Protocatechuic acid reverses myocardial infarction mediated by ß-adrenergic agonist via regulation of Nrf2/HO-1 pathway, inflammatory, apoptotic, and fibrotic events.

Myocardial infarction (MI) is an instant ischemic death of cardiomyocytes that remains a major global cause of mortalities. MI is accompanied by oxidative, inflammatory, apoptotic, and fibrotic insults. Protocatechuic acid (PCA) is a polyphenolic compound with various potent biological activities. In this study, we explored the possible cardioprotective role of PCA against isoproterenol (ISO)-mediated MI. Rats were either injected with ISO (85 mg/kg, subcutaneously) or pretreated with PCA (100 or 200 mg/kg, orally). PCA supplementation markedly normalized ISO-induced disturbed cardiac function markers (creatine kinase-MB, lactate dehydrogenase, and troponin T). Notably, PCA administration exerted remarkable increases in glutathione and its derived enzymes, superoxide dismutase, and catalase, as well as decreases in malondialdehyde and nitric oxide levels in the injured cardiac tissue. The molecular findings validated the augmented cellular antioxidative capacity by PCA via increasing the gene expressions of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1. The cardioprotective efficacy of PCA extended to suppress cardiac inflammation as demonstrated by the decreased levels of tumor necrosis factor-alpha, interleukin-1 beta, and nuclear factor kappa B. Additionally, PCA prevented cardiomyocyte loss and fibrosis by decreasing Bax, caspase-3, transforming growth factor-ß1 and matrix metalloproteinase-9, and enhancing B-cell lymphoma 2 and tissue inhibitors of metalloproteinase-3. The cardiac histological screening further confirmed the PCA's protective action. The obtained data recommend PCA as an alternative therapeutic agent to attenuate the molecular, biochemical, and histological alterations associated with MI development.

Sex differences in excessive oral corticosteroid exposure in poor adherent adult asthmatics overusing short-acting ß-2 agonists.

BACKGROUND: We know that excessive short-acting ß2-agonists (SABA) use in asthma may be associated to high exacerbation risks. We studied whether such excessive SABA consumption is connected with different higher oral corticosteroid (OC) prescriptions in the two sexes. METHODS: In our prescribing database, we searched subjects aged 18-40 years that were prescribed at least one SABA package/year and/or at least two ICS or two ICS/LABA boxes/year to identify asthmatics. Their OC prescriptions/year were also examined. Subjects were divided into 4 groups according to SABA packages/year prescribed (0, 1-2,3-6 and ≥7), considering sexes separately. RESULTS: Individuals recruited were 9,102. Subjects with at least one OC prescription were higher in each group and were females (P<0.001). The OC packages/year number was also more elevated in women especially those with >7 SABA prescriptions/year (0.96 in males vs. 2.64 in females, P<0.001). 94.7%/93.6% males/females, who never used SABA, took at least one ICS/LABA (mean 5.84/5.48 packages/year), while the subject percentage adhering to ICS/LABA dropped to 28-47% (mean 0.94-3.82 packages/year) in those who used SABA (P<0.001). Higher SABA prescriptions were associated with an increasing OC dispensation (ß=0.057, P<0.0001). We observed also a greater risk of using >3 OC packages/year in subjects with 3-6 (OR: 2.98 [95% CI: 2.19-4.06], P<0.001) and ≥7 (OR: 3.49 [95% CI: 2.39-5.10], P<0.001) SABA prescriptions compared to those that never used SABA. Besides, we found that using ICS (OR:0.51 [95% CI: 0.35-0.75], P<0.001) or ICS/LABA (OR:0.07 [95% CI: 0.05-0.09], P<0.001) may significantly reduce SABA prescriptions. CONCLUSIONS: Poor adherence to maintenance treatment appears to associated with excessive SABA prescriptions that may lead to a higher OC consumption particularly noticeable in women.

