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1.
Br J Anaesth ; 123(4): 439-449, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383364

RESUMO

BACKGROUND: Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemia-reperfusion injury and explored the underlying mechanisms. METHODS: In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemia-reperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified. RESULTS: NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemia-reperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P<0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P<0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P<0.05), which was blocked by the TRPV1 antagonist 5'-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture. CONCLUSIONS: Spinal NGF contributes to myocardial ischaemia-reperfusion injury by mediating nociceptive signal transmission.


Assuntos
Terapia Genética/métodos , Lentivirus/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator de Crescimento Neural/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Arritmias Cardíacas/prevenção & controle , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Injeções Espinhais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/prevenção & controle , Fator de Crescimento Neural/biossíntese , Células PC12 , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
2.
Arch Dis Child Fetal Neonatal Ed ; 104(6): F643-F647, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31154421

RESUMO

OBJECTIVE: To report outcomes to 1 year, in infants born with congenital diaphragmatic hernia (CDH), explore factors associated with infant mortality and examine the relationship between surgical techniques and postoperative morbidity. DESIGN: Prospective national population cohort study. SETTING: Paediatric surgical centres in the UK and Ireland. METHOD: Data were collected to 1 year for infants with CDH live-born between 1 April 2009 to 30 September 2010. Factors associated with infant mortality are explored using logistic regression. Postoperative morbidity following patch versus primary closure, minimally invasive versus open surgery and biological versus synthetic patch material is described. Data are presented as n (%) and median (IQR). RESULTS: Overall known survival to 1 year was 75%, 95% CI 68% to 81% (138/184) and postoperative survival 93%, 95% CI 88% to 97% (138/148). Female sex, antenatal diagnosis, use of vasodilators or inotropes, being small for gestational age, patch repair and use of surfactant were all associated with infant death. Infants undergoing patch repair had a high incidence of postoperative chylothorax (11/54 vs 2/96 in infants undergoing primary closure) and a long length of hospital stay (41 days, IQR 24-68 vs 16 days, IQR 10-25 in primary closure group). Infants managed with synthetic patch material had a high incidence of chylothorax (11/34 vs 0/19 with biological patch). CONCLUSION: The majority of infant deaths in babies born with CDH occur before surgical correction. Female sex, being born small for gestational age, surfactant use, patch repair and receipt of cardiovascular support were associated with a higher risk of death. The optimum surgical approach, timing of operation and choice of patch material to achieve lowest morbidity warrants further evaluation.


Assuntos
Hérnias Diafragmáticas Congênitas/mortalidade , Hérnias Diafragmáticas Congênitas/cirurgia , Herniorrafia/métodos , Cardiotônicos/administração & dosagem , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Irlanda/epidemiologia , Tempo de Internação , Modelos Logísticos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos/mortalidade , Complicações Pós-Operatórias/epidemiologia , Diagnóstico Pré-Natal/estatística & dados numéricos , Estudos Prospectivos , Surfactantes Pulmonares/administração & dosagem , Fatores Sexuais , Reino Unido/epidemiologia
3.
Int J Cardiovasc Imaging ; 35(9): 1651-1659, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31053980

RESUMO

We investigated the influence of the extent of viability using low dose dobutamine wall motion score index (WMS) on the survival benefit of surgical revascularization (CABG) versus medical therapy. In the STICH trial, viability assessment was not helpful in determining the benefit of CABG. However, the extent of viable myocardium with contractile function was not assessed in the trial. Dobutamine echocardiography was performed in 250 patients with ischemic left ventricular dysfunction (125-medically treated, 125-CABG). The mean ejection fraction (EF) was 32% in both groups. WMS during low dose dobutamine infusion was used to classify patients into groups with extensive (WMS < 2.00), intermediate (WMS 2.00-2.49), and limited (WMS ≥ 2.50) viability. Survival free of cardiac death was assessed at 2 years and for the complete duration of follow-up. There were 44 (35.2%) and 67 (53.6%) cardiac deaths in the revascularized and medically treated patients respectively (follow-up of 5.7 ± 5.8 years). Revascularized and medically treated patients with extensive viability had similar 2-year survival (p = 0.567) but revascularized patients had improved long-term survival (p = 0.0001). In those with intermediate viability, revascularization improved both 2 year (p = 0.014) and long-term survival (p = 0.0001). In patients with limited viability, 2-year survival was worse in revascularized patients (p = 0.04) and long-term survival was similar (p = 0 .25) in revascularized and medically treated groups. Patients with extensive and intermediate amounts of viability have improved survival with CABG but those with limited viability have poorer short-term outcome and no long-term benefit.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Cardiotônicos/administração & dosagem , Ponte de Artéria Coronária , Dobutamina/administração & dosagem , Ecocardiografia sob Estresse/métodos , Isquemia Miocárdica/diagnóstico por imagem , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Idoso , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Cardiomiopatias/cirurgia , Fármacos Cardiovasculares/uso terapêutico , Tomada de Decisão Clínica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/mortalidade , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/cirurgia , Miocárdio/patologia , Seleção de Pacientes , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Sobrevivência de Tecidos , Resultado do Tratamento , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/cirurgia
4.
Expert Opin Drug Saf ; 18(6): 537-547, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31117845

