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1.
Can J Surg ; 61(3): 185-194, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29806816

RESUMO

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is a mostly asymptomatic condition that is strongly associated with 30-day mortality; however, it remains mostly undetected without systematic troponin T monitoring. We evaluated the cost and consequences of postoperative troponin T monitoring to detect MINS. METHODS: We conducted a model-based cost-consequence analysis to compare the impact of routine troponin T monitoring versus standard care (troponin T measurement triggered by ischemic symptoms) on the incidence of MINS detection. Model inputs were based on Canadian patients enrolled in the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) study, which enrolled patients aged 45 years or older undergoing inpatient noncardiac surgery. We conducted probability analyses with 10 000 iterations and extensive sensitivity analyses. RESULTS: The data were based on 6021 patients (48% men, mean age 65 [standard deviation 12] yr). The 30-day mortality rate for MINS was 9.6%. We determined the incremental cost to avoid missing a MINS event as $1632 (2015 Canadian dollars). The cost-effectiveness of troponin monitoring was higher in patient subgroups at higher risk for MINS, e.g., those aged 65 years or more, or with a history of atherosclerosis or diabetes ($1309). CONCLUSION: The costs associated with a troponin T monitoring program to detect MINS were moderate. Based on the estimated incremental cost per health gain, implementation of postoperative troponin T monitoring seems appealing, particularly in patients at high risk for MINS.

2.
PeerJ ; 3: e1428, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26618091

RESUMO

Background. Adipose tissue contributes to the inflammatory response through production of cytokines, recruitment of macrophages and modulation of the adiponectin system. Previous studies have identified a down-regulation of adiponectin in pathologies characterised by acute (sepsis and endotoxaemia) and chronic inflammation (obesity and type-II diabetes mellitus). In this study, we investigated the hypothesis that LPS would reduce adiponectin receptor expression in a murine model of endotoxaemia and in adipoocyte and myocyte cell cultures. Methods. 25 mg/kg LPS was injected intra-peritoneally into C57BL/6J mice, equivalent volumes of normal saline were used in control animals. Mice were killed at 4 or 24 h post injection and tissues harvested. Murine adipocytes (3T3-L1) and myocytes (C2C12) were grown in standard culture, treated with LPS (0.1 µg/ml-10 µg/ml) and harvested at 4 and 24 h. RNA was extracted and qPCR was conducted according to standard protocols and relative expression was calculated. Results. After LPS treatment there was a significant reduction after 4 h in gene expression of adipo R1 in muscle and peri-renal fat and of adipo R2 in liver, peri-renal fat and abdominal wall subcutaneous fat. After 24 h, significant reductions were limited to muscle. Cell culture extracts showed varied changes with reduction in adiponectin and adipo R2 gene expression only in adipocytes. Conclusions. LPS reduced adiponectin receptor gene expression in several tissues including adipocytes. This reflects a down-regulation of this anti-inflammatory and insulin-sensitising pathway in response to LPS. The trend towards base line after 24 h in tissue depots may reflect counter-regulatory mechanisms. Adiponectin receptor regulation differs in the tissues investigated.

3.
Pain ; 155(11): 2408-17, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25250722

RESUMO

Complex regional pain syndrome (CRPS) is a limb-confined posttraumatic pain syndrome with sympathetic features. The cause is unknown, but the results of a randomized crossover trial on low-dose intravenous immunoglobulins (IVIG) treatment point to a possible autoimmune mechanism. We tested purified serum immunoglobulin G (IgG) from patients with longstanding CRPS for evidence of antibodies interacting with autonomic receptors on adult primary cardiomyocytes, comparing with control IgG from healthy and diseased controls, and related the results to the clinical response to treatment with low-dose IVIG. We simultaneously recorded both single-cell contractions and intracellular calcium handling in an electrical field. Ten of 18 CRPS preparations and only 1/57 control preparations (P<0.0001) increased the sensitivity of the myocytes to the electric field, and this effect was abrogated by preincubation with α-1a receptor blockers. By contrast, effects on baseline calcium were blocked by preincubation with atropine. Interestingly, serum-IgG preparations from all 4 CRPS patients who had responded to low-dose IVIG with meaningful pain relief were effective in these assays, although 4/8 of the nonresponders were also active. To see if there were antibodies to the α-1a receptor, CRPS-IgG was applied to α-1a receptor-transfected rat-1 fibroblast cells. The CRPS serum IgG induced calcium flux, and fluorescence-activated cell sorting showed that there was serum IgG binding to the cells. The results suggest that patients with longstanding CRPS have serum antibodies to α-1a receptors, and that measurement of these antibodies may be useful in the diagnosis and management of the patients.


