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1.
Artigo em Russo | MEDLINE | ID: mdl-34481450

RESUMO

Antidepressants are one of the most important classes of psychotropic drugs and they are widely used in clinical practice, mainly in psychiatry and neurology. The main indications for the use of antidepressants are depression and anxiety disorders. First-line antidepressants are selective serotonin reuptake inhibitors, as well as serotonin-norepinephrine reuptake inhibitors which due to their dual pharmacological action have an additional effect on pain syndromes that determines their use in the treatment of neuropathic pain and fibromyalgia. A special place among the serotonin-norepinephrine reuptake inhibitors has duloxetine, which is characterized by proven efficacy in the treatment of depression, anxiety disorders, as well as isolated and comorbid pain. The optimal balance of efficacy and tolerability determines the possibility of safe use of duloxetine in patients with severe neurological disorders.


Assuntos
Neurologia , Psiquiatria , Humanos , Norepinefrina , Serotonina , Inibidores de Captação de Serotonina/uso terapêutico
2.
Eur J Anaesthesiol ; 38(10): 1077-1084, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524157

RESUMO

BACKGROUND: Studies comparing phenylephrine and norepinephrine for the treatment of postspinal hypotension in pre-eclamptic patients are limited. OBJECTIVE: To compare bolus doses of phenylephrine and norepinephrine for treating hypotension in pre-eclamptic mothers undergoing caesarean section under spinal anaesthesia. It was hypothesised that norepinephrine and phenylephrine use would be associated with similar neonatal outcome. DESIGN: Randomised controlled study. SETTING: Single centre, tertiary care, university teaching hospital, from December 2018 to March 2020. PATIENTS: A total of 86 women with pre-eclampsia and a singleton pregnancy who developed postspinal hypotension during caesarean section. INTERVENTIONS: Patients received intravenous phenylephrine (50 µg) or norepinephrine (4 µg) for treatment of hypotension, defined as a fall in baseline systolic BP by ≥ 20% or an absolute value < 100 mmHg. MAIN OUTCOME MEASURES: The primary outcome was umbilical artery pH. Secondary outcomes included Apgar scores, the number of hypotensive episodes, vasopressor requirements, the incidence of tachycardia/bradycardia/arrhythmias/hypertension and maternal complications. RESULTS: Umbilical artery pH was not different between the phenylephrine and norepinephrine groups (7.26 ±â€Š0.06 and 7.27 ±â€Š0.06, respectively; P = 0.903). The median [IQR] number of hypotensive episodes was higher in the norepinephrine than the phenylephrine group: 2 [1 to 3] vs 1 [1 to 2], respectively; P = 0.014. Apgar scores, total number of vasopressor boluses required, systolic BP trends and the incidence of maternal complications were comparable in the two groups. Heart rate (HR) values were lower in phenylephrine group (P = 0.026), and one patient in phenylephrine group and none in the norepinephrine group developed bradycardia (HR < 50 bpm), P = 1.000. CONCLUSIONS: In women with pre-eclampsia undergoing caesarean section, bolus doses of phenylephrine (50 µg) and norepinephrine (4 µg) used to treat hypotension after spinal anaesthesia are equally effective with similar neonatal and maternal outcomes. TRIAL REGISTRATION: CTRI/2018/11/016478.


Assuntos
Anestesia Obstétrica , Raquianestesia , Hipotensão , Pré-Eclâmpsia , Anestesia Obstétrica/efeitos adversos , Raquianestesia/efeitos adversos , Cesárea/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hipotensão/induzido quimicamente , Hipotensão/diagnóstico , Hipotensão/tratamento farmacológico , Recém-Nascido , Infusões Intravenosas , Norepinefrina , Fenilefrina , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Vasoconstritores/uso terapêutico
3.
Pan Afr Med J ; 39: 177, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34584603