Inclusão da ractopamina na nutrição de peixes: revisão de literatura / Inclusion of ractopamine in fish nutrition: literature review / Inclusión de ractopamina en nutrición de peces: revisión de literatura

A demanda da população mundial por produtos aquáticos esta se incrementando, enquanto que a produção da pesca extrativa reduzindo, alcançando em muitos casos, seu máximo potencial produtivo. Como consequência, não será possível em curto prazo, sustentar o fornecimento de produtos aquáticos, direcionado a uma população que constantemente cresce e demanda pescados. O setor produtivo segue a tendência atual de outros sistemas de produção animal, os quais vêm buscando o aumento da produtividade, de maneira sustentável, do ponto de vista econômico e ambiental, requerendo, principalmente, o aporte da nutrição para contribuir com essa tendência. Os estudos com os aditivos adicionados a dieta dos animais de cativeiro é uma estratégia que tem demonstrado alto potencial para sua inclusão na aquicultura, havendo a possibilidade de um aumento nos índices produtivos e/ou melhora na qualidade do produto para o consumidor. A ractopamina é um aditivo classificado como um agonista beta-adrenérgico e seu mecanismo de ação esta associado com efeitos sobre o metabolismo dos peixes que diminuem o acúmulo de gorduras, por meio da inibição da lipogêneses e estimulo da lipólise, e por mecanismos que favorecem a síntese de proteínas muscular. Os estudos realizados até o momento comprovam que existem alterações metabólicas nos peixes, embora, não se tem encontrado, em todos os estudos, diferenças significativas nos índices zootécnicos, para assim, estabelecer seu uso na indústria. A realização de mais pesquisas é necessária para o melhor entendimento da ractopamina na alimentação dos peixes, sobretudo, no entendimento dos receptores e mecanismos de ação dos peixes.(AU)

The demand of the global population for aquatic products is increasing while the production of extractive fisheries is reducing, and, in many cases, even reaching its maximum productive potential. As a consequence, it will not be possible in the short term to sustain the supply of aquatic products aimed at a population in constant growth and in demand for fish. The productive sector follows the current trend of other animal production systems, which have been seeking to sustainably increase productivity from an economic and environmental point of view, mainly requiring the contribution of nutrition to this trend. Studies with additives to the diet of captive animals is a strategy that has shown high potential for inclusion in aquaculture, with the possibility of an increase in production rates and/or improvement in the quality of the product for the consumer. Ractopamine is an additive classified as a beta-adrenergic agonist and its mechanism of action is associated with effects on fish metabolism that reduce the accumulation of fats through the inhibition of lipogenesis and stimulation of lipolysis, and by mechanisms that favor the synthesis of muscle protein. The studies carried out so far prove that there are metabolic changes in fish, although no significant differences have been found in zootechnical indexes in order to establish its use in the industry. Further research is required for a better understanding of ractopamine in fish nutrition, especially in understanding the receptors and mechanisms of action in fish.(AU)

La demanda de la población mundial por productos acuáticos va en aumento, mientras que la producción de la pesca extractiva se reduce, alcanzando, en muchos casos, su máximo potencial productivo. Como consecuencia, no será posible en corto plazo sostener el suministro de productos acuáticos, dirigidos a una población que crece constantemente y demanda pescado. El sector productivo sigue la tendencia actual de otros sistemas de producción animal, que han venido buscando incrementar la productividad, de manera sostenible, desde el punto de vista económico y ambiental, requiriendo, principalmente, del aporte de la nutrición para contribuir a esa tendencia. Los estudios con aditivos agregados a la dieta de animales en cautiverio es una estrategia que ha mostrado un alto potencial para su inclusión en la acuicultura, con posibilidad de incremento en los índices de producción y/o mejora en la calidad del producto para el consumidor. La ractopamina es un aditivo clasificado como agonista beta-adrenérgico y su mecanismo de acción está asociado con efectos sobre el metabolismo de los peces que reducen la acumulación de grasas, a través de la inhibición de la lipogénesis y estimulación del lipólisis, y por mecanismos que favorecen la síntesis de proteínas musculares. Los estudios realizados hasta el momento prueban que existen cambios metabólicos en los peces, aunque en todos los estudios no se han encontrado diferencias significativas en los índices zootécnicos, con el fin de establecer su uso en la industria. Se necesita más investigación para comprender mejor la ractopamina en la nutrición de los peces, especialmente para comprender los receptores y los mecanismos de acción en los peces.(AU)

Visnagin prevents isoproterenol-induced myocardial injury by attenuating oxidative stress and inflammation and upregulating Nrf2 signaling in rats.