Assuntos
Autoanticorpos/sangue , Síndromes da Dor Regional Complexa/sangue , Síndromes da Dor Regional Complexa/imunologia , Receptores Adrenérgicos alfa 1/imunologia , Adulto , Animais , Atropina/farmacologia , Cálcio/metabolismo , Células Cultivadas , Síndromes da Dor Regional Complexa/terapia , Estudos Cross-Over , Dioxanos/farmacologia , Feminino , Humanos , Imunoglobulina G/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Potenciais da Membrana/efeitos dos fármacos , Pessoa de Meia-Idade , Antagonistas Muscarínicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Ligação Proteica/efeitos dos fármacos , Ratos , Transfecção , Adulto Jovem
4.
Naunyn Schmiedebergs Arch Pharmacol ; 387(10): 991-1000, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25012093

RESUMO

Amylmetacresol and dichloro-benzylalcohol are ingredients of lozenges used for the treatment of sore throat. In a former in vitro study, a local anaesthetic-like effect of these substances has been described. Since amylmetacresol and dichloro-benzylalcohol are co-administered in over-the-counter lozenges, the intention of this study is to evaluate the in vitro effects of the combination of these compounds on the voltage-gated sodium channel. We analysed the block of inward sodium currents induced by the combination of amylmetacresol, dichloro-benzylalcohol and the local anaesthetic lidocaine. Tonic and use-dependent block and effects on the inactivated channel state of the neuronal sodium channel were examined. Therefore, the α-subunit of the voltage-gated NaV1.2 sodium channel was heterologously expressed in HEK 293 cells in vitro. Inward sodium currents were investigated in the whole-cell configuration of the patch-clamp technique. The combination of amylmetacresol and dichloro-benzylalcohol and the combination of amylmetacresol and lidocaine induced a block of resting and inactivated sodium channels both displaying a pronounced block at the inactivated channel state. In addition, the combination of all three compounds also resulted in a voltage-dependent block of inward sodium currents. While use-dependent block by co-application of amylmetacresol and dichloro-benzylalcohol was moderate (<20 %), lidocaine and amylmetacresol induced a robust use-dependent block (up to 50 %). This study demonstrates local anaesthetic-like effects of a combination of amylmetacresol and dichloro-benzylalcohol as established ingredients of lozenges. In the presence of amylmetacresol, dichloro-benzylalcohol and lidocaine, a prominent block of inward sodium currents is apparent.


Assuntos
Anestésicos Locais/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Lidocaína/administração & dosagem , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Faringite , Bloqueadores dos Canais de Sódio/administração & dosagem , Administração Tópica , Álcoois Benzílicos , Cresóis/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Células HEK293 , Humanos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Faringite/tratamento farmacológico
5.
Anesthesiology ; 120(3): 564-78, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24534856

RESUMO

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. METHODS: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. RESULTS: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. CONCLUSION: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.