RESUMO

Staphylococcal scalded skin syndrom is a bullous dermatosis induced by exfoliating staphylococcal exotoxins. Children are most often affected. We report the case of a 6-month-old infant who had angina in the few days before leading up to bullous erythroderma and whose skin biopsy showed characteristic appearance of staphylococcal scalded skin syndrom. The development was rapidly unfavourable and the infant died in a refractory septic shock chart, despite the introduction of norepinephrine and anti-SAMR antibiotic therapy. The term staphylococcal scalded skin syndrome (SSSS) was separated from the toxic or allergic epidermal necrolysis by Lyell into the opposite anatomical aspect of these two entities: in scalded skin syndrome, Skin detachment is done by cleavage of the superficial part of the epidermis at the granular layer, while in toxic Lyell syndrome, the cleavage sits deeper at the level of the mucous body.


Assuntos
Choque Séptico/etiologia , Síndrome da Pele Escaldada Estafilocócica/diagnóstico , Antibacterianos/administração & dosagem , Biópsia , Evolução Fatal , Humanos , Lactente , Masculino , Norepinefrina/administração & dosagem , Síndrome da Pele Escaldada Estafilocócica/tratamento farmacológico , Síndrome da Pele Escaldada Estafilocócica/fisiopatologia
4.
Adv Ther ; 38(10): 5025-5045, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34514552

RESUMO

INTRODUCTION: Hot flushes/flashes (HFs) or other vasomotor symptoms affect between 45 and 97% of women during menopause. Hormone replacement therapy (HRT) is effective at alleviating menopausal symptoms, but some women cannot or prefer not to take HRT. Since current non-hormonal options have suboptimal efficacy/tolerability, there is a pressing need for an effective, well-tolerated alternative. The neurokinin 3 receptor (NK3R) has recently been implicated in the generation of menopausal HFs and represents a novel therapeutic target to ameliorate HF symptoms. This review aims to assess if NK3R antagonists (NK3Ras) are more effective than Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)-currently a common choice for non-hormonal treatment of menopausal HFs. METHODS: Studies were identified after systematically searching Ovid MEDLINE and EMBASE databases based on PRISMA guidelines. Trial quality and bias were assessed. Key efficacy outcomes (HF frequency, HF severity and number of night-time awakenings/night-sweats) and selected safety outcomes were extracted and analysed. RESULTS: Seven SNRI and four NK3Ra placebo-controlled randomised trials (plus four follow-up reports) were included in this review. NK3Ra administration resulted in a larger reduction from baseline in HF frequency, HF severity and night-sweats compared to SNRIs. Five of seven SNRI trials showed a reduction in HF frequency that was statistically significant (by 48-67% from baseline at weeks 8 or 12) whereas all NK3Ra trials showed a statistically significant reduction in HF frequency (by 62-93% from baseline at weeks 2, 4 or 12). While SNRI trials reported poor tolerability, particularly nausea, NK3Ra trials reported good tolerability overall, although two trials reported elevation in transaminases. CONCLUSION: NK3Ras trials show encouraging efficacy and tolerability/safety. Completion of phase 3 NK3Ra trials are required to confirm efficacy and uphold safety/tolerability data but phase 2 results suggest that NK3Ras are more effective than SNRIs for non-hormonal treatment of menopausal HFs.


Assuntos
Inibidores de Captação de Serotonina , Serotonina , Feminino , Humanos , Menopausa , Norepinefrina , Receptores da Neurocinina-3 , Inibidores de Captação de Serotonina/uso terapêutico
5.
Behav Neurosci ; 135(5): 629-641, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34582223

