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1.
Acta Cir Bras ; 35(9): e202000903, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33027360

RESUMO

PURPOSE: To evaluate protective effects of dexmedetomidine, calcitriol and their combination. METHODS: Forty Wistar-albino rats were divided into 4 groups; group of Sham (Group Sham); group of dexmedetomidine (Group DEX); group of calcitriol (Group CAL) and group of dexmedetomidineandcalcitriol (Group DEX-CAL). Photographic analysis was used for macroscopic analysis and perfusion analyses were evaluated by scintigraphy. Additionally, tissue malondialdehyde (MDA) and total oxidant status (TOS) and total antioxidant activity (TAS) were recorded and oxidative stress index (OSI) was calculated. Each flap was assessed by histopathology. RESULTS: Compared to Group Sham, the viable flap areas were higher in all treatment groups both by photographic image analyses and perfusion analyses (p<0.05). Group DEX-CAL had the highest viable flap percentage both in scintigraphic and photographic analyses; whereas Group Sham had the lowest viable flap percentage. Similarly, TAS and MDA levels were elevated and TOS levels were declined in all treatment groups compared to Group Sham (p<0.005). Histopathological analysis at flap demarcation zone confirmed neovascularization was significantly higher and edema, necrosis and inflammation were significantly lower in all treatment groups compared to Group Sham. CONCLUSION: The outcomes show that additional premedication with either dexmedetomidine or calcitriol or their combination reduces ischemia-reperfusion injury of flap area and show significant increase in the percentage of viable flap tissue.


Assuntos
Calcitriol , Dexmedetomidina , Traumatismo por Reperfusão , Retalhos Cirúrgicos , Animais , Calcitriol/farmacologia , Dexmedetomidina/farmacologia , Ratos , Ratos Wistar
2.
Br J Anaesth ; 125(4): 518-528, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32773216

RESUMO

BACKGROUND: Coherent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity. METHODS: Forty-seven healthy males received either dexmedetomidine (n=23) or propofol (n=24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontal-frontal and anterior-posterior functional connectivity in the alpha band (8-14 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI). RESULTS: Prefrontal-frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontal-frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: -0.13 to -0.40) in contrast to baseline (dPLI: 0.01-0.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anterior-posterior connectivity in the alpha band did not differentiate LOR and ROR. CONCLUSIONS: Local prefrontal-frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents. CLINICAL TRIAL REGISTRATION: NCT01889004.


Assuntos
Dexmedetomidina/farmacologia , Eletroencefalografia/efeitos dos fármacos , Propofol/farmacologia , Adulto , Relação Dose-Resposta a Droga , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/fisiologia , Humanos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia
3.
J Med Life ; 13(2): 206-210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742515

RESUMO

Nausea is a mental sensation of unease and discomfort before vomiting. Vomiting refers to the return of the contents of the upper gastrointestinal tract to the mouth caused by contractions of chest and abdomen muscles. Postoperative nausea and vomiting is an unpleasant experience with high treatment costs. Therefore, this study aimed to compare the effects of haloperidol, metoclopramide, dexmedetomidine, and ginger on postoperative nausea and vomiting after laparoscopy. This double-blind clinical trial was performed on all laparoscopy candidates at Valiasr hospital, Arak, Iran. The patients were randomly divided into four groups (haloperidol, metoclopramide, dexmedetomidine and ginger), and all patients underwent general anesthesia using fentanyl, midazolam, atracurium, and propofol. After intubation, tube fixation, and stable hemodynamic conditions, the patients received four ginger capsules with a hint of lemon. A group of patients received 25 µg of dexmedetomidine. In the Plasil group, 10 mg of metoclopramide was given 30 minutes before the completion of surgery. In addition, 0.5 cc of haloperidol (5 mg) was administered to a group of patients. Heart rate, blood pressure, and oxygen saturation were recorded from the beginning of surgery, every 15 minutes until the end of the surgery. Furthermore, the occurrence of nausea and vomiting was recorded during recovery, 2 and 4 hours after surgery. Data were then analyzed using the SPSS software v.23. Eighty-eight patients were enrolled in the study. The youngest and the oldest were 30 years and 70 years old, respectively, and the mean age was 48.02 ± 9.31 years. Moreover, the number of women in the four groups was higher than that of men. Blood pressure in the dexmedetomidine group was lower than the other four groups (P <0.05). The lowest heart rate was observed in the haloperidol group, while the highest heart rate was seen in the plasil group (P <0.05). The occurrence of vomiting and nausea was not significantly different between the four groups (P <0.05). Our results showed no significant difference in postoperative nausea and vomiting between the four drugs. Due to the hemodynamic changes induced by each drug, it is best to use these drugs based on the patient's condition. Ginger is also a herbal remedy that has fewer side effects, and this drug can be a good option for patients when there is no contraindication.


