves were built to evaluate the performance of ANI, ANI1 min and ∆ANI to predict hemodynamic reactivity (increase by more than 20 % in heart rate and/or systolic blood pressure within 5 min). For the prediction of hemodynamic reactivity, better performance was observed with ∆ANI (area under ROC curve (AUC ROC) = 0.90) in comparison to ANI (ROC AUC = 0.50) and ANI1min (ROC AUC = 0.77). A ∆ANI threshold of -19 % predicts hemodynamic reactivity with 85 % [95 % CI 77-91] sensitivity and 85 % [95 % CI 81-89] specificity. Dynamic variations of ANI provide better performance than static values to predict hemodynamic reactivity during desflurane/remifentanil general anesthesia. These findings may be of interest for the individual adaptation of remifentanil doses guided by ∆ANI during general anesthesia, although this remains to be demonstrated.


Assuntos
Analgesia/métodos , Hemodinâmica , Manejo da Dor/métodos , Medição da Dor/métodos , Adulto , Anestesia Geral/métodos , Anestésicos Intravenosos/administração & dosagem , Área Sob a Curva , Desflurano , Feminino , Frequência Cardíaca , Humanos , Isoflurano/análogos & derivados , Isoflurano/química , Masculino , Pessoa de Meia-Idade , Nociceptividade , Dor , Piperidinas/química , Probabilidade , Propofol/administração & dosagem , Estudos Prospectivos , Curva ROC , Remifentanil , Sístole , Fatores de Tempo
20.
Artigo em Inglês | MEDLINE | ID: mdl-27222158

RESUMO

For the development of emission control strategies, activated carbon, zeolite, molecular sieves, and a silica gel were tested for adsorption of the newer anesthetic gases isoflurane, sevoflurane, and desflurane from air. The activated carbon Norit GCA 48 was selected for the best performance, and adsorption isotherms at room temperature were developed for the three anesthetics. Equilibrium capacities for this carbon were in the range of 500 to 1,000 mg g(-1) for these anesthetics at partial pressures ranging from 5 to 45 Torr, with the most volatile compound (desflurane) showing the least favorable adsorption. Activated carbons are therefore suggested for use as effective adsorbents in emission control of these anesthetic gases from hospitals.


Assuntos
Adsorção , Anestésicos Inalatórios/química , Carvão Vegetal/química , Isoflurano/química , Éteres Metílicos/química , Sílica Gel/química , Zeolitas/química , Poluentes Atmosféricos/química , Hospitais
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