RESUMO

Prenatal protein malnutrition (PPM) alters the developing brain including changes in monoaminergic systems and attention. In the present study, we used in vivo microdialysis to examine the relationship between PPM, acute stress, and extracellular serotonin (5HT), dopamine (DA) and norepinephrine (NE) in both hemispheres of lateral orbital frontal cortices (lOFC) in the adult rat. We hypothesized that prenatal protein malnutrition would alter extracellular concentrations of cortical monoamines. The effects of an acute restraint stress were also assessed because PPM alters the brain's response to stress. We used adult male, Long-Evans rats [10 prenatally malnourished (6% casein) and 10 prenatally well-nourished (25% casein)]. Samples were collected from the left and right hemispheres of the lOFC every 20 min for 6 hr total and quantified using high-performance liquid chromatography (HPLC). After 2 hr of sampling, animals were exposed to a 40-min restraint stress. Extracellular levels of NE were significantly higher in PPM animals than in well-nourished controls across both hemispheres at all time-points. In contrast, baseline levels of 5HT and DA levels did not differ between nutritional groups. 5HT levels, but not NE or DA levels, were elevated compared to baseline levels in both nutritional groups and in both hemispheres during the first 20 min of stress exposure. These data highlight the impact of PPM on neuromodulatory systems and the profile of changes in response to acute stress. Additional studies are needed to determine how these basal and stress-related responses impact cognitive performance and whether these differences persist during cognitive testing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Dopamina , Desnutrição , Animais , Feminino , Masculino , Microdiálise , Norepinefrina , Córtex Pré-Frontal , Gravidez , Ratos , Ratos Long-Evans , Serotonina
6.
Free Radic Biol Med ; 175: 171-183, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474105

RESUMO

Stress induces emotional arousal causing anxiety, irritability, exaggerated startle behaviour, and hypervigilance observed in patients with trauma and stress-related mental disorders, including acute stress disorder and post-traumatic stress disorder. Central norepinephrine release promotes stress-induced emotional arousal. However, the regulator of emotional arousal remains unknown. Here, we show that the arachidonate-derived metabolite produced by stress-activated leukocyte 12/15-lipoxygenase is remarkably elevated in the plasma and upregulates the central norepinephrine release, resulting in the enhancement of the struggle behaviour (= escape behaviour) in the tail suspension test. Struggle behaviour is mimicking a symptom of emotional arousal. This stress-induced struggle behaviour was absent in 12/15-lipoxygenase deficient mice; however, intravenous administration of a 12/15-lipoxygenase metabolite to these mice after stress exposure rekindled the struggle behaviour. Furthermore, tocotrienols and geranylgeraniol reduced stress-induced 12/15-lipoxygenase metabolite production and suppressed the struggle behaviour. Our findings indicate that arachidonate-derived 12/15-lipoxygenase metabolite is involved in the regulation of stress-enhanced central norepinephrine release and struggle behaviour. In addition, we propose 12/15-lipoxygenase as a potential therapeutic target for the treatment of emotional arousal observed in stress-related mental disorders.


Assuntos
Araquidonato 15-Lipoxigenase , Tocotrienóis , Animais , Ansiedade , Araquidonato 12-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase , Humanos , Leucócitos , Camundongos , Norepinefrina
7.
Med Klin Intensivmed Notfmed ; 116(6): 541-553, 2021 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-34338810

RESUMO

Circulatory shock requires treatment of the underlying pathology in addition to supportive pharmacological therapy that is guided by hemodynamic monitoring. Based on the evaluation of the patient's volume, perfusion and cardiac status, the following therapeutic goals should be achieved: (1) Normalization of the intra- and extravascular fluid volume. (2) Provision of sufficient perfusion pressure and organ perfusion. (3) Optimization of cardiac function including protecting an ischemic and exhausted myocardium from overload. The most important therapeutic substances are balanced electrolyte solutions and the vasopressor noradrenaline. Because there is little scientific evidence for the use of alternative drugs, these should only be given if there is a good pathophysiologic rationale and if their effect is continuously monitored and re-evaluated.