Assuntos
Colecistectomia Laparoscópica/efeitos adversos , Dexmedetomidina/uso terapêutico , Gengibre/química , Haloperidol/uso terapêutico , Metoclopramida/uso terapêutico , Extratos Vegetais/uso terapêutico , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Náusea e Vômito Pós-Operatórios/etiologia , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Dexmedetomidina/farmacologia , Método Duplo-Cego , Feminino , Haloperidol/farmacologia , Humanos , Irã (Geográfico) , Masculino , Metoclopramida/farmacologia , Pessoa de Meia-Idade , Oxigênio/metabolismo
4.
Life Sci ; 259: 118249, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798558

RESUMO

AIMS: We aimed to evaluate the effect of Dexmedetomidine (Dex) on immunology function of macrophages and inflammatory reactions in non-ventilated lung tissues from both humans and rats. MAIN METHODS: Patients scheduled for lung lobectomy were randomly assigned to traditional anesthesia group or Dex anesthesia group, 15 subjects in each group. CD68, CD86 and CD206 were used to mark activate and polarized macrophages using immunofluorescence staining in human lung tissues. Sprague-Dawley rats were used to set lung injury model and randomly divided into Control group, one-lung ventilation group (CLI group) and CLI + Dex group. Lung tissues and bronchoalveolar lavage fluid (BALF) from non-ventilated lungs were collected. The acquired lung tissues were subjected to hematoxylin-eosin (H&E) staining and the inflammatory cells in BALF were calculated. Levels of cytokines and chemokines were detected by enzyme-linked immunosorbent assays (ELISA). KEY FINDINGS: Results from humans showed that anesthesia with Dex decreased the number of both CD68 positive cells and CD86 positive cells and down-regulated level of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein 1 (MCP-1) in human lung. Results from rats demonstrated that treatment with Dex reversed the increased inflammatory cells in lung and the increased levels of TNF-α, interleukin-1ß (IL-ß), MCP-1 and chemokine (C-X-C motif) ligand 1 (CXCL1) resulted from non-ventilation; Dex increased the anti-inflammatory cytokine interleukin-10 (IL-10) in BALF from non-ventilated lung. SIGNIFICANCE: This study showed that Dex modulated the activation and immunological function of macrophages in non-ventilated lung and revealed a protective role in collapsed lung injury.


Assuntos
Dexmedetomidina/farmacologia , Lesão Pulmonar/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Idoso , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Dexmedetomidina/metabolismo , Feminino , Humanos , Pulmão/citologia , Pulmão/metabolismo , Lesão Pulmonar/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 1013-1017, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701242

RESUMO

OBJECTIVE: To investigate the effect of dexmedetomidine combined with pulmonary protective ventilation against lung injury in patients undergoing surgeries for esophageal cancer with one-lung ventilation (OLV). METHODS: Forty patients with undergoing surgery for esophageal cancer with OLV were randomly divided into pulmonary protective ventilation strategy group (F group) and dexmedetomidine combined with protective ventilation strategy group (DF group; n=20). In F group, lung protective ventilation strategy during anesthesia was adopte, and in DF group, the patients received intravenous infusion of dexmedetomidine hydrochloride (0.3 µg · kg-1 ·h-1) during the surgery starting at 10 min before anesthesia induction in addition to protective ventilation strategy. Brachial artery blood was sampled before ventilation (T0), at 30 and 90 min after the start of OLV (T1 and T2, respectively) and at the end of the surgery (T3) for analysis of superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), arterial oxygenation pressure (PaO2), oxygenation index (OI) and lung compliance (CL). RESULTS: At the time points of T1, T2 and T3, SOD level was significantly higher and IL-6 level was significantly lower in the DF group than in F group (P < 0.05). The patients in DF group showed significantly higher PaO2, OI and CL index than those in F group at all the 3 time points. CONCLUSIONS: Dexmedetomidine combined with pulmonary protective ventilation strategy can reduce perioperative lung injury in patients undergoing surgery for esophageal cancer with OLV by suppressing inflammation and oxidative stress to improve lung function and reduce adverse effects of the surgery.