Assuntos
Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/epidemiologia , Avaliação de Resultados da Assistência ao Paciente , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Operatórios , Distribuição por Idade , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Complicações Pós-Operatórias/sangue , Prognóstico , Estudos Prospectivos , Troponina T/sangue
6.
BMC Anesthesiol ; 14: 124, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25580089

RESUMO

BACKGROUND: Adipose tissue has been identified as an endocrine organ secreting adipokines involved in metabolic and inflammatory pathways. Adiponectin, an anti-inflammatory adipokine, is reduced in sepsis. High Molecular Weight (HMW) adiponectin, the biologically most relevant molecule, has been investigated very little in human sepsis. Zinc-alpha2-glycoprotein (ZAG) is a novel adipokine and its expression in adipose tissue is positively correlated with adiponectin expression. It is not yet known whether ZAG has a role in sepsis. In this study we assessed levels of HMW adiponectin and ZAG during different stages of sepsis. METHODS: A prospective observational pilot study was carried out on 21 septic patients. Serum samples were taken on day 1 and 2 post ICU admission and on day of discharge. Samples were analysed for total and HMW adiponectin, HMW/total adiponectin ratio, and ZAG. Results were correlated with clinical and metabolic data. RESULTS: There were no differences in total adiponectin, HMW adiponectin and ZAG plasma concentrations between day 1 (admission) and day 2 of the sepsis episode. Compared to admission, a significant increase in total and HMW adiponectin and ZAG was observed on the day of discharge when clinical improvement had been achieved. There was also an increase in the HMW/total adiponectin ratio at that time. CONCLUSIONS: Our data demonstrate an increase in both HMW adiponectin and total adiponectin in patients who had clinically recovered from sepsis. The increase in HMW/total adiponectin ratio with improvement of the clinical condition suggests that HMW adiponectin may have a greater role in the inflammatory process and insulin resistance seen in sepsis. In this pilot study, we have also demonstrated a significant increase in ZAG in critically ill patients temporally related to recovery from sepsis.


Assuntos
Adiponectina/metabolismo , Proteínas de Plasma Seminal/metabolismo , Sepse/fisiopatologia , Idoso , Feminino , Seguimentos , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Peso Molecular , Projetos Piloto , Estudos Prospectivos , Fatores de Tempo
7.
BMC Neurol ; 12: 104, 2012 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-23006332

RESUMO

BACKGROUND: The mammalian neurological disorder hereditary hyperekplexia can be attributed to various mutations of strychnine sensitive glycine receptors. The clinical symptoms of "startle disease" predominantly occur in the newborn leading to convulsive hypertonia and an exaggerated startle response to unexpected mild stimuli. Amongst others, point mutations R271Q and R271L in the α1-subunit of strychnine sensitive glycine receptors show reduced glycine sensitivity and cause the clinical symptoms of hyperekplexia.Halogenation has been shown to be a crucial structural determinant for the potency of a phenolic compound to positively modulate glycine receptor function.The aim of this in vitro study was to characterize the effects of 4-chloropropofol (4-chloro-2,6-dimethylphenol) at four glycine receptor mutations. METHODS: Glycine receptor subunits were expressed in HEK 293 cells and experiments were performed using the whole-cell patch-clamp technique. RESULTS: 4-chloropropofol exerted a positive allosteric modulatory effect in a low sub-nanomolar concentration range at the wild type receptor (EC50 value of 0.08 ± 0.02 nM) and in a micromolar concentration range at the mutations (1.3 ± 0.6 µM, 0.1 ± 0.2 µM, 6.0 ± 2.3 µM and 55 ± 28 µM for R271Q, L, K and S267I, respectively). CONCLUSIONS: 4-chloropropofol might be an effective compound for the activation of mutated glycine receptors in experimental models of startle disease.


Assuntos
Cloro/metabolismo , Clorofenóis/administração & dosagem , Epilepsia/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Receptores da Glicina/agonistas , Receptores da Glicina/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Mutagênese Sítio-Dirigida , Receptores da Glicina/genética , Reflexo Anormal , Xilenos
8.
JAMA ; 307(21): 2295-304, 2012 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-22706835

RESUMO

CONTEXT: Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE: To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS: A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES: Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS: A total of 15,133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT ≤ 0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSION: Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.