RESUMO

Introduction: Nicorandil may exert cardioprotective effects in ischemic heart disease. However, its efficacy in combination with early reperfusion is uncertain. The authors performed a meta-analysis of the short- and long-term clinical outcomes of nicorandil administration at the time of primary percutaneous coronary intervention (PCI) in patients with ST-elevated myocardial infarction (STEMI). Methods: PubMed, MEDLINE, Embase, and the Cochrane Library databases were systematically searched for eligible randomized controlled studies. The primary endpoint was major adverse cardiovascular events (MACE), both in-hospital and post-discharge. The secondary endpoint was the incidence of no-reflow phenomenon. Results: Ten studies were included (n = 1105). Mean patient age was 63.0 ± 10.0 years; 76.6% of patients were male. Compared with controls who received primary PCI, combined nicorandil/primary PCI significantly reduced in-hospital MACE (pooled odds ratio [OR] 0.16; 95% confidence interval [CI] 0.09-0.27), follow-up MACE (pooled OR 0.53; 95% CI 0.37-0.75), and total MACE (pooled OR 0.27; 95% CI 0.15-0.49). The combined treatment also reduced the incidence of no-reflow phenomenon (pooled OR 0.34; 95% CI 0.23-0.50). Conclusion: Nicorandil administration at the time of primary PCI is associated with reduced MACE (both short- and long-term) and no-reflow phenomenon in patients with STEMI.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Nicorandil/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Animais , Antiarrítmicos/administração & dosagem , Cardiotônicos/administração & dosagem , Doenças Cardiovasculares/epidemiologia , Terapia Combinada , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fenômeno de não Refluxo/epidemiologia , Fenômeno de não Refluxo/prevenção & controle , Intervenção Coronária Percutânea/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
5.
Medicine (Baltimore) ; 98(14): e15088, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946364

RESUMO

Polymorphisms of organic anion transporting polypeptides (OATPs) have been reported to affect trough serum digoxin concentration (SDC). However, the association of these polymorphisms with trough SDC in Chinese heart failure patients has not been studied. We aim to explore whether OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A influence trough SDC in Chinese heart failure patients and to make clinical recommendations.Chinese patients (n = 104) diagnosed with heart failure under long-term digoxin therapy (0.125 mg daily) were enrolled in this study. Blood samples were collected for the analysis of trough SDC (immunofluorescence) and the polymorphisms of OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A (PCR-RFLP and Sanger sequencing).Patients with glomerular filtration rate (GFR) under 30 mL/min had significantly higher trough SDC (1.20 ±â€Š0.50 ng/mL) than recommended trough SDC for heart failure patients. Trough SDC was not significantly influenced by mutations of OATP1B1 388A>G (P = .890), 521T>C (P = .054), and OATP1B3 699G>A (P = .854). Patients with OATP1B1 521T>C mutant-type carrier had slightly higher trough SDC (0.98 ±â€Š0.53 ng/mL) than those with wild-type carrier (0.74 ±â€Š0.40 ng/mL) when they have repaired renal function.Heart failure patients with severe renal dysfunction (GFR<60 mL/min) and/or OATP1B1 521T>C mutant-type carriers are recommended a smaller dosage of digoxin and strict therapeutic drug monitoring.


Assuntos
Cardiotônicos/sangue , Digoxina/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Mutação , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Idoso , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , China , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos Prospectivos
6.
Biomed Pharmacother ; 113: 108731, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851549