Assuntos
Dexmedetomidina , Neoplasias Esofágicas , Ventilação Monopulmonar , Analgésicos não Entorpecentes/farmacologia , Analgésicos não Entorpecentes/uso terapêutico , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/cirurgia , Estresse Oxidativo/efeitos dos fármacos , Resultado do Tratamento
6.
Life Sci ; 257: 118004, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621918

RESUMO

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI. OBJECTIVES: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection. METHOD: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test. RESULTS: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress. CONCLUSIONS: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.


Assuntos
Dexmedetomidina/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/prevenção & controle , Idoso , Animais , Apoptose/efeitos dos fármacos , China , Dexmedetomidina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Humanos , Isquemia/metabolismo , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estudos Prospectivos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Gene ; 758: 144973, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32707303

RESUMO

Renal ischemia-reperfusion (rI/R) is a risk factor for acute lung injury (ALI). Alveolar macrophages (AMs) activation mediated by rI/R-induced ALI is one of the pathogeneses associated with the development of ALI. In rI/R, α2-adrenergic receptor agonists have been indicated to be effective in decreasing urea nitrogen concentrations. In this study, we explored the underlying pathogenesis of the clinically obtainable α2-adrenergic receptor agonist dexmedetomidine (DEX) in protecting against rI/R -mediated AMs activation. We incubated AMs with the serum of sham and rI/R rats in the presence or absence of various concentrations of DEX. We used an enzyme-linked immunosorbent assay to detect the secretion levels of GSH, LDH, IL-18, IL-1ß, and HMGB1 in the culture supernatant. We employed real-time polymerase chain reaction to assess the expression of NOX-4 mRNA, and western blotting to observe the protein levels of NOX-4, the NLRP3 inflammasome, AMPK, and eNOS. In addition, we used immunofluorescence to analyze ROS and MMP activity. Incubation of AMs with DEX suppressed rI/R-mediated cellular LDH production and ROS release. DEX also abolished the rI/R-mediated decrease in the activity of GSH and increased the levels of the rI/R-related NADPH oxidase protein NOX-4. Furthermore, DEX reduced the amelioration of the mitochondrial potential induced by rI/R. Our study showed that DEX inhibits rI/R-mediated levels of the NLRP3 inflammasome proteins ASC, NLRP3, HMGB1 and p20, and ameliorates rI/R-mediated AMPK signaling inactivation. Therefore, DEX reduces the levels of two mediators that are activated by the NLRP3 inflammasome: IL-18 and IL-1ß. Finally, our study established that DEX mitigates the rI/R-mediated decrease in eNOS, demonstrating its protective functions against AMs activation. In conclusion, our study demonstrated that the protective action of DEX in AMs is induced through amelioration of HMGB1-NLRP3 inflammasome-AMPK signaling. Our results suggest that the anesthetic reagent DEX exerts beneficial effects to ameliorate rI/R-induced ALI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Proteína HMGB1/metabolismo , Isquemia/patologia , Macrófagos Alveolares/patologia , NADPH Oxidase 4/biossíntese , NADPH Oxidase 4/genética , Óxido Nítrico Sintase Tipo III/metabolismo , RNA Mensageiro/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real
8.
Br J Anaesth ; 125(3): 267-274, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32660717