Assuntos
Biomarcadores/sangue , Procedimentos Cirúrgicos Operatórios/mortalidade , Troponina T/sangue , Idoso , Feminino , Humanos , Pacientes Internados/estatística & dados numéricos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Período Pós-Operatório , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco
9.
Pharmacology ; 87(5-6): 311-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21606664

RESUMO

Polysialic acid (polySia) is a large, negatively charged homopolymer of 2,8-linked N-acetylneuraminic acid residues resulting from remodeling and extension of protein-bound sialic acid (Sia) residues and seems to have a key role in regulating neural cell development and function. The aim of this study was to explore and compare the effects of polySia and sialylation on gating of voltage-gated sodium channels. The skeletal muscle α-subunit NaV1.4 was transiently expressed in wild-type Chinese hamster ovary (CHO) cells or in mutant CHO cells with deficits in their capacity to produce sialylated or polysialylated membrane components. Expression in both mutant cell lines resulted in larger peak current amplitudes as compared to wild-type CHO cells. Loss of Sia and polySia also resulted in significant shifts of voltage-dependent activation and steady-state inactivation, however, in opposite directions. Furthermore, only the loss of Sia had a significant effect on recovery from fast inactivation. Our data demonstrate for the first time that gating of voltage-gated sodium channels seems to be differentially regulated by polySia and Sia.


Assuntos
Ativação do Canal Iônico/fisiologia , Ácido N-Acetilneuramínico/metabolismo , Ácidos Siálicos/metabolismo , Canais de Sódio/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Potenciais da Membrana/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.4 , Canais de Sódio/genética
10.
Pharmacology ; 87(1-2): 115-20, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21282969

RESUMO

Paracetamol (acetaminophen) is a widely used antipyretic and analgesic drug for mild or moderate pain states. As the primary site of action of paracetamol is still the subject of ongoing discussion, the focus of this study is the investigation of a potential mechanism which might contribute to its beneficial effects in the therapy of pain. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. In this study we investigated the interaction of paracetamol with strychnine-sensitive α(1)-glycine receptors (α(1)-GlyR). α(1)-GlyR subunits transiently expressed in HEK-293 cells were studied using the whole-cell patch-clamp technique and a piezo-controlled liquid filament fast application system. Paracetamol fails to show a positive allosteric modulatory effect in low nano- to micromolar concentrations and lacks direct activation in micromolar concentrations at the α(1)-GlyR. Consequently, the analgesic actions of paracetamol leading to pain relief appear to be mediated via other mechanisms, but not via activation of spinal glycinergic pathways.


Assuntos
Acetaminofen/farmacologia , Analgésicos não Entorpecentes/farmacologia , Antipiréticos/farmacologia , Receptores da Glicina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Cloretos/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Glicinérgicos/farmacologia , Células HEK293 , Humanos , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Concentração Osmolar , Técnicas de Patch-Clamp , Subunidades Proteicas/agonistas , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores da Glicina/agonistas , Receptores da Glicina/genética , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Análise de Célula Única
11.
Naunyn Schmiedebergs Arch Pharmacol ; 381(5): 477-82, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20339834

RESUMO

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Ajulemic acid and HU210 are non-psychotropic, synthetic cannabinoids. Cannabidiol is a non-psychotropic plant constituent of cannabis sativa. There are hints that non-cannabinoid receptor mechanisms of these cannabinoids might be mediated via glycine receptors. In this study, we investigated the impact of the amino acid residue serine at position 267 on the glycine-modulatory effects of ajulemic acid, cannabidiol and HU210. Mutated alpha(1)S267I glycine receptors transiently expressed in HEK293 cells were studied by utilising the whole-cell clamp technique. The mutation of the alpha(1) subunit TM2 serine residue to isoleucine abolished the co-activation and the direct activation of the glycine receptor by the investigated cannabinoids. The nature of the TM2 (267) residue of the glycine alpha(1) subunit is crucial for the glycine-modulatory effect of ajulemic acid, cannabidiol and HU210. An investigation of the impact of such mutations on the in vivo interaction of cannabinoids with glycine receptors should permit a better understanding of the molecular determinants of action of cannabinoids.