RESUMO

BACKGROUND: Cisplatin (CP) has been used in wide range for cancer treatment. Although nephrotoxicity of CP was the main complication, cardiotoxicity has been reported. OBJECTIVES: This study investigates the protective role of green tea extract (GTE) and vitamin E (Vit-E) against CP-induced cardiotoxicity, and assesses their impact on CP antitumor efficacy. MATERIALS AND METHODS: Forty-eight male albino Balb/c mice were randomly divided into six groups, 8 per/group (Gp) were included. Gp1 served as control; Gp2 and Gp3 received oral GTE (400 mg/kg) and Vit-E (100 mg/kg) for 30 consecutive days respectively. Gp4 had received CP (7 mg/kg i.p.) once on the 27th day; Gp5 had received GTE (400 mg/kg p.o.) for 30 days and CP (7 mg/kg i.p.) on the 27th day. Gp6 had received Vit-E (100 mg/kg p.o.) for 30 days and CP (7 mg/kg i.p.) on the 27th day. Blood and tissues samples were harvested for biochemical and histopathological investigations. To evaluate the effect of GTE and Vit-E on the antitumor efficacy of CP, 49 female albino mice were inoculated intraperitoneally by Ehrlich ascetic carcinoma -cells (2 × 106/mouse) then treated with none, corn oil, CP, CP/GTE, CP/Vit-E, GTE or Vit-E. RESULTS: CP injection significantly increased Troponin I, CPK, CK-MB, malondialdehyde (MDA), and nitric oxide (NO) levels, while glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase levels were significantly reduced with disruption of cardiac muscle fibers, loss of striations, absence of intercalated disc, and the nuclei are pyknotic. Treatment with GTE and Vit-E improve the biochemical and histological parameters. Treatment with CP alone led to eradication of the tumor cells from the tumor-bearing mice. However, co-administration of GTE or Vit-E orally with CP did not interfere with its therapeutic effects. CONCLUSION: Treatment with GTE and Vit-E significantly ameliorated the CP cardiotoxicity and improved the myocardial histopathological architecture. GTE and Vit-E may be combined with CP to alleviate cardiotoxicity in cancer chemotherapy without interfering with its antitumor activity.


Assuntos
Cardiotoxicidade/prevenção & controle , Cisplatino/toxicidade , Extratos Vegetais/farmacologia , Chá/química , Vitamina E/farmacologia , Animais , Antineoplásicos/toxicidade , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/patologia , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Cardiotoxicidade/etiologia , Catalase/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Extratos Vegetais/administração & dosagem , Superóxido Dismutase/metabolismo , Resultado do Tratamento , Vitamina E/administração & dosagem
7.
Nutrients ; 11(3)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884808

RESUMO

Hydroxytyrosol (HT) and Punicalagin (PC) exert cardioprotective and anti-atherosclerotic effects. This study evaluates the effect of oral supplementation with HT and PC (SAx) on early atherosclerosis markers in middle-aged, seemingly healthy adults. A randomized, double-blinded, placebo-controlled, crossover trial was performed for 20 weeks. There were two treatment sequences (Placebo/SAx, n = 41; SAx/Placebo, n = 43) for which the intervention periods (Placebo and SAx) were 8 weeks long, followed by a 4-week wash out period. The supplement was composed of 9.9 mg of HT and 195 mg of PC, and the placebo was composed of maltodextrin. SAx increased endothelial function (Flow-mediated dilatation [FMD]: 2.36%; p < 0.001) in the endothelial dysfunction subgroup compared to the placebo (2.36 ± 3.9 vs. 0.76 ± 3.5%, p < 0.05). SAx also reduced oxLDL by -28.74 ng/mL (p < 0.05) in subjects with higher levels of oxLDL, which was an improvement compared with the placebo (-28.74 ± 40.2 vs. 25.64 ± 93.8 ng/mL, p < 0.001). The prehypertension and hypertension subgroups exhibited decreased systolic (-15.75 ± 9.9 mmHg; p < 0.001) and diastolic (-6.36 ± 8.7 mmHg; p < 0.001) blood pressure after SAx consumption. Moreover, the systolic prehypertension and hypertension subgroups presented significant differences in systolic blood pressure compared to the placebo (-15.75 ± 9.9 vs. -2.67 ± 12.0 mmHg, p < 0.05). In conclusion, the supplement exerted anti-atherosclerotic effects by improving endothelial function, blood pressure, and levels of circulating oxLDL, especially for persons in whom these parameters were altered.


Assuntos
Aterosclerose/terapia , Cardiotônicos/administração & dosagem , Suplementos Nutricionais , Taninos Hidrolisáveis/administração & dosagem , Álcool Feniletílico/análogos & derivados , Idoso , Aterosclerose/etiologia , Aterosclerose/fisiopatologia , Biomarcadores/metabolismo , Pressão Sanguínea/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Álcool Feniletílico/administração & dosagem , Pré-Hipertensão/complicações , Pré-Hipertensão/fisiopatologia , Pré-Hipertensão/terapia , Resultado do Tratamento
8.
J Pharmacol Sci ; 139(3): 193-200, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827890