Assuntos
Choque , Hidratação , Hemodinâmica , Humanos , Monitorização Fisiológica , Norepinefrina , Choque/tratamento farmacológico , Vasoconstritores/efeitos adversos
8.
BMC Musculoskelet Disord ; 22(1): 724, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425806

RESUMO

BACKGROUND: The influence of the sympathetic nervous system (SNS) on metabolism of bone and cartilage expressing ß-adrenergic receptors (AR) was suggested. Here, we investigated whether the SNS functions as a modulator of cartilage metabolism induced by interleukin-1beta (IL-1ß). METHODS: Human articular chondrocytes and articular cartilage were collected from patients with osteoarthritis (OA). Chondrocyte monolayer and cartilage explant culture were stimulated with IL-1ß. The activity of ß-ARs was modulated by an agonist, norepinephrine (NE), and antagonists, including propranolol, atenolol, nebivolol, and nadolol. RESULTS: The levels of ß1-, ß2-, and ß3-AR in OA cartilage and IL-1ß-treated chondrocytes were lower than normal cartilage and untreated cells. Treatment of chondrocytes with IL-1ß and ß-blockers, including propranolol, atenolol, nebivolol, and nadolol, for 6 h significantly upregulated IL-1ß-induced expression of MMP-1, -3, and - 13, compared to chondrocytes treated with IL-1ß alone, indicating that antagonism of ß-AR confers catabolic signals. On the other hand, NE antagonized IL-1ß-induced catabolic response. In addition, NE significantly inhibited IL-1ß-induced release of glycosaminoglycan (GAG) from cartilage explant culture. In addition, ß-AR activity significantly affected IL-1ß-stimulated phosphorylation of JNK and ERK. These results indicate that ß-AR signal is associated with cartilage metabolism. CONCLUSIONS: Our findings showed that ß-ARs is a regulator of cartilage catabolism induced with IL-1ß.


Assuntos
Cartilagem Articular , Osteoartrite , Condrócitos , Humanos , Interleucina-1beta , Norepinefrina/farmacologia , Osteoartrite/tratamento farmacológico
9.
Neuroscience ; 473: 13-28, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34418519

RESUMO

The present study was undertaken to identify the noradrenergic receptors underlying the production of hippocampal formation (HPC) type 2 theta rhythm. The experiments were performed on urethanized rats wherein type 2 theta is the only rhythm present. In three independent stages of experiments, the effects of noradrenaline (NE) and selective noradrenergic α and ß agonists and antagonists were tested. We indicate that the selective activation of three HPC noradrenergic receptors, α1, α2 and ß1, induced a similar effect (i.e., inhibition) on type 2 theta rhythm. The remaining HPC ß2 and ß3 noradrenergic receptors do not seem to be directly involved in the pharmacological mechanism responsible for the suppression of theta rhythm in anaesthetized rats. Obtained results provide evidence for the suppressant effect of exogenous NE on HPC type 2 theta rhythm and show the crucial role of α1, α2 and ß1 noradrenergic receptors in the modulation of HPC mechanisms of oscillations and synchrony. This finding is in contrast to the effects of endogenous NE produced by electrical stimulation of the locus coeruleus (LC) and procaine injection into the LC (Broncel et al., 2020).


Assuntos
Hipocampo , Ritmo Teta , Animais , Locus Cerúleo , Norepinefrina , Procaína , Ratos
10.
Life Sci ; 284: 119895, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34450166