Oxidative tissue injury and inflammatory responses play major roles in cardiovascular diseases and heart failure. Visnagin (VIS) is a natural bioactive component of Ammi visnaga, with promising radical scavenging and anti-inflammatory activities. This study explored the protective effect of VIS against isoproterenol (ISO)-induced acute myocardial injury and oxidative stress in rats. VIS was supplemented for 14 days, and the rats received ISO (100 mg/kg) twice at an interval of 24 h. ISO-induced myocardial injury was characterized by elevated serum CK-MB, LDH, and troponin-I associated with increased heart weight and several histopathological changes. ISO increased reactive oxygen species (ROS), malondialdehyde (MDA), NF-κB p65, TNF-α, IL-6, and decreased glutathione and antioxidant enzymes in rats' hearts. VIS prevented myocardial injury and ameliorated the cardiac function markers, ROS, MDA, NF-κB p65, and pro-inflammatory cytokines in ISO-intoxicated rats. In addition, VIS decreased Bax mRNA and caspases, and upregulated Nrf2, HO-1, Bcl-2, and PPARγ. Molecular docking simulations revealed the binding method of VIS to NF-κB, Keap1, and PPARγ. In conclusion, VIS protects against ISO-induced acute myocardial injury by attenuating oxidative tissue injury and reducing key inflammatory and apoptosis markers. In vivo and in silico results showed that activation of Nrf2/HO-1 signaling and PPARγ mediates the cardioprotective effect of VIS.

Early activation of the cardiac CX3CL1/CX3CR1 axis delays ß-adrenergic-induced heart failure.

We recently highlighted a novel potential protective paracrine role of cardiac myeloid CD11b/c cells improving resistance of adult hypertrophied cardiomyocytes to oxidative stress and potentially delaying evolution towards heart failure (HF) in response to early ß-adrenergic stimulation. Here we characterized macrophages (Mφ) in hearts early infused with isoproterenol as compared to control and failing hearts and evaluated the role of upregulated CX3CL1 in cardiac remodeling. Flow cytometry, immunohistology and Mφ-depletion experiments evidenced a transient increase in Mφ number in isoproterenol-infused hearts, proportional to early concentric hypertrophy (ECH) remodeling and limiting HF. Combining transcriptomic and secretomic approaches we characterized Mφ-enriched CD45+ cells from ECH hearts as CX3CL1- and TNFα-secreting cells. In-vivo experiments, using intramyocardial injection in ECH hearts of either Cx3cl1 or Cx3cr1 siRNA, or Cx3cr1-/- knockout mice, identified the CX3CL1/CX3CR1 axis as a protective pathway delaying transition to HF. In-vitro results showed that CX3CL1 not only enhanced ECH Mφ proliferation and expansion but also supported adult cardiomyocyte hypertrophy via a synergistic action with TNFα. Our data underscore the in-vivo transient protective role of the CX3CL1/CX3CR1 axis in ECH remodeling and suggest the participation of CX3CL1-secreting Mφ and their crosstalk with CX3CR1-expressing cardiomyocytes to delay HF.

Gastroesophageal reflux-like symptoms are associated with hyposalivation and oropharyngeal problems in patients with asthma.

BACKGROUND: Previous studies have suggested a significant relationship between hyposalivation and inhalation therapy-induced oropharyngeal problems. However, salivary secretion tests are not widely performed in daily clinical practice. In fact, xerostomia, the complaint of dry mouth, may not indicate hyposalivation. Therefore, we determined the clinical factors associated with hyposalivation in patients with asthma. METHODS: This study is a post-hoc analysis of our previous studies. Adult patients with asthma on maintenance inhalation therapy were enrolled. The participants completed questionnaires on oropharyngeal symptoms and underwent a salivary secretion test. Symptom severity was evaluated using a numerical rating scale (NRS), and salivary secretion was measured using the modified cotton roll method. Using logistic regression analysis, we identified the clinical factors associated with hyposalivation. RESULTS: In total, 531 patients completed the questionnaire (43.8 ± 16.9 years and male/female = 171/360), and 234 patients successfully performed a salivary secretion test, of which 126 (53.8%) were diagnosed with hyposalivation (<0.25 g/min). The patients with hyposalivation were significantly older (p < 0.0001) and had severe xerostomia and/or gastroesophageal reflux-like symptoms (GERLS) (p < 0.0001). Many of these patients had also used inhaled long-acting beta agonists (p = 0.012) and high-dose inhaled corticosteroids (p = 0.024). Multivariate analysis revealed that advanced age (odds ratio [OR] 1.05, p < 0.0001), severe xerostomia (OR 1.02, p = 0.0006) and severe GERLS (OR 1.02, p = 0.001) were independently and significantly associated with hyposalivation. CONCLUSIONS: Age, xerostomia, and GERLS were significantly related to hyposalivation in patients with asthma. To identify oropharyngeal problems in these patients, a careful assessment of the suspected symptoms of gastroesophageal reflux may be useful.