RESUMO

Ischemia/reperfusion (I/R)-induced oxidative stress is a serious clinical problem in the reperfusion therapy for ischemic diseases. Tumstatin is an endogenous bioactive peptide cleaved from type IV collagen α3 chain. We previously reported that T3 peptide, an active subfragment of tumstatin, exerts cytoprotective effects on H2O2-induced apoptosis through the inhibition of intracellular reactive oxygen species (ROS) production in H9c2 cardiomyoblasts. In this study, we investigated whether T3 peptide has cardioprotective effects against I/R injury by using in vitro and ex vivo experimental models. H9c2 cardiomyoblasts were stimulated with oxygen and glucose deprivation (OGD) for 12 h followed by reoxygenation for 1-8 h (OGD/R; in vitro model). The cells were treated with T3 peptide (30-1000 ng/ml) during OGD. Ten minutes after the pre-perfusion of T3 peptide (300 ng/ml), Langendorff perfused rat hearts were exposed to ischemia for 30 min followed by reperfusion for 1 h (ex vivo model). T3 peptide inhibited OGD/R-induced apoptosis through the inhibition of mitochondrial ROS production and dysfunction in H9c2 cardiomyoblasts. T3 peptide also prevented I/R-induced cardiac dysfunction, arrhythmia and myocardial infarction in the perfused rat heart. In conclusion, we for the first time demonstrated that T3 peptide exerts cardioprotective effects against I/R injury.


Assuntos
Apoptose/efeitos dos fármacos , Autoantígenos/administração & dosagem , Cardiotônicos/administração & dosagem , Colágeno Tipo IV/administração & dosagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Autoantígenos/química , Autoantígenos/farmacologia , Cardiotônicos/farmacologia , Linhagem Celular , Colágeno Tipo IV/química , Colágeno Tipo IV/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/complicações , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
9.
Br J Anaesth ; 122(4): 428-436, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30857599

RESUMO

BACKGROUND: The vasoactive-inotropic score (VIS) predicts mortality and morbidity after paediatric cardiac surgery. Here we examined whether VIS also predicted outcome in adults after cardiac surgery, and compared predictive capability between VIS and three widely used scoring systems. METHODS: This single-centre retrospective cohort study included 3213 cardiac surgery patients. Maximal VIS (VISmax) was calculated using the highest doses of vasoactive and inotropic medications administered during the first 24 h post-surgery. We established five VISmax categories: 0-5, >5-15, >15-30, >30-45, and >45 points. The predictive accuracy of VISmax was evaluated for a composite outcome, which included 30-day mortality, mediastinitis, stroke, acute kidney injury, and myocardial infarction. RESULTS: VISmax showed good prediction accuracy for the composite outcome [area under the curve (AUC), 0.72; 95% confidence interval (CI), 0.69-0.75]. The incidence of the composite outcome was 9.6% overall and 43% in the highest VISmax group (>45). VISmax predicted 30-day mortality (AUC, 0.76; 95% CI, 0.69-0.83) and 1-yr mortality (AUC, 0.70; 95% CI, 0.65-0.74). Prediction accuracy for unfavourable outcome was significantly better with VISmax than with Acute Physiology and Chronic Health Evaluation II (P=0.01) and Simplified Acute Physiological Score II (P=0.048), but not with the Sequential Organ Failure Assessment score (P=0.32). CONCLUSIONS: In adults after cardiac surgery, VISmax predicted a composite of unfavourable outcomes and predicted mortality up to 1 yr after surgery.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiotônicos/administração & dosagem , Vasoconstritores/administração & dosagem , APACHE , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos/mortalidade , Cuidados Críticos/métodos , Relação Dose-Resposta a Droga , Feminino , Finlândia/epidemiologia , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco/métodos , Índice de Gravidade de Doença , Adulto Jovem
10.
Pharmacology ; 103(5-6): 291-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820014

RESUMO

BACKGROUND/AIMS: Rhapontigenin (RPG) is a stilben derivative and is known to bear several effects such as antiallergic, anticoagulative, hypoglycemic, antiangiogenic, and purgative. The investigation was conducted to evaluate the cardioprotective efficacy of RPG in rats having acute myocardial infarction (MI) induced by isoproterenol (ISO). METHODS: Animals were divided into 6 groups: group I (control group), group II (ISO-treated), group III (1.0 mg/kg/day RPG and ISO-treated), group IV (2.5 mg/kg/day RPG and ISO-treated), group V (5.0 mg/kg/day RPG and ISO-treated), and group VI (treated with RPG 5.0 mg/kg/day). Various cardiac stress markers, including infarct size and heart/body weight index, were investigated in animals with ISO-induced MI, such as inducible nitric oxide synthase (iNOS), creatinine kinase (CK), lactate dehydrogenase (LD), cardiac troponin-T (CTT), superoxide dismutase (SOD), and malondialdehyde. INOS, p38, caspase-3, and connexin 43 expressions were analyzed in animals. Inflammatory mediators, tissue necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were detected in serum of experimental animals. RESULTS: Group I animals indicated normal levels of biochemical parameters, whereas group II animals indicated high levels of these parameters and successful induction of MI. Pretreatment of animal groups III, IV, and V with RPG revealed amelioration of infarct size, heart/body weight index, CK, LD, CTT in rats, whereas group VI animals were treated only with RPG (5.0 mg/kg/day) and not with ISO. Levels of TNF-α, IL-6, MD, SOD, p38, and iNOS expressions were significantly downregulated by RPG administration (5.0 mg/kg/day). CONCLUSION: RPG ameliorates MI caused by ISO in rats and provides cardioprotective effect, via anti-inflammatory, antioxidant, and antiapoptotic effect.


