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1.
Br J Anaesth ; 125(5): 779-801, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32798067

RESUMO

BACKGROUND: Despite common use, the benefit of adding steroids to local anaesthetics (SLA) for chronic non-cancer pain (CNCP) injections is uncertain. We performed a systematic review and meta-analysis of English-language RCTs to assess the benefit and safety of adding steroids to local anaesthetics (LA) for CNCP. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases from inception to May 2019. Trial selection and data extraction were performed in duplicate. Outcomes were guided by the Initiative in Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) statement with pain improvement as the primary outcome and pooled using random effects model and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: Among 5097 abstracts, 73 trials were eligible. Although SLA increased the rate of success (42 trials, 3592 patients; RR=1.14; 95% CI, 1.03-1.25; number needed to treat [NNT], 13), the effect size decreased by nearly 50% (NNT, 22) with the removal of two intrathecal injection studies. The differences in pain scores with SLA were not clinically meaningful (54 trials, 4416 patients, MD=0.44 units; 95% CI, 0.24-0.65). No differences were observed in other outcomes or adverse events. No subgroup effects were detected based on clinical categories. Meta-regression showed no significant association with steroid dose or length of follow-up and pain relief. CONCLUSIONS: Addition of cortico steroids to local anaesthetic has only small benefits and a potential for harm. Injection of local anaesthetic alone could be therapeutic, beyond being diagnostic. A shared decision based on patient preferences should be considered. If used, one must avoid high doses and series of steroid injections. CLINICAL TRIAL REGISTRATION: PROSPERO #: CRD42015020614.


Assuntos
Corticosteroides/uso terapêutico , Anestésicos Locais/uso terapêutico , Dor Crônica/tratamento farmacológico , Manejo da Dor/métodos , Corticosteroides/efeitos adversos , Anestésicos Locais/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
JAMA Netw Open ; 2(6): e195614, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173131

RESUMO

Importance: Preoperative anxiety is associated with poor behavioral adherence during anesthetic induction and adverse postoperative outcomes. Research suggests that temperament can affect preoperative anxiety and influence its short- and long-term effects, but these associations have not been systematically examined. Objective: To examine the associations of temperament with preoperative anxiety in young patients undergoing surgery. Data Sources: Studies from MEDLINE, Embase, CINAHL, PsycINFO, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched from database inception to June 2018. Study Selection: All prospective studies reporting associations of temperament with preoperative anxiety were included. Overall, 43 of 5451 identified studies met selection criteria. Data Extraction and Synthesis: Using the PRISMA guidelines, reviewers independently read 43 full-text articles, extracted data on eligible studies, and assessed the quality of each study. Data were pooled using the Lipsey and Wilson random-effects model. Main Outcomes and Measures: Primary outcome was the association of temperament with preoperative anxiety in patients undergoing surgery. Results: A total of 23 studies, with 4527 participants aged 1 to 18 years, were included in this review. Meta-analysis of 12 studies including 1064 participants revealed that emotionality (r = 0.11; 95% CI, 0.04 to 0.19), intensity of reaction (r = 0.29; 95% CI, 0.11 to 0.46), and withdrawal (r = 0.40; 95% CI, 0.23 to 0.55) were positively associated with preoperative anxiety, whereas activity level (r = -0.23; 95% CI, -0.31 to -0.16) was negatively correlated with preoperative anxiety. Impulsivity was not significantly associated with preoperative anxiety. Conclusions and Relevance: This systematic review and meta-analysis provided evidence suggesting that temperament may help identify pediatric patients at risk of preoperative anxiety and guide the design of prevention and intervention strategies. Future studies should continue to explore temperament and other factors influencing preoperative anxiety and their transactional effects to guide the development of precision treatment approaches and to optimize perioperative care.


Assuntos
Anestesia Geral/psicologia , Ansiedade , Cooperação do Paciente/psicologia , Procedimentos Cirúrgicos Operatórios/psicologia , Temperamento , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Medicina de Precisão , Cuidados Pré-Operatórios
3.
Arch Virol ; 164(4): 1095-1110, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790105

RESUMO

Dengue disease is characterized by a marked decrease in platelet count, which is life threatening. In the present study, we investigated the antiviral activity of an aqueous extract of Carica papaya leaves (PLE) against dengue virus (DENV) and its effect on platelet augmentation. The anti-dengue activity of PLE in DENV-infected THP-1 cells was examined by immunoblotting and flow cytometry. The effect of PLE on erythrocyte damage was investigated using hemolytic and anti-hemolytic assays. Virus-infected THP-1 cells were assayed for IFN-α secretion. The effect of PLE on platelet augmentation in rats with cyclophosphamide-induced thrombocytopenia was also investigated. The platelet count of blood from the retro-orbital plexus of rats was determined on the 1st, 4th, 7th, 11th and 14th day of study. On the 14th day, the rats were sacrificed for histopathological examination of the liver, kidney and spleen. Plasma of thrombocytopenic rats was tested for thrombopoietin (TPO) and IL-6 secretion. The data suggest that PLE significantly decreases the expression of the envelope and NS1 proteins in DENV-infected THP-1 cells. A marked decrease in intracellular viral load upon PLE treatment confirmed its antiviral activity. This also resulted in a significant decrease in erythrocyte damage and hydrogen-peroxide-induced lipid peroxidation. A significant increase in the number of platelets was found in thrombocytopenic rats treated with PLE, along with an increase in IL-6 and TPO levels. These findings suggest that PLE can potentially be used as an antiviral agent, as it helps in platelet augmentation and exhibits antiviral activity against DENV.