Isoproterenol Causing Coronary Vasospasm and ST Elevations During Tilt Table Testing.

Syncope is a sudden but reversible brief loss of consciousness secondary to an acute reduction of cerebral perfusion. Reflex syncope denotes neurologically mediated syncope, which includes vasovagal, carotid sinus syndrome, and other situational syncope. The most frequent form of syncope is vasovagal, which is triggered by emotional stress or prolonged standing, and may be diagnosed with the tilt table test. A thorough investigation of syncope is necessary as serious cardiovascular disorders may also be a cause. A tilt table test is a widely used tool utilized by clinicians to diagnose vasovagal syncope and is sometimes augmented with isoproterenol, a ß-sympathomimetic that acts on the heart. This report seeks to explain a case of a 48-year-old previously healthy woman who experienced inferior wall ST elevations during tilt table test supplemented with isoproterenol. There is reason to believe that the results of this patient's tilt table test were due to vasovagal syncope in conjunction with right coronary artery vasospasm.

Deletion of Microfibrillar-Associated Protein 4 Attenuates Left Ventricular Remodeling and Dysfunction in Heart Failure.

Background Cardiac remodeling predisposes individuals to heart failure if the burden is not solved, and heart failure is a growing cause of morbidity and mortality worldwide. The cardiac extracellular matrix not only provides structural support, but also is a core aspect of the myocardial response to various biomechanical stresses and heart failure. MFAP4 (microfibrillar-associated protein 4) is an integrin ligand located in the extracellular matrix, whose biological functions in the heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods and Results MFAP4-deficient (MFAP4-/-) and wild-type mice were subjected to aortic banding surgery and isoproterenol to establish models of cardiac remodeling. We also evaluated the functional effects of MFAP4 on cardiac hypertrophy, fibrosis, and cardiac electrical remodeling. The expression of MFAP4 was increased in the animal cardiac remodeling models induced by pressure overload and isoproterenol. After challenge of 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol, MFAP4-/- mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias than wild-type mice. However, there was no significant effect on cardiomyocyte hypertrophy. In addition, there was no significant difference in cardiac fibrosis severity, hypertrophy, or ventricular arrhythmia incidence between wild-type-sham and knockout-sham mice. Conclusions These findings are the first to demonstrate that MFAP4 deficiency inhibits cardiac fibrosis and ventricular arrhythmias after challenge with 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol but does not significantly affect the hypertrophy response. In addition, MFAP4 deficiency had no significant effect on cardiac fibrosis, hypertrophy, or ventricular arrhythmia in the sham group in this study.

Keeping the Finger on the Pulse: Cardiac Arrhythmias in Hand Surgery Using Local Anesthesia with Adrenaline.