Assuntos
Cardiotônicos/farmacologia , Infarto do Miocárdio/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Isoproterenol/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley , Estilbenos/administração & dosagem
11.
J Vet Pharmacol Ther ; 42(3): 285-293, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30724383

RESUMO

This study aimed to assess the effects of incremental doses of dobutamine on diastolic function in healthy and rapid ventricular apical pacing (RVAP)-induced cardiac dysfunction anesthetized dogs. Inotropic and lusitropic effects of dobutamine (2, 4, 8, and 12 µg kg-1  min-1 ) were assessed through left ventricle (LV) pressure-volume relation and Doppler echocardiography in six female dogs before and after 8 weeks of RVAP. Peak rate of LV pressure fall (-dP/dtmin ) improved with doses >4 µg kg-1  min-1 in healthy (4,490 ± 970 vs. 3,265 ± 471 mmHg/s, p < 0.05) and >8 µg kg-1  min-1 in RVAP dogs (3,385 ± 1,122 vs. 1,864 ± 849 mmHg/s, p < 0.05) while the time constant of relaxation (tau) reduced with doses >4 µg kg-1  min-1 in both groups (healthy: 24.0 ± 3.7 vs. 28.2 ± 4.9 ms; RVAP: 32.6 ± 8.5 vs. 37.5 ± 11.4 ms, p < 0.05) comparing with baseline. Indices of relaxation (-dP/dtmin and tau) suggested preserved lusitropic response in contrast with markedly reduced indices of contractility in the RVAP group compared with healthy group at same infusion rates. Doppler echocardiography showed significant reduction of elastic recoil in failing hearts. The results of this study demonstrated maximal positive lusitropic effects of dobutamine at a dose of 8 µg kg-1  min-1 in ventricular pacing-induced cardiac dysfunction without further impairment of ventricular filling.


Assuntos
Arritmias Cardíacas/veterinária , Cardiotônicos/uso terapêutico , Dobutamina/uso terapêutico , Doenças do Cão/tratamento farmacológico , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Cardiotônicos/administração & dosagem , Dobutamina/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Ecocardiografia Doppler/veterinária , Feminino , Ventrículos do Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
12.
J Pharmacol Sci ; 139(3): 180-185, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30738725

RESUMO

We analyzed how the enhancement of net sarcoplasmic reticulum (SR) Ca2+ uptake may affect cardiac electrophysiological properties in vivo by using caldaret which can decrease SR diastolic Ca2+ leak, enhance SR Ca2+ reuptake and inhibit reverse-mode Na+/Ca2+ exchanger. Caldaret in doses of 0.5, 5 and 50 µg/kg was intravenously administered over 10 min to the halothane-anesthetized beagle dogs (n = 5), attaining pharmacologically active plasma concentration. The low and middle doses of caldaret increased the ventricular contraction, which could be explained by its on-target pharmacological activities. The high dose enhanced the sinus automaticity followed by its suppression in addition to the increase of the total peripheral resistance, which may be unfavorable for treating diastolic heart failure. The low and middle doses enhanced the atrioventricular conduction, which may have some potential for predisposing the atria to the onset of atrial fibrillation via an induction of mitral and/or tricuspid regurgitation. The middle and high doses of caldaret prolonged the ventricular effective refractory period without altering the intraventricular conduction or repolarization period, which may prevent the onset of ventricular arrhythmias. Thus, modulation of intracellular Ca2+ handling by caldaret can induce not only inotropic effect, but also various electrophysiological actions on the in situ heart.