Assuntos
Canabidiol/farmacologia , Dronabinol/análogos & derivados , Receptores da Glicina/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Sequência de Aminoácidos , Linhagem Celular , Dronabinol/farmacologia , Humanos , Mutação , Técnicas de Patch-Clamp , Receptores da Glicina/genética , Receptores da Glicina/metabolismo
12.
Naunyn Schmiedebergs Arch Pharmacol ; 380(2): 161-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19367399

RESUMO

Lozenges for the treatment of sore throat provide relief of discomfort in cases of oral inflammation. This effect has not been fully explained so far. Here, we have examined the proposition that key components of pharmaceutical preparations for the treatment of sore throat which are routinely regarded antiseptics might have sodium channel-blocking, i.e. local anaesthetic-like effects. We investigated the effects of hexylresorcinol, amylmetacresol and dichloro-benzylalcohol on voltage-operated neuronal (Na(V)1.2) sodium channels heterologously expressed in HEK 293 cells in vitro. Hexylresorcinol, amylmetacresol and dichloro-benzylalcohol reversibly blocked depolarisation-induced whole-cell sodium inward currents. The half-maximum blocking concentrations (EC(50)) at -150 mV were 23.1, 53.6 and 661.6 microM, respectively. Block induced by hexylresorcinol and amylmetacresol was increased at depolarised potentials and use-dependent during trains of depolarisations applied at high frequency (100 Hz) indicating that both drugs bind more tightly to inactivated conformations of the channel. Estimates for the inactivated state affinity were 1.88 and 35 microM for hexylresorcinol and amylmetacresol, respectively. Hexylresorcinol and amylmetacresol are 10-20 fold more potent than the local anaesthetic lidocaine in blocking sodium inward current. Both drugs show an increased effect at depolarised membrane potentials or in conditions of high-frequency discharges.


Assuntos
Anestésicos Locais/farmacologia , Anti-Infecciosos Locais/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Faringite/tratamento farmacológico , Anestésicos Locais/administração & dosagem , Animais , Anti-Infecciosos Locais/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/farmacologia , Linhagem Celular , Cresóis/administração & dosagem , Cresóis/farmacologia , Relação Dose-Resposta a Droga , Hexilresorcinol/administração & dosagem , Hexilresorcinol/farmacologia , Humanos , Lidocaína/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.2 , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio , Transfecção
13.
Pharmacology ; 83(5): 270-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19307742

RESUMO

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. HU210 is a non-psychotropic, synthetic cannabinoid. As we hypothesized that non-CB receptor mechanisms of HU210 might contribute to its anti-inflammatory and anti-nociceptive effects we investigated the interaction of HU210 with strychnine-sensitive alpha(1 )glycine receptors by using the whole-cell patch clamp technique. HU210 showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50): 5.1 +/- 2.6 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50): 188.7 +/- 46.2 micromol/l). These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for HU210 mediating some of its anti-inflammatory and anti-nociceptive properties.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Dronabinol/análogos & derivados , Potenciais da Membrana/efeitos dos fármacos , Receptores da Glicina/agonistas , Linhagem Celular Transformada , Dronabinol/farmacologia , Glicina/administração & dosagem , Humanos , Transfecção
15.
Pharmacology ; 83(4): 217-22, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19204413

RESUMO

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa. As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique. Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l). These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.