RESUMO

AIMS: Dipeptidyl peptidase-4 inhibitor (DPP4i), a new antidiabetic agent, is reported to affect the progression of chronic liver diseases. The study aims to investigate the effects of DPP4i on contractile response, splanchnic hemodynamics, and portal pressure in cirrhotic rats. MATERIALS AND METHODS: A rat model of carbon tetrachloride-induced cirrhosis was used in this study. Sixteen rats with cirrhosis were treated with DDP4i sitagliptin for 5 consecutive days. Portal and systemic pressures and portal blood flow were measured. Mesenteric arterioles were isolated, and concentration-response curves to norepinephrine (NE) were evaluated. The expression of NADPH oxidase (Nox)1, Nox2, Nox4, and soluble epoxide hydrolase (sEH) were detected. Reactive oxygen species (ROS) and epoxyeicosatrienoic acid (EET) levels in mesenteric arteries were also measured. KEY FINDINGS: In cirrhotic rats, sitagliptin significantly reduced portal blood flow and portal pressure without effects on systemic pressure and reversed the decreased response of mesenteric arterioles to NE in an endothelium-dependent manner. Sitagliptin suppressed the increased Nox4 expression and ROS production. In vitro studies showed that Nox4 inhibitor enhanced arteriolar response to NE and reduced hydrogen peroxide (H2O2) level in cirrhotic rats. Sitagliptin also reduced EET levels and increased sEH expression of mesenteric vessels. Pre-incubation with sEH inhibitor in vitro reversed sitagliptin-induced augmentation of response to NE in cirrhotic rats. SIGNIFICANCE: DPP4 inhibition by sitagliptin in vivo has beneficial effects on portal hypertension in cirrhotic rats through normalizing arterial hypocontractility. DDP4 inhibitor may be a novel strategy in the treatment of patients with cirrhosis and portal hypertension.


Assuntos
Artérias/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/complicações , Cirrose Hepática/fisiopatologia , Vasoconstrição , Animais , Artérias/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hemodinâmica/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Hipertensão Portal/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , NADPH Oxidase 4/metabolismo , Norepinefrina/farmacologia , Ratos Sprague-Dawley , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos
11.
Am J Physiol Endocrinol Metab ; 321(3): E433-E442, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370596

RESUMO

Sepsis is a dysregulated systemic response to infection and can lead to organ damage and death. Obesity is a significant problem worldwide and affects outcomes from sepsis. Our laboratory demonstrated that white adipose tissue (WAT) undergoes browning during sepsis, a process whereby WAT adopts a brown adipose tissue phenotype. However, this browning process was not observed in obese mice during sepsis. White adipose tissue browning is detrimental in patients with burn injury and cancer. We hypothesize that norepinephrine (NE) induces WAT browning in nonobese mice but not in obese mice similarly to sepsis-induced WAT browning. Six-week-old C57BL/6 male mice were randomized to a high-fat diet or normal diet. After 6-7 wk of feeding, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Norepinephrine was administered intraperitoneally via osmotic minipumps for 18 h or 72 h (no CLP) at which time tissue and plasma were harvested. Controls were mice that underwent CLP (no NE) with 18-h harvest. A separate group of mice underwent pretreatment with NE or vehicle infusion for 72 h, CLP was performed, and at 18 h had tissue and plasma harvested. Sepsis resulted in significant weight loss in both nonobese and obese mice. NE treatment alone caused weight loss in obese mice. Septic nonobese mice had higher uncoupling protein-1 (UCP1) expression compared with control and obese septic mice. NE treatment increased UCP1 expression in nonobese, but not obese mice. NE-treated obese septic mice had lower lung myeloperoxidase (MPO) activity, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNFα, and IL-6 levels compared with NE-treated nonobese septic mice. Obesity protects mice from septic-induced and NE-induced WAT browning.NEW & NOTEWORTHY White adipose tissue browning is detrimental in patients with burn injury and cancer. WAT browning occurs in nonobese mice and can be induced by ß receptor norepinephrine infusion, but obese mice are resistant to sepsis-induced and norepinephrine-induced WAT browning. We propose that the lack of WAT browning and unchanged inflammatory cytokine response may contribute to the protection of obese mice from sepsis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Norepinefrina/administração & dosagem , Obesidade/metabolismo , Sepse/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/diagnóstico por imagem , Animais , Dieta Hiperlipídica , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Sepse/complicações
12.
13.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298984