Assuntos
Benzenossulfonatos/farmacologia , Cálcio/administração & dosagem , Cardiotônicos/farmacologia , Piperazinas/farmacologia , Retículo Sarcoplasmático/efeitos dos fármacos , Animais , Arritmias Cardíacas/prevenção & controle , Benzenossulfonatos/administração & dosagem , Cálcio/metabolismo , Cardiotônicos/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Técnicas Eletrofisiológicas Cardíacas , Feminino , Halotano/administração & dosagem , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Piperazinas/administração & dosagem , Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismo
13.
J Pharm Pharmacol ; 71(5): 826-838, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30604484

RESUMO

OBJECTIVES: To evaluate the advantages and disadvantages of using different standard concentration infusions for high-alert inotropic and vasoactive drugs in paediatric intensive care units (ICUs). METHODS: Retrospective data analysis was performed on drug prescriptions for patients in paediatric ICUs. A matrix was developed based on optimal concentration recommendations for each drug, taking into consideration solution stability and patient safety. Hypothetical volumes were calculated for three standard solutions (high concentration - HC, low concentration - LC and fluid restriction - FR) and compared to the actual administered volumes to evaluate the impact of the volumes of each standard solution for varying weight ranges in paediatric care. Finally, a risk assessment of the standard infusions was conducted using the NPSA 20 tool along with an assessment of the pharmacoeconomic impact. KEY FINDINGS: The results suggest the need for at least two standard concentrations for each of the studied drugs in order to attend to the different weight ranges and clinical conditions of paediatric patients in intensive care. CONCLUSIONS: High concentration is ideal for patients up to 20 kg. For patients over 20 kg, FR is recommended, while LC should only be used in specific situations. Modifying the hospital pharmacotherapy system to include standard solutions is safer and reduces the risks of adverse effects. The pharmacoeconomic analysis did not show any impact on costs, although a reduction in adverse effects should be considered.


Assuntos
Cardiotônicos/administração & dosagem , Unidades de Terapia Intensiva Pediátrica , Segurança do Paciente/normas , Vasoconstritores/administração & dosagem , Vasodilatadores/administração & dosagem , Criança , Pré-Escolar , Dobutamina/administração & dosagem , Dopamina/administração & dosagem , Epinefrina/administração & dosagem , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas/normas , Concentração Máxima Permitida , Milrinona/administração & dosagem , Estudos Retrospectivos , Medição de Risco
14.
Life Sci ; 219: 294-302, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668954

RESUMO

AIMS: Exogenous tetrahydrobiopterin (BH4), an indispensable cofactor of endothelial nitric oxide synthase (eNOS), supplementation has been proved to be of advantage to improve cardiovascular function. Nevertheless, due to its highly redox-sensitive and easy to be oxidized, there is an urgent need to develop an appropriate BH4 formulation for clinical therapy. Gum Arabic (GA) has been considered as an alternative biopolymer for the stabilization and coating of drugs. The effects of GA on protecting BH4 from being oxidized were investigated in a rat model of myocardial ischemia-reperfusion (I/R). MAIN METHODS: Rats were subjected to 60-min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic GA-coated BH4 supplementation (10 mg/kg, oral). Myocardial infarction, fibrotic area and left ventricle ejection fraction were correlated with cardiac BH4 content, eNOS protein, NOS enzyme activity, and ROS/NO generation. KEY FINDINGS: Pretreatment of rats with GA-coated 6R-BH4, 24 h before myocardial ischemia, resulted in smaller myocardial infarction, improved left ventricular function and inhibited fibrosis, correlated with maintained high levels of cardiac BH4 content, preserved eNOS activation and dimerization, and decreased ROS generation. However in uncoated group, 6R-BH4 treatment did not reduce acute and chronic myocardial I/R injury compared with control I/R rats, which was closely related with the marked loss of myocardial BH4 levels during I/R. SIGNIFICANCE: These findings provide evidence that in vivo pre-ischemic oral GA-coated BH4 administration preserves eNOS function secondary to maintaining cardiac BH4 content, and confers cardioprotection after I/R.


Assuntos
Biopterina/análogos & derivados , Cardiotônicos/uso terapêutico , Goma Arábica/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Biopterina/administração & dosagem , Biopterina/uso terapêutico , Cardiotônicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Ecocardiografia , Immunoblotting , Masculino , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Veículos Farmacêuticos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
15.
J Cardiothorac Vasc Anesth ; 33(3): 651-660, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30683595