RESUMO

BACKGROUND: Anaesthetic agents are likely to alter circulating cytokine concentrations. Because preceding studies have not been able to exclude the contribution of surgical trauma, perioperative stress, or both to circulating cytokine concentrations, the effects of anaesthesia remain unclear. The aim of this study was to quantify serum cytokines in healthy volunteers administered i.v. anaesthetic agents in the absence of surgical trauma and perioperative stress. METHODS: Serum samples obtained during previous standardised studies from healthy volunteers were compared before and 6-8 h after induction of anaesthesia with propofol (n=31), propofol/remifentanil (n=30), dexmedetomidine (n=17) or dexmedetomidine/remifentanil (n=15). Anaesthetic regimens were standardised and volunteers did not undergo any surgical intervention. Serum concentrations of interleukin (IL)2, IL4, IL6, IL10, IL17, IL18, IL21, IL22, IL23, C-X-C motif ligand 8, interferon gamma, E-selectin, L-selectin, major histocompatibility complex class I chain-polypeptide-related sequence (MIC)A, MICB, Granzyme A, and Granzyme B were quantified using a multiplexed antibody-based assay (Luminex). RESULTS: Samples were obtained from volunteers of either sex aged 18-70 yr. After anaesthesia with propofol alone, concentrations of IL4 (P=0.012), IL6 (P=0.027), IL21 (P=0.035), IL22 (P=0.002), C-X-C motif ligand 8 (P=0.004), MICB (P=0.046), and Granzyme A (P=0.045) increased. After anaesthesia with propofol and remifentanil, IL17 (P=0.013), interferon gamma (P=0.003), and MICA (P=0.001) decreased, but IL6 (P=0.006) and L-selectin (P=0.001) increased. After dexmedetomidine alone, IL18 (P=0.002), L-selectin (P=0.017), E-selectin (P=0.002), and Granzyme B (P=0.023) decreased. After dexmedetomidine with remifentanil no changes were observed. CONCLUSIONS: In healthy volunteers not undergoing surgery, different i.v. anaesthesia regimens were associated with differential effects on circulating cytokines.


Assuntos
Citocinas/sangue , Citocinas/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Propofol/farmacologia , Remifentanil/farmacologia , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
9.
Biomed Environ Sci ; 33(5): 323-330, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32553076

RESUMO

Objective: To explore the protective effects of dexmedetomidine (Dex) against high glucose-induced epithelial-mesenchymal transition in HK-2 cells and relevant mechanisms. Methods: HK-2 cells were exposed to either glucose or glucose+Dex for 6 h. The production of ROS, morphology of HK-2 cells, and cell cycle were detected. Moreover, the expression of AKT, p-AKT, ERK, p-ERK, PI3K, E-Cadherin, Claudin-1, and α-SMA were determined and compared between HK-2 cells exposed to glucose and those exposed to both glucose and Dex with or without PI3K/AKT pathway inhibitor LY294002 and ERK pathway inhibitor U0126. Results: Compared with HK-2 cells exposed to high level of glucose, the HK-2 cells exposed to both high level of glucose and Dex showed: (1) lower level of ROS production; (2) cell morphology was complete; (3) more cells in G1 phase; (4) lower expression of p-AKT, p-ERK and α-SMA, higher expression of E-Cadherin and Claudin-1. PI3K/AKT inhibitor LY294002 and ERK inhibitor U0126 decreased the expression of p-AKT, p-ERK and α-SMA, and increased the expression of E-Cadherin and Claudin-1. Conclusion: Dex can attenuate high glucose-induced HK-2 epithelial-mesenchymal transition by inhibiting AKT and ERK.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Linhagem Celular , Humanos , Transdução de Sinais/efeitos dos fármacos
10.
Am J Physiol Endocrinol Metab ; 319(1): E217-E231, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516026

RESUMO

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.


Assuntos
Quimiotaxia de Leucócito/imunologia , Vesículas Extracelulares/imunologia , Doenças das Valvas Cardíacas/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Rim/imunologia , Neutrófilos/imunologia , Insuficiência Renal/imunologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Animais , Estudos de Casos e Controles , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Dexmedetomidina/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Feminino , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/imunologia , Proteína Forkhead Box O3/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Fosforilação , Fator Plaquetário 4/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Fator Plaquetário 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insuficiência Renal/metabolismo , Vasodilatação
11.
Gen Physiol Biophys ; 39(3): 293-300, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32525823