RESUMO

While much of biomedical research since the middle of the twentieth century has focused on molecular pathways inside the cell, there is increasing evidence that extracellular signaling pathways are also critically important in health and disease. The neuromodulators norepinephrine (NE), serotonin (5-hydroxytryptamine, 5HT), dopamine (DA), acetylcholine (ACH), and melatonin (MT) are extracellular signaling molecules that are distributed throughout the brain and modulate many disease processes. The effects of these five neuromodulators on Alzheimer's disease (AD) are briefly examined in this paper, and it is hypothesized that each of the five molecules has a u-shaped (or Janus-faced) dose-response curve, wherein too little or too much signaling is pathological in AD and possibly other diseases. In particular it is suggested that NE is largely functionally opposed to 5HT, ACH, MT, and possibly DA in AD. In this scenario, physiological "balance" between the noradrenergic tone and that of the other three or four modulators is most healthy. If NE is largely functionally opposed to other prominent neuromodulators in AD, this may suggest novel combinations of pharmacological agents to counteract this disease. It is also suggested that the majority of cases of AD and possibly other diseases involve an excess of noradrenergic tone and a collective deficit of the other four modulators.


Assuntos
Doença de Alzheimer/fisiopatologia , Neurotransmissores/antagonistas & inibidores , Norepinefrina/fisiologia , Transmissão Sináptica/fisiologia , Adrenérgicos/administração & dosagem , Adrenérgicos/uso terapêutico , Neurônios Adrenérgicos/fisiologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Química Encefálica , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Melatonina/uso terapêutico , Camundongos , Modelos Neurológicos , Neurotransmissores/fisiologia , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Norepinefrina/farmacologia , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Proteínas tau/metabolismo
14.
Biomolecules ; 11(7)2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202543

RESUMO

Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.


Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/metabolismo , Receptores Adrenérgicos/química , Receptores Adrenérgicos/metabolismo , Sequência de Aminoácidos , Animais , Cristalografia por Raios X/métodos , Epinefrina/química , Epinefrina/metabolismo , Humanos , Ligantes , Norepinefrina/química , Norepinefrina/metabolismo , Ligação Proteica/fisiologia , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Adrenérgicos/genética
15.
J Card Surg ; 36(10): 3711-3718, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34310744

RESUMO

BACKGROUND AND AIM OF THE STUDY: Although dopamine and norepinephrine are recommended as first-line agents in the treatment of shock, it is unclear which is the optimal vasoactive inotropic agent (VIA) to manage postcardiotomy circulatory shock. This single-center, randomized clinical trial aimed to investigate the efficacy and safety of dopamine versus norepinephrine in postcardiotomy circulatory shock. METHODS: We randomly assigned the patients with postcardiotomy circulatory shock to receive either dopamine or norepinephrine. When shock persisted despite the dose of 20 µg/kg/min of dopamine or the dose of 0.2 µg/kg/min of norepinephrine, epinephrine or vasopressin could be added. The primary endpoint was new-onset tachyarrhythmic event during drug infusion. Secondary endpoints included requirement of additional VIAs, postoperative complications, and all-cause mortality within 30 days of drug initiation. RESULTS: At the planned interim analysis of 100 patients, the boundary for the benefit of norepinephrine has been crossed, and the study was stopped early. Excluding two patients withdrawing a consent, 48 patients were assigned to dopamine and 50 patients to norepinephrine. New-onset tachyarrhythmic event occurred in 12 (25%) patients in the dopamine and one (2%) patient in the norepinephrine group (p = .009). The requirement for additional VIAs was more common in the dopamine group (p < .001). Other secondary endpoints were similar between groups. CONCLUSIONS: Despite the limited study subjects with early determination, in patients with postcardiotomy circulatory shock, dopamine as a first-line vasopressor was associated with higher tachyarrhythmic events and greater need for additional VIAs compared with norepinephrine.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Choque Séptico , Choque , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Dopamina , Humanos , Norepinefrina , Choque/tratamento farmacológico , Choque/etiologia , Choque Séptico/tratamento farmacológico , Vasoconstritores , Vasopressinas
16.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281286

RESUMO

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane ß2-adrenergic receptors (ARs). Evidence indicates that ß2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.