RESUMO

OBJECTIVE: To report the authors' 12 years of experience with intratracheal milrinone administration and to assess the efficacy and limitations of intratracheal milrinone bolus administration for the treatment of unexpected acute right ventricular (RV) failure in patients undergoing cardiac surgery. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: One hundred seventy-six patients (4.6%) undergoing on-pump cardiac surgery. INTERVENTIONS: Endotracheal tube administration of milrinone (5-mg bolus) after unexpected acute RV failure during separation from cardiopulmonary bypass (CPB) weaning. RV failure was defined as the simultaneous presence of all of the following criteria: (1) hemodynamic instability or difficult separation from CPB with associated elevated central venous pressure or abnormal RV pressure waveform, (2) >20% reduction of RV fractional area change from baseline evaluated by transesophageal echocardiography, and (3) anatomical visualization of impaired or absent RV wall motion by direct intraoperative visual inspection. MEASUREMENTS AND MAIN RESULTS: Intratracheal milrinone administration was found to improve RV failure in 109 patients (61.9%) whereas RV failure persisted in 67 patients (38.1%). Using a multiple logistic regression model, severely decreased left ventricular ejection fraction (<35% v >50%) (adjusted odds ratio [OR] 3.72; 95% confidence interval [CI] 1.2-11.3; p = 0.012), longer CPB time (adjusted OR 1.014; CI 1.01-1.02; p = 0.001) and elevated postoperative fluid balance (adjusted OR 1.39; CI 1.1-1.8; p = 0.02) were found to be significant predictors of persistent RV failure. CONCLUSION: Intratracheal instillation of milrinone was associated with clinical improvement of RV failure occurring during separation from CPB in almost two-thirds of patients. Factors limiting its therapeutic efficacy include severe left ventricular dysfunction, increased fluid balance, and long CPB time.


Assuntos
Ponte Cardiopulmonar/tendências , Cardiotônicos/administração & dosagem , Intubação Intratraqueal/tendências , Milrinona/administração & dosagem , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/cirurgia , Doença Aguda , Idoso , Ecocardiografia Transesofagiana/tendências , Feminino , Insuficiência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Disfunção Ventricular Direita/diagnóstico por imagem
16.
Artigo em Inglês | MEDLINE | ID: mdl-30352307

RESUMO

Alternagin-C (ALT-C) is a disintegrin-like peptide purified from Rhinocerophis alternatus snake venom with the property of inducing vascular endothelial growth factor (VEGF) expression, endothelial cell proliferation and migration, and angiogenesis. Therefore, this protein could be interesting as a new approach for ischemic heart diseases, an imbalance between myocardial oxygen supply and demand, leading to cardiac dysfunction. We investigated the effects of a single dose of alternagin-C (0.5 mg kg-1, via intra-arterial), after 7 days, on hypoxia/reoxygenation challenge in isolated ventricle strips and on morphological changes and density of blood vessels of the heart, using fish as an alternative experimental model. ALT-C treatment provided protection of cardiomyocytes against hypoxia/reoxygenation-induced negative inotropism. ALT-C also stimulated angiogenesis and improved excitation-contraction coupling during hypoxic conditions. Our results provide a new insight into a functional role of ALT-C against hypoxia/reoxygenation-induced cardiomyocyte injury pointing out to a potential therapeutic strategy for ischemia-related diseases.


Assuntos
Bothrops , Cardiotônicos/uso terapêutico , Venenos de Crotalídeos/química , Modelos Animais de Doenças , Desintegrinas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Proteínas de Répteis/uso terapêutico , Indutores da Angiogênese/administração & dosagem , Indutores da Angiogênese/uso terapêutico , Animais , Aquicultura , Cardiotônicos/administração & dosagem , Caraciformes , Colágeno/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Desintegrinas/administração & dosagem , Acoplamento Excitação-Contração/efeitos dos fármacos , Proteínas de Peixes/metabolismo , Coração/efeitos dos fármacos , Coração/fisiologia , Coração/fisiopatologia , Injeções Intra-Arteriais , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas de Répteis/administração & dosagem
17.
Biomed Pharmacother ; 109: 2136-2144, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551471

RESUMO

Metformin is one of the most commonly prescribed antidiabetic drugs. A recent clinical study has highlighted the protective role of metformin against cardiac complications in type I diabetes. Curcumin is a natural compound with well-known antioxidant and anti-inflammatory properties. The present study was designed to investigate the possible role of curcumin in potentiating metformin`s putative effects. Rats received single injection of 52.5 mg/kg streptozocin and the diabetic rats were treated with metformin (200 mg/kg/day), curcumin (100 mg/kg/day) and their combination for 6 weeks. Diabetic rats showed degenerated myocardium as well as significant increase in Creatine Kinase-MB (CK-MB), troponin I and TGF-ß1 levels. In addition, cardiac levels of lipid peroxidation, IL-6, and NF-κB were significantly elevated. Although treatment with metformin restored most of the measured parameters, it showed insignificant improvement in histopathological architecture accompanied by absence of antioxidant effect. Interestingly, concomitant administration of curcumin along with metformin revealed more protection than metformin alone. Inhibition of JAK/STAT pathway and activation of Nrf2/HO-1 pathway seems to be among the mechanisms mediating the effects of curcumin and metformin. The findings of this study highlight the benefits of metformin/curcumin combination in preventing diabetic cardiomyopathy.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Cardiotônicos/administração & dosagem , Curcumina/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Metformina/administração & dosagem , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Sinergismo Farmacológico , Coração/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Resultado do Tratamento
18.
Biochem Soc Trans ; 47(1): 265-272, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30578348

RESUMO

Recent and exciting in vivo studies show that supplementation with the polyamine spermidine (Spd) is cardioprotective and prolongs lifespan in both mice and humans. The mechanisms behind Spd-induced cardioprotection are supposed to involve Spd-evoked stimulation of autophagy, mitophagy and mitochondrial respiration and improved the mechano-elastical function of cardiomyocytes. Although cellular uptake of Spd was not characterized, these results suggest that Spd is imported by the cardiomyocytes and acts intracellularly. In the light of these new and thrilling data, we discuss in the present review cellular polyamine import with a special focus on mechanisms that may be relevant for Spd uptake by electrically excitable cells such as cardiomyocytes.