RESUMO

Dexmedetomidine (Dex) is a selective α2-adrenoceptor agonist and has ability to prevent inflammation and apoptosis in tissues injury. However, whether Dex could alleviate smoke-induced lung injury remains unknown. This study aimed to explore the protective effects of Dex against smoke-induced lung injury. Bronchial and alveolar epithelial cells were treated with cigarette smoke extract (CSE) for 24 h to simulate cigarette smoke-induced lung injury. Results showed that CSE reduced cell viability and increased levels of pro-inflammatory cytokines TNFα, IL-1ß and IL-6, thus activating NF-κB and COX2 expression. CSE also increased ROS generation, whereas lessened MnSOD and catalase generation. Besides, the ratio of apoptotic cells was enhanced upon CSE stimuli, together with disturbance of apoptotic-related proteins including Bcl-2, Bax and caspase-3. However, Dex reduced the damage of CSE to cell viability. The increased activities of TNFα, IL-1ß and IL-6 induced by CSE were partially attenuated by Dex. Dex also recovered the levels of NF-κB and COX2, as well as mnSOD, catalase and ROS. Furthermore, the increase of cell apoptosis together with imbalance of apoptotic proteins induced by CSE was rescued by Dex. Our results demonstrated that Dex alleviated CSE-induced lung injury through inhibition of inflammation, oxidative stress and apoptosis.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Dexmedetomidina/farmacologia , Fumaça/efeitos adversos , Células A549 , Linhagem Celular , Humanos , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Tabaco
12.
Anaesthesia ; 75(11): 1461-1468, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32533791

RESUMO

Children may develop changes in their behaviour following general anaesthesia. Some examples of negative behaviour include temper tantrums and nightmares, as well as sleep and eating disorders. The aim of this study was to determine whether dexmedetomidine reduces the incidence of negative behaviour change after anaesthesia for day case surgery in children aged two to seven years. Children were randomly allocated to one of three groups: a premedication group received 2 mg.kg-1 intranasal dexmedetomidine; an intra-operative group received 1 mg.kg-1 intravenous dexmedetomidine; and a control group. The primary outcome was the incidence of negative behaviour on postoperative day 3 using the Post-Hospitalisation Behaviour Questionnaire for Ambulatory Surgery (PHBQ-AS) and the Strength and Difficulties Questionnaire (SDQ). Secondary outcomes included: the incidence of negative behaviour on postoperative days 14 and 28; anxiety at induction; emergence delirium; pain; length of recovery and hospital stay; and any adverse events. The data for 247 patients were analysed. Negative behaviour change on postoperative day 3 was similar between all three groups when measured with the PHBQ-AS (47%, 44% and 51% respectively; adjusted p=0.99) and the SDQ (median scores 7.5, 6.0 and 8.0 respectively; adjusted p=0.99). The incidence of negative behaviour in the group who received dexmedetomidine intra-operatively was less at postoperative day 28 (15% compared with 36% in the dexmedetomidine premedication group and 41% in the control group, p<0.001). We conclude that dexmedetomidine does not reduce the incidence of negative behaviour on postoperative day 3 in two to seven-year olds having day case procedures.


Assuntos
Comportamento Infantil/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Cuidados Intraoperatórios/métodos , Complicações Pós-Operatórias/prevenção & controle , Pré-Medicação/métodos , Procedimentos Cirúrgicos Ambulatórios , Criança , Pré-Escolar , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/uso terapêutico , Masculino , Inquéritos e Questionários
13.
Medicine (Baltimore) ; 99(20): e20177, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443335