Assuntos
Metanfetamina/antagonistas & inibidores , Metanfetamina/toxicidade , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Adrenérgicos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Compartimento Celular/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Estimulantes do Sistema Nervoso Central/toxicidade , Desipramina/farmacologia , Relação Dose-Resposta a Droga , Metanfetamina/administração & dosagem , Microscopia Eletrônica de Transmissão , Modelos Neurológicos , Neurônios/ultraestrutura , Fármacos Neuroprotetores/farmacologia , Norepinefrina/metabolismo , Células PC12 , Ratos , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Vacúolos/ultraestrutura
17.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201675

RESUMO

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/síntese química , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Escala de Avaliação Comportamental , Depressão/fisiopatologia , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Mirtazapina/farmacologia , Mirtazapina/uso terapêutico , Norepinefrina/metabolismo , Piperidinas/química , Ratos , Receptores de Serotonina/genética , Serotonina/metabolismo , Natação
18.
Soft Matter ; 17(28): 6765-6772, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34196338

RESUMO

Recently, carbon dots (CDs) have attracted wide attention for their potential use as fluorescence probes in biological and analytical chemistry due to their great stability and high fluorescence quantum yields. In our work, norepinephrine (NE)-derived CDs with green luminescence and an average size of 10 nm were fabricated using a one-step hydrothermal route. As-prepared CDs show a strong emission at a wavelength of 520 nm when excited at 420 nm, and demonstrate pH and concentration dependent fluorescence behaviour. Multiple functional groups on the CDs allow their protonation/deprotonation and thus alter fluorescence intensity and peak position in different pH conditions. Prepared CDs show significant potential to be used as a live-cell imaging agent with long-term photostability. Furthermore, a simple but effective method to determine the concentration of hemoglobin (Hb) in diluted human blood samples was also developed based on the inner filter effect (IFE). The method demonstrates good linearity from 0.01-10 µM, with a limit of determination (LOD) of 52 nM.


Assuntos
Carbono , Pontos Quânticos , Corantes Fluorescentes , Hemoglobinas , Humanos , Norepinefrina , Espectrometria de Fluorescência
20.
Neuropsychopharmacology ; 46(11): 1918-1926, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34168279

RESUMO

Compulsion-like alcohol drinking (CLAD), where consumption continues despite negative consequences, is a major obstacle to treating alcohol use disorder. The locus coeruleus area in the brainstem and norepinephrine receptor (NER) signaling in forebrain cortical regions have been implicated in adaptive responding under stress, which is conceptually similar to compulsion-like responding (adaptive responding despite the presence of stress or conflict). Thus, we examined whether anterior insula (aINS)-to-brainstem connections and alpha-1 NERs regulated compulsion-like intake and alcohol-only drinking (AOD). Halorhodopsin inhibition of aINS-brainstem significantly reduced CLAD, with no effect on alcohol-only or saccharin intake, suggesting a specific aINS-brainstem role in aversion-resistant drinking. In contrast, prazosin inhibition of alpha-1 NERs systemically reduced both CLAD and AOD. Similar to systemic inhibition, intra-aINS alpha-1-NER antagonism reduced both CLAD and AOD. Global aINS inhibition with GABAR agonists also strongly reduced both CLAD and AOD, without impacting saccharin intake or locomotion, while aINS inhibition of calcium-permeable AMPARs (with NASPM) reduced CLAD without impacting AOD. Finally, prazosin inhibition of CLAD and AOD was not correlated with each other, systemically or within aINS, suggesting the possibility that different aINS pathways regulate CLAD versus AOD, which will require further study to definitively address. Together, our results provide important new information showing that some aINS pathways (aINS-brainstem and NASPM-sensitive) specifically regulate compulsion-like alcohol consumption, while aINS more generally may contain parallel pathways promoting CLAD versus AOD. These findings also support the importance of the adaptive stress response system for multiple forms of alcohol drinking.


Assuntos
Consumo de Bebidas Alcoólicas , Etanol , Córtex Cerebral , Locus Cerúleo , Norepinefrina
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