Assuntos
Canabidiol/farmacologia , Canabinoides/farmacologia , Receptores da Glicina/agonistas , Linhagem Celular Transformada , Células Cultivadas , Células-Tronco Embrionárias , Glicina/farmacologia , Humanos , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Receptores da Glicina/genética , Transfecção
16.
Eur J Anaesthesiol ; 26(1): 17-22, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19122546

RESUMO

BACKGROUND AND OBJECTIVE: In 2005, we developed and implemented the Emergency Anaesthetic Simulated Experience course at the Cheshire and Merseyside Simulation Centre.Emergency Anaesthetic Simulated Experience aims to teach clinical and team resource management skills to junior trainees in anaesthesia. Here we present 'proof-of-concept' in terms of long-term retention and transferability of acquired skills into subsequent clinical practice. METHODS: An electronic questionnaire sent to 73 trainees, 9-20 months after the course, invited open-ended responses, addressing four areas; namely, real-life encounters with the same scenario as on the course, approach to real-life anaesthetic emergencies in general, approach to real-life routine anaesthesia and need to attend similar courses in the future, with their underlying reasons. RESULTS: Qualitative analysis of the descriptive responses showed that the lessons learnt in the context of simulated emergencies were applied by candidates themselves to real-life emergencies in general and to routine practice. CONCLUSION: Team resource management skills learnt in a single educational intervention, based on simulated anaesthetic emergencies, are retained over the long term, translated into clinical practice and are transferable across the breadth of clinical activities.


Assuntos
Anestesiologia/educação , Simulação por Computador , Humanos , Treinamento de Resistência , Inquéritos e Questionários , Fatores de Tempo
17.
Pflugers Arch ; 457(4): 731-41, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18677510

RESUMO

The proposition that white adipose tissue is involved in the inflammatory response and metabolic dysregulation of endotoxaemia has been examined. Mice were injected with lipopolysaccharide (LPS; 25 mg/kg) and epididymal, perirenal and subcutaneous adipose tissue removed 4 or 24 h later. The expression of genes encoding key inflammation-related adipokines was measured by real-time polymerase chain reaction. At 24 h after the administration of LPS, there was no change in leptin mRNA level, and adiponectin mRNA fell. However, major increases in TNFalpha, MCP-1 (up to 40-fold) and IL-6 (up to 250-fold) mRNA levels were evident; a substantial elevation in these mRNAs occurred by 4 h, and adipose tissue IL-6 protein also increased (three- to eightfold). At 24 h, the responses in the subcutaneous depot were much lower than in epididymal and perirenal adipose tissue, but at 4 h, the subcutaneous tissue showed major increases in IL-6, MCP-1 and TNFalpha gene expression. In contrast to the inflammatory adipokines, the mRNA level of two macrophage markers, F4/80 and MAC-1, was unaltered in adipose tissue during endotoxaemia. Expression of the hypoxia-sensitive transcription factor, HIF-1alpha, gene was increased at both 4 and 24 h, and HIF-1alpha protein was elevated at 4 h, suggesting that the tissue was hypoxic. It is concluded that white adipose tissue may play an important role in the production of inflammatory mediators in endotoxaemia.


Assuntos
Adipocinas , Tecido Adiposo Branco/imunologia , Endotoxemia , Regulação da Expressão Gênica , Adipocinas/genética , Adipocinas/imunologia , Animais , Endotoxemia/imunologia , Endotoxemia/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Pharmacology ; 83(2): 95-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19065063

RESUMO

Modulation of inhibitory synaptic transmission within the central nervous system contributes considerably to the anaesthetic effects of propofol and its analogues in vivo. We have studied the effects of the non-anaesthetic propofol analogue 2,6-di-tert-butylphenol on rat alpha(1)beta(2)gamma(2) GABA(A) receptors expressed in a mammalian expression system (HEK 293 cells) using the whole-cell patch clamp technique. Our experiments showed that 2,6-di-tert-butylphenol completely lacks co-activation and direct activation of the inhibitory GABA(A) receptor. Our results support the assumption that modulation of inhibitory GABA(A) receptor function is responsible for the anaesthetic effects of propofol in vivo.