RESUMO

BACKGROUND: Although many studies have reported the effects of dexmedetomidine on cognitive function (CF) in elderly patients after laparoscopic cholecystectomy (LCT), to this date, its effects are still not well understood. The aim of this study is to produce a qualitative synthesis of assessing the effects of dexmedetomidine on CF in elderly patients after LCT. METHODS: We will conduct a comprehensive search in Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, Scopus, VIP Database, WANGFANG Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from the commencement to March 31, 2020 without restrictions of language and publication status. In addition, we will also search grey literature, including conference abstracts, dissertations, reference lists of included studies and relevant reviews. All potential studies will be identified independently by 2 authors to determine their inclusion against previously defined eligibility criteria. The quality of selected papers will be assessed using Cochrane risk of bias tool. All statistical analysis will be performed using RevMan 5.3 software. RESULTS: This study will provide a synthesis of the current available data on assessing the effects of dexmedetomidine on CF in elderly patients after LCT. CONCLUSIONS: Its findings will provide qualitative evidence to better understand the effects of dexmedetomidine on CF in elderly patients after LCT.INPLASY Registration Number: INPLASY202040030.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Colecistectomia Laparoscópica/métodos , Cognição/efeitos dos fármacos , Dexmedetomidina/farmacologia , Idoso , Analgésicos não Entorpecentes/uso terapêutico , China/epidemiologia , Dexmedetomidina/uso terapêutico , Feminino , Humanos , Masculino , Pesquisa Qualitativa , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança
14.
Anesthesiology ; 133(2): 377-392, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32412932

RESUMO

BACKGROUND: Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. METHODS: Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. RESULTS: Ca signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, -0.745 [-1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, -0.498 [-0.664; -0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, -0.329 [-1.220; -0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 µg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). CONCLUSIONS: Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation.


Assuntos
Dexmedetomidina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipnóticos e Sedativos/farmacologia , Área Tegmentar Ventral/metabolismo , Animais , Neurônios Dopaminérgicos/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Fotometria/métodos , Área Tegmentar Ventral/química , Área Tegmentar Ventral/efeitos dos fármacos
15.
PLoS One ; 15(4): e0224720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348301

RESUMO

Small intestinal strangulation associated with ischaemia-reperfusion injury (IRI) is common in horses. In laboratory animals IRI can be ameliorated by ischaemic preconditioning (IPC) and pharmacological preconditioning (PPC) with dexmedetomidine. The aim of this study was to determine the effect of PPC with dexmedetomidine or IPC in an equine model of small intestinal ischaemia-reperfusion (IR). In a randomized controlled experimental trial, 15 horses were assigned to three groups: control (C), IPC, and PPC with dexmedetomidine (DEX). All horses were placed under general anaesthesia and 90% jejunal ischaemia was induced for 90 minutes, followed 30 minutes of reperfusion. In group IPC, three short bouts of ischaemia and reperfusion were implemented, and group DEX received a continuous rate infusion of dexmedetomidine prior to the main ischaemia. Jejunal biopsies were collected before ischaemia (P), and at the end of ischaemia (I) and reperfusion (R). Mucosal injury was assessed by the Chiu-Score, inflammatory cells were stained by cytosolic calprotectin. The degree of apoptosis and cell necrosis was assessed by cleaved-caspase-3 and TUNEL. Parametric data were analyzed by two-way ANOVA for repeated measurements followed by Dunnetts t-test. Non parametric data were compared between groups at the different time points by a Kruskal-Wallis-Test and a Wilcoxon-2-Sample-test. The mucosal injury score increased during I in all groups. After reperfusion, IRI further progressed in group C, but not in IPC and DEX. In all groups the number of cleaved caspase-3 and TUNEL positive cells increased from P to I. The number of TUNEL positive cells were lower in group DEX compared to group C after I and R. Infiltration with calprotectin positive cells was less pronounced in group DEX compared to group C, whereas in group IPC more calprotectin positive cells were seen. In conclusion, IPC and DEX exert protective effects in experimental small intestinal ischaemia in horses.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Dexmedetomidina/uso terapêutico , Isquemia/terapia , Precondicionamento Isquêmico/métodos , Jejuno/irrigação sanguínea , Traumatismo por Reperfusão/terapia , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Cavalos , Isquemia/tratamento farmacológico , Jejuno/efeitos dos fármacos , Jejuno/patologia , Distribuição Aleatória , Traumatismo por Reperfusão/tratamento farmacológico
16.
Exp Mol Pathol ; 115: 104444, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32335082