Assuntos
Antivirais/administração & dosagem , Carica/química , Vírus da Dengue/efeitos dos fármacos , Dengue/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Trombocitopenia/tratamento farmacológico , Animais , Antivirais/química , Antivirais/isolamento & purificação , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Dengue/sangue , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/metabolismo , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Contagem de Plaquetas , Ratos Sprague-Dawley , Trombocitopenia/sangue , Trombocitopenia/metabolismo , Trombocitopenia/virologia , Proteínas Virais/genética , Proteínas Virais/metabolismo
4.
J Physiol Biochem ; 72(4): 763-779, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27534650

RESUMO

Decline in oxygen availability experienced under hypobaric hypoxia (HH) mediates imbalance in lung fluid clearance and is a causative agent of acute lung injury. Here, we investigate the pathological events behind acute HH mediated lung injury and assess the therapeutic efficacy of nanocurcumin in its amelioration. We assess the protective efficacy of nanotized curcumin (nanocurcumin) in ameliorating HH induced lung injury and compare to curcumin. Rats exposed to acute HH (6, 12, 24, 48 and 72 h) were subjected to histopathology, blood-gas analysis and clinical biochemistry, cytokine response and redox damage. HH induced lung injury was analysed using markers of lung injury due to pulmonary vasoconstriction (ET-1/2/3 and endothelin receptors A and B) and trans-vascular fluid balance mediator (Na+/K+ ATPase). The protective efficacy of nanocurcumin was analysed by examination of Akt/Erk signalling cascade by western blot. HH induced lung injury was associated with discrete changes in blood analytes, differential circulatory cytokine response and severe pulmonary redox damages. Up-regulation of ET-1/2/3 and its receptors along with down-regulation of Na+/K+ ATPase confirmed defective pulmonary fluid clearance which promoted edema formation. Nanocurcumin treatment prevented lung edema formation and restored expression levels of ET-1/2/3 and its receptors while restoring the blood analytes, circulatory cytokines and pulmonary redox status better than curcumin. Modulation in Akt/Erk signalling pathway in rat lungs under HH confirmed the protective efficacy of nanocurcumin.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Curcumina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Nanoestruturas/uso terapêutico , Substâncias Protetoras/farmacologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelina-2/genética , Endotelina-2/metabolismo , Endotelina-3/genética , Endotelina-3/metabolismo , Hipóxia/complicações , Hipóxia/genética , Hipóxia/patologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Nanoestruturas/química , Oxirredução/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo
5.
PLoS One ; 10(9): e0139121, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406246

RESUMO

Hypoxia induced oxidative stress incurs pathophysiological changes in hypertrophied cardiomyocytes by promoting translocation of p53 to mitochondria. Here, we investigate the cardio-protective efficacy of nanocurcumin in protecting primary human ventricular cardiomyocytes (HVCM) from hypoxia induced damages. Hypoxia induced hypertrophy was confirmed by FITC-phenylalanine uptake assay, atrial natriuretic factor (ANF) levels and cell size measurements. Hypoxia induced translocation of p53 was investigated by using mitochondrial membrane permeability transition pore blocker cyclosporin A (blocks entry of p53 to mitochondria) and confirmed by western blot and immunofluorescence. Mitochondrial damage in hypertrophied HVCM cells was evaluated by analysing bio-energetic, anti-oxidant and metabolic function and substrate switching form lipids to glucose. Nanocurcumin prevented translocation of p53 to mitochondria by stabilizing mitochondrial membrane potential and de-stressed hypertrophied HVCM cells by significant restoration in lactate, acetyl-coenzyme A, pyruvate and glucose content along with lactate dehydrogenase (LDH) and 5' adenosine monophosphate-activated protein kinase (AMPKα) activity. Significant restoration in glucose and modulation of GLUT-1 and GLUT-4 levels confirmed that nanocurcumin mediated prevention of substrate switching. Nanocurcumin prevented of mitochondrial stress as confirmed by c-fos/c-jun/p53 signalling. The data indicates decrease in p-300 histone acetyl transferase (HAT) mediated histone acetylation and GATA-4 activation as pharmacological targets of nanocurcumin in preventing hypoxia induced hypertrophy. The study provides an insight into propitious therapeutic effects of nanocurcumin in cardio-protection and usability in clinical applications.


Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Hipóxia Celular , Células Cultivadas , Curcumina/análogos & derivados , Ciclosporina/farmacologia , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Ventrículos do Coração/citologia , Histona Acetiltransferases/metabolismo , Homeostase , Humanos , Ácido Láctico/metabolismo , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo
6.
J Physiol Biochem ; 71(2): 239-51, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25846484

RESUMO

Hypoxia-induced cardiomyocyte hypertrophy is evident; however, the distinct molecular mechanism underlying the oxidative stress-mediated damages to cardiomyocytes remains unknown. Curcumin (diferuloylmethane) is known for anti-hypertrophic effects, but low bioavailability makes it unsuitable to exploit its pharmacological properties. We assessed the efficacy of nanotized curcumin, i.e. nanocurcumin, in ameliorating hypoxia-induced hypertrophy and apoptosis in H9c2 cardiomyoblasts and compared it to curcumin. H9c2 cardiomyoblasts were challenged with 0.5 % oxygen, for 24 h to assess hypoxia-induced oxidative damage, hypertrophy and consequent apoptosis. The molecular mechanism underlying the protective efficacy of nanocurcumin was evaluated in regulating Raf-1/Erk-1/2 apoptosis by caspase-3/-7 pathway and oxidative stress. Nanocurcumin ameliorated hypoxia-induced hypertrophy and apoptosis in H9c2 cells significantly (p ≤ 0.01), by downregulating atrial natriuretic factor expression, caspase-3/-7 activation, oxidative stress and stabilizing hypoxia-inducible factor-1α (HIF-1α) better than curcumin. Nanocurcumin provides insight into its use as a potential candidate in curing hypoxia-induced cardiac pathologies by restoring oxidative balance.


Assuntos
Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Curcumina/química , Curcumina/farmacocinética , Hipertrofia/metabolismo , Mioblastos Cardíacos/patologia , Nanoestruturas/química , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Proteínas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
J Cardiovasc Pharmacol ; 64(4): 375-84, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24921631

RESUMO

BACKGROUND: Hypoxia-induced rise in intracellular calcium concentration is a causative agent of apoptosis and oxidative damage in cardiomyocytes. We examined the efficacy of calcium channel blocker amlodipine in preventing hypoxia-induced apoptosis in H9c2 cells and restoring oxidative balance. METHODS: H9c2 cells were exposed to hypoxia (0.5% oxygen) to evaluate the efficacy of amlodipine in restoring cellular calcium levels. Cellular markers of apoptosis (Bax/Bcl2 and caspase-3, -7, and -9) and pro-survival markers (Akt/p-Akt levels) were evaluated under hypoxia. Redox damage was evaluated by assessing markers of oxidative damage, that is, glutathione reduced, glutathione oxidized, lipid peroxidation, reactive oxygen species, and manganese superoxide dismutase activity. Cellular adenosine triphosphate (ATP) pool and AMPKα levels were measured to evaluate regulation of metabolism under hypoxia. RESULTS: Amlodipine treatment at 25 nM prevented apoptosis and restored cellular calcium levels and oxidative damage in cardiomyocytes. Stabilization of caspase-3, -7, and -9 along with restoration of Akt/p-Akt levels depicted pro-survival efficacy of amlodipine. Also, restoration of cellular ATP and AMPKα levels indicates that amlodipine prevents cardiomyocytes from hypoxia-induced metabolic stress. CONCLUSIONS: Amlodipine thus protects H9c2 cells from hypoxia-induced apoptosis by regulating Akt/p-Akt-mediated caspase-3, -7, and -9 activation and restoring cellular ATP and redox status.


Assuntos
Anlodipino/farmacologia , Apoptose/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Mioblastos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cálcio/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Mioblastos Cardíacos/patologia , Ratos
8.
Med Chem ; 7(3): 200-12, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21486203

RESUMO

In this paper, an attempt was made to develop a Quantitative Structure Activity Relationship (QSAR) model on a series of quinazoline derivatives acting as Protein tyrosine kinases (erbB-2) inhibitors using Multiple Linear Regression, Principal Component Regression and Partial Least Squares Regression methods. Among these three methods, Multiple Linear Regression (MLR) method has come out with a very promising result as compared to other two methods. Various 2D descriptors were calculated and used in the present analysis. For model validation, the dataset was divided into training and test sets using spherical exclusion method. The developed MLR- QSAR model was found to be statistically significant with respect to training (r2 =0.956), cross-validation (q2 = 0.915), and external validation (pred_r2= 0.6170). The developed MLR model suggests that Estate Contribution descriptors SaaOE-Index (30.07%) and SsCIE-index (15.79%) are the most important descriptors in predicting Tyrosine kinase (erbB-2) inhibitory activity. Electron withdrawing group at 4th position of quinazoline enhances the activity as evident by positive value of SsClE-index (15.79). In addition, for quinazoline substituents, estate contribution descriptors SsCH3E -index has a large deactivating effect.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Desenho de Fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Estereoisomerismo , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 46(6): 2327-46, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21458891

RESUMO

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 µM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.


Assuntos
Antineoplásicos/farmacologia , Quinazolinas/farmacologia , Quinoxalinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinoxalinas/síntese química , Quinoxalinas/química , Estereoisomerismo , Relação Estrutura-Atividade
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