Assuntos
Cardiotônicos/administração & dosagem , Cardiotônicos/metabolismo , Suplementos Nutricionais , Longevidade , Miócitos Cardíacos/efeitos dos fármacos , Espermidina/administração & dosagem , Espermidina/metabolismo , Animais , Transporte Biológico , Cardiotônicos/farmacologia , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Espermidina/farmacologia
19.
Biomed Pharmacother ; 111: 1-5, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30551029

RESUMO

The interleukin-1 (IL-1) signaling pathway plays a vital role in multiple mechanisms associated with myocardial ischemia-reperfusion (I/R) injury, including inflammation and apoptosis. An IL-1 receptor antagonist (IL-1Ra) can block IL-1 by competitive binding to the IL-1 receptor type I (IL-1RI) and thus may provide a cardioprotective effect. In the present investigation, we determined whether exogenous administration of recombinant human IL-1Ra (rhIL-1Ra) provides a protective role against myocardial I/R injury. Sprague-Dawley rats underwent surgical coronary artery ligation (or sham operation) by occlusion of the left anterior descending artery (LAD) for 30 min followed by reperfusion. After 30 min of reperfusion, a 2 mg/kg dose of rhIL-1Ra was injected subcutaneously. This was followed up with once daily injections for seven days. Echocardiography revealed that ejection fraction (EF) values were significantly greater in the rhIL-1Ra-treated animals. RhIL-1Ra was found to reduce the severity of myocardial injury and increase the viability of the cardiac tissue. There was found to be less IL-1ß expression in rhIL-1Ra-treated animals than in controls. These results provide compelling data to suggest administration of IL-1Ra could have a significant cardioprotective effect against myocardial I/R injury and thus IL-1Ra could emerge as a potential clinical drug for the treatment of myocardial I/R injury.


Assuntos
Cardiotônicos/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem
20.
Medicine (Baltimore) ; 97(30): e11383, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30045259

RESUMO

OBJECTIVES: This study assessed the efficacy of oral consumption of N-acetyl cysteine (NAC) and melatonin (ML) in reducing early reperfusion injury and acute oxidative stress in patients undergoing coronary artery bypass grafting (CABG) with respect to the measurements of cardiac troponin I, lactate, malondealdehyde (MDA), and tumor necrosis factor-α (TNF-α) levels in the blood. METHODS: This study was a randomized, open-label, placebo-controlled trial. Eighty eight patients, aged between 39 to 76 years and eligible for CABG, were recruited and randomly assigned into 3 intervention groups through a simple randomization method and underwent CABG surgery. Blood samples were withdrawn from arterial line, before the induction of anesthesia (before the start of surgery), after incision (before aortic cross-clamping), during global ischemia (during aortic cross-clamping), after aortic cross-clamping (on set of reperfusion), 15 minutes after reperfusion, and after recovery at the intense care unit. The blood samples were analyzed for troponin I, lactate, MDA and TNF-α levels. RESULTS: There was no significant difference in influencing variables among the groups at the baseline. Overall mean troponin I, lactate, and TNF- α levels were significantly different between the intervention groups (all P < .001) at the recovery phase. Post-hoc pairwise comparisons showed that the differences of mean serum levels between ML and control groups were statistically significant for MDA, TNF- α, lactate, and troponin I (P < .001, P = .001, and P = .001, respectively). The differences between NAC and control groups and between ML and NAC groups were only significant for mean lactate level (P < .001). CONCLUSION: The current study revealed that ML and NAC are potent antioxidants with similar efficacy in terms of reducing CABG related cardiac injury and oxidative stress with the dosage employed for the intervention.


Assuntos
Acetilcisteína/administração & dosagem , Ponte de Artéria Coronária/efeitos adversos , Doença das Coronárias , Melatonina/administração & dosagem , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Antioxidantes/administração & dosagem , Cardiotônicos/administração & dosagem , Ponte de Artéria Coronária/métodos , Doença das Coronárias/metabolismo , Doença das Coronárias/cirurgia , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Resultado do Tratamento
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