RESUMO

Intestinal ischemia-reperfusion (I/R) is a life-threatening condition associated with high morbidity and mortality. Dexmedetomidine (DEX), an agonist of α2-adrenoceptor with sedation and analgesia effect, has recently been identified with protective function against I/R injury in multiple organs. However, the mechanism underlying the beneficial effect of DEX on intestine after I/R injury remained poorly understood. In the present study, using in both in vitro and in vivo models, we found that intestinal I/R injury was associated with the activation of p38 MAPK cascade, while DEX was capable of deactivating p38 MAPK and thus protect intestinal cells from apoptosis by inhibiting p38 MAPK-mediated mitochondrial depolarization and cytochrome c (Cyto C) release. Moreover, through inhibiting p38 MAPK activity, the downstream production of pro-inflammatory cytokines-regulated by NF-κB was also suppressed by DEX treatment, leading to the resolution of I/R-induced inflammation in intestine. In general, our study provided evidence that DEX protected intestine from I/R injury by inhibiting p38 MAPK-mediated mitochondrial apoptosis and inflammatory response.


Assuntos
Dexmedetomidina/uso terapêutico , Intestinos/patologia , Sistema de Sinalização das MAP Quinases , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células CACO-2 , Dexmedetomidina/farmacologia , Glucose/deficiência , Humanos , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Oxigênio , Substâncias Protetoras/farmacologia , Ratos Wistar , Traumatismo por Reperfusão/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
17.
Nat Chem Biol ; 16(5): 507-512, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152538

RESUMO

The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to ßAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the α2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α2AR-selective activation and provides insights into Gi/o coupling specificity.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/química , Dexmedetomidina/química , Receptores Adrenérgicos alfa 2/química , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Sítios de Ligação , Microscopia Crioeletrônica , Dexmedetomidina/metabolismo , Dexmedetomidina/farmacologia , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/metabolismo , Insetos/citologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Complexos Multiproteicos/química , Receptores Adrenérgicos alfa 2/genética , Simpatolíticos/química , Simpatolíticos/farmacologia
18.
Acta Vet Scand ; 62(1): 14, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164761

RESUMO

BACKGROUND: General anaesthesia in pigs maintained with intravenous drugs such as propofol may cause respiratory depression. Alfaxalone gives less respiratory depression than propofol in some species. The aim of the investigation was to compare respiratory effects of propofol-ketamine-dexmedetomidine and alfaxalone-ketamine-dexmedetomidine in pigs. Sixteen pigs premedicated with ketamine 15 mg/kg and midazolam 1 mg/kg intramuscularly were anaesthetised with propofol or alfaxalone to allow endotracheal intubation, followed by propofol 8 mg/kg/h or alfaxalone 5 mg/kg/h in combination with ketamine 5 mg/kg/h and dexmedetomidine 4 µg/kg/h given as a continuous infusion for 60 min. The pigs breathed spontaneously with an FIO2 of 0.21. Oxygen saturation (SpO2), end-tidal CO2 concentration (PE'CO2), respiratory rate (fR) and inspired tidal volume (VT) were measured, and statistically compared between treatments. If the SpO2 dropped below 80% or if PE'CO2 increased above 10.0 kPa, the pigs were recorded as failing to complete the study, and time to failure was statistically compared between treatments. RESULTS: Alfaxalone treated pigs had significantly higher respiratory rates and lower PE'CO2 than propofol treated pigs, with a fR being 7.3 /min higher (P = 0.01) and PE'CO2 0.8 kPa lower (P = 0.05). SpO2 decreased by 0.6% and fR by 1.0 /min per kg increase in body weight in both treatment groups. Three of eight propofol treated and two of eight alfaxalone treated pigs failed to complete the study, and times to failure were not significantly different between treatments (P = 0.75). CONCLUSIONS: No major differences in respiratory variables were found when comparing treatments. Respiratory supportive measures must be available when using both protocols.