Assuntos
Fenóis/farmacologia , Propofol/análogos & derivados , Receptores de GABA-A/fisiologia , Anestésicos Intravenosos/agonistas , Anestésicos Intravenosos/farmacologia , Animais , Linhagem Celular , Agonistas de Receptores de GABA-A , Humanos , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Fenóis/agonistas , Ratos , Receptores de GABA-A/efeitos dos fármacos , Transfecção , Ácido gama-Aminobutírico/farmacologia
19.
Naunyn Schmiedebergs Arch Pharmacol ; 379(4): 371-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18985319

RESUMO

The synthetic cannabinoid ajulemic acid (CT-3) is a potent cannabinoid receptor agonist which was found to reduce pain scores in neuropathic pain patients in the absence of cannabis-like psychotropic adverse effects. The reduced psychotropic activity of ajulemic acid has been attributed to a greater contribution of peripheral CB receptors to its mechanism of action as well as to non-CB receptor mechanisms. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. As we hypothesised that additional non-CB receptor mechanisms of ajulemic acid might contribute to its effect in neuropathic pain, we investigated the interaction of ajulemic acid with strychnine-sensitive alpha(1)- and alpha(1)beta-glycine receptors by using the whole-cell patch clamp technique. Ajulemic acid showed a positive allosteric modulating effect in a concentration range which can be considered close to clinically relevant concentrations (EC(50) values: alpha(1) = 9.7 +/- 2.6 microM and alpha(1)beta = 12.4 +/- 3.4 microM). Direct activation of glycine receptors was observed at higher concentrations above 100 microM (EC(50) values: alpha(1) = 140.9 +/- 21.5 microM and alpha(1)beta = 154.3 +/- 32.1 microM). These in vitro results demonstrate that ajulemic acid modulates strychnine-sensitive glycine receptors in clinically relevant concentrations.


Assuntos
Dronabinol/análogos & derivados , Receptores da Glicina/efeitos dos fármacos , Linhagem Celular , Dronabinol/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Glicina/farmacologia , Humanos , Técnicas de Patch-Clamp , Conformação Proteica/efeitos dos fármacos , Receptores da Glicina/agonistas , Receptores da Glicina/genética , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/efeitos dos fármacos , Receptores de Neurotransmissores/genética , Transfecção
20.
Anesth Analg ; 107(6): 1875-83, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19020133

RESUMO

BACKGROUND: Propofol, well known for its anesthetic effects, acts as a positive allosteric modulator of the alpha-aminobutyric acid type A (GABA(A)) receptor but also enhances the function of the glycine receptor. The GABA modulatory effects of propofol are influenced by an amino acid residue located within the second transmembrane domain (TM2) of the GABA(A) receptor beta subunit. In glycine alpha(1) subunits, the homologous residue (serine 267) affects the glycine modulatory actions of alcohols and alkane anesthetics. In the present study we investigated the role of this residue on the interaction of propofol with the glycine alpha(1) and alpha(1)beta receptor. METHODS: The influence of propofol on wild type and mutant (alpha(1)S267M, alpha(1)S267I, alpha(1)S267Mbeta, alpha(1)S267Ibeta) glycine receptors expressed in human embryonic kidney 293 cells was investigated by using the whole-cell clamp technique. RESULTS: Mutation of the alpha(1) subunit TM2 serine residue to either isoleucine or methionine decreased the sensitivity of the receptor to glycine, and abolished the direct activation of the glycine receptor by propofol. Additionally, the methionine and particularly the isoleucine mutation decreased the glycine-enhancing actions of propofol. CONCLUSIONS: The nature of the TM2 residue (267) of the glycine alpha(1) subunit influences the glycine modulatory effect of propofol and direct activation of the receptor by this anesthetic. A comparison of the impact of such complementary mutations on the interaction of propofol with glycine and GABA(A) receptors should permit a better understanding of the molecular determinants of action of propofol on these structurally related receptors and may aid in the development of selective glycine receptor modulators.


Assuntos
Anestésicos Intravenosos/farmacologia , Propofol/farmacologia , Receptores da Glicina/efeitos dos fármacos , Estricnina/farmacologia , Células Cultivadas , Humanos , Mutagênese Sítio-Dirigida , Receptores de GABA-A/química , Receptores de GABA-A/efeitos dos fármacos , Receptores da Glicina/química , Relação Estrutura-Atividade
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