Assuntos
Anestesia Geral/métodos , Anestésicos Gerais , Respiração/efeitos dos fármacos , Anestésicos Gerais/administração & dosagem , Anestésicos Gerais/farmacologia , Animais , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Quimioterapia Combinada , Feminino , Ketamina/administração & dosagem , Ketamina/farmacologia , Masculino , Pregnanodionas/administração & dosagem , Pregnanodionas/farmacologia , Propofol/administração & dosagem , Propofol/farmacologia , Taxa Respiratória/efeitos dos fármacos , Suínos
19.
Niger J Clin Pract ; 23(2): 172-178, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32031091

RESUMO

Background: One of the drawbacks of subarachnoid block is the short duration of analgesia particularly when adjuvants are not added to local anesthetics agent used. However, dexmedetomidine an α2-adrenergic agent has been found to possess analgesic effect. Aims: This study seeks to determine the analgesic efficacy of intrathecal 7.5 µg of dexmedetomidine and its side effects when used for open reduction and internal fixation (ORIF) of femoral fractures. Methodology: It is a prospective randomized, double-blinded study that was carried out in a Nnamdi Azikiwe University Teaching Hospital, Nnewi in Nigeria. Seventy American Society of Anesthesiologists I or II patients were randomized into two groups of 35 each to receive 3 ml of 0.5% hyperbaric bupivacaine combined with either 7.5 µg of dexmedetomidine in 0.3 ml of normal saline (Group D) or 0.3 ml of normal saline alone (Group S). Patient's outcome measures noted (time to first request of analgesia, proportion of patients with pain score <4 postoperatively using numerical rating scale [NRS], and total analgesic consumed in 24 h.). Results: The patients in Group D had a longer time to first request of analgesia, larger proportion of patients with pain score <4 using NRS in the 2nd h postoperatively and lower amount of total analgesic consumed compared to those in Group S. These differences between the two groups were all statistically significant. Furthermore, there was no difference in the incidences of side effects between the two groups (P > 0.05). However, the patient satisfaction was better in Group D. Conclusion: The addition of 7.5 µg of dexmedetomidine to bupivacaine for subarachnoid block in the management of femoral fractures using ORIF provided better anesthetic profile, particularly prolonged duration of postoperative analgesia without significant side effects.


Assuntos
Analgésicos/administração & dosagem , Bupivacaína/administração & dosagem , Dexmedetomidina/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Adulto , Analgesia/métodos , Analgésicos/farmacologia , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/farmacologia , Raquianestesia , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Dexmedetomidina/farmacologia , Método Duplo-Cego , Feminino , Fraturas do Fêmur/cirurgia , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Bloqueio Nervoso/métodos , Nigéria , Manejo da Dor , Período Pós-Operatório , Estudos Prospectivos , Adulto Jovem
20.
Life Sci ; 247: 117359, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001264

RESUMO

AIMS: Dexmedetomidine (DEX) is a selective agonist of α2-adrenergic receptors with anesthetic attributes and neuroprotective effects. This study was designed to explore the mechanisms of DEX in the propofol-induced neuronal injury in rat hippocampus. MATERIALS AND METHODS: Rat hippocampi were treated with propofol, and then neuronal injury, neuronal apoptosis, PSD95 and apoptosis-related protein expression in CA1 region were measured after DEX administration and/or ant-miR-34a. miR-34a expression was detected using RT-qPCR, while the binding of miR-34a and Sirtuin1 (SIRT1) was identified with dual luciferase reporter gene assay, and the activation of PI3K/Akt signaling pathway was detected. Additionally, hippocampal neurons were cultured in vitro and treated with DEX and propofol. The viability and apoptosis of hippocampal neurons, fluorescence intensity of Ca2+ and neuronal morphology were detected. KEY FINDINGS: In vivo experiments, propofol induced obvious neuronal injury in rat hippocampus, while DEX at different doses reduced hippocampal neuronal apoptosis and miR-34a expression but increased PSD95 expression in rat hippocampus. Low expression of miR-34a reduced propofol-induced neuronal injury by targeting SIRT1 and activating the PI3K/Akt pathway. In vitro experiments, propofol induced neuronal injury, which was alleviated by DEX treatment, accompanied with increased neuronal viability, but decreased apoptosis and fluorescence intensity of Ca2+. The attenuation of neuronal injury achieved by DEX was impaired by over-expression of miR-34a. Meanwhile, over-expression of SIRT1 in neurons with overexpressed miR-34a improved p-Akt and p-PI3K expression. SIGNIFICANCE: DEX could inhibit propofol-induced neuronal injury in rat hippocampus by inhibiting miR-34a expression, upregulating SIRT1 and activating the PI3K/Akt pathway.


Assuntos
Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs , Propofol/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/metabolismo
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