BACKGROUND: The wide-awake local anesthesia no tourniquet (WALANT) technique in hand surgery is gaining popularity. The authors aimed to prospectively analyze the frequency and type of arrhythmias in patients undergoing hand surgery under local anesthesia and to examine whether the addition of adrenaline affects their incidence. METHODS: Adult patients undergoing hand surgery under local anesthesia were randomized into two groups: group 1, local anesthesia with lidocaine and tourniquet; and group 2, local anesthesia with lidocaine and adrenaline (WALANT). Patients with a history of arrhythmias were excluded. Patients were connected to Holter electrocardiographic monitoring before surgery and up until discharge. The records were blindly compared between the groups regarding types of arrhythmias, and frequency and timing relative to injection and tourniquet inflation. RESULTS: One hundred two patients were included between August of 2018 and August of 2019 (age, 59.7 ± 13.6 years; 71 percent women; 51 in each group). No major arrhythmia (ventricular tachycardia, ventricular fibrillation, atrial fibrillation) or arrhythmia-related symptoms were recorded for either group. Minor arrhythmias (including atrial premature beats, ventricular premature beats, and atrial tachycardia) were recorded in 68 patients (66.6 percent), with no statistical difference between the groups. There were three patients with minor arrhythmias during inflation of the tourniquet. Patients in the adrenaline group had 2 percent sinus tachycardia during injection and 4 percent asymptomatic bradyarrhythmias. These findings do not require any further treatment. CONCLUSIONS: The authors' results show that hand operations using WALANT technique in patients with no history of arrhythmia are safe and are not arrhythmogenic; therefore, there is no need for routine perioperative continuous electrocardiographic monitoring. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Severe hypokalemia secondary to abuse of ß-adrenergic agonists in a pediatric patient: Case report / Hipocalemia grave secundária a abuso de agonistas ß-adrenérgicos em paciente pediátrico: relato de caso

ABSTRACT This study reports a case of a 13-year-old male with a 3-year history of severe and intermittent hypokalemia episodes of unknown origin, requiring admission to the intensive care unit (ICU) for long QT syndrome (LQTS), finally diagnosed of redistributive hypokalemia secondary to the abuse of β-adrenergic agonists in the context of a probable factitious disorder.

RESUMO O presente estudo relata o caso de um jovem de 13 anos de idade com histórico, há três anos, de episódios de hipocalemia grave intermitente de origem desconhecida, internado em unidade de terapia intensiva (UTI) por síndrome do QT longo (SQTL). O paciente foi diagnosticado com hipocalemia por redistribuição secundária ao abuso de agonistas β-adrenérgicos, em contexto de provável transtorno factício.

Heat stress-induced deficits in growth, metabolic efficiency, and cardiovascular function coincided with chronic systemic inflammation and hypercatecholaminemia in ractopamine-supplemented feedlot lambs.

Heat stress hinders growth and well-being in livestock, an effect that is perhaps exacerbated by the ß1 agonist ractopamine. Heat stress deficits are mediated in part by reduced feed intake, but other mechanisms involved are less understood. Our objective was to determine the direct impact of heat stress on growth and well-being in ractopamine-supplemented feedlot lambs. Commercial wethers were fed under heat stress (40 °C) for 30 d, and controls (18 °C) were pair-fed. In a 2 × 2 factorial, lambs were also given a daily gavage of 0 or 60 mg ractopamine. Growth, metabolic, cardiovascular, and stress indicators were assessed throughout the study. At necropsy, 9th to 12th rib sections (four-rib), internal organs, and feet were assessed, and sartorius muscles were collected for ex vivo glucose metabolic studies. Heat stress increased (P < 0.05) rectal temperatures and respiration rates throughout the study and reduced (P < 0.05) weight gain and feed efficiency over the first week, ultrasonic loin-eye area and loin depth near the end of the study, and four-rib weight at necropsy. Fat content of the four-rib and loin were also reduced (P < 0.05) by heat stress. Ractopamine increased (P < 0.05) loin weight and fat content and partially moderated the impact of heat stress on rectal temperature and four-rib weight. Heat stress reduced (P < 0.05) spleen weight, increased (P < 0.05) adrenal and lung weights, and was associated with hoof wall overgrowth but not organ lesions. Ractopamine did not affect any measured indicators of well-being. Heat stress reduced (P < 0.05) blood urea nitrogen and increased (P < 0.05) circulating monocytes, granulocytes, and total white blood cells as well as epinephrine, TNFα, cholesterol, and triglycerides. Cortisol and insulin were not affected. Heat stress reduced (P < 0.05) blood pressure and heart rates in all lambs and increased (P < 0.05) left ventricular wall thickness in unsupplemented but not ractopamine-supplemented lambs. No cardiac arrhythmias were observed. Muscle glucose uptake did not differ among groups, but insulin-stimulated glucose oxidation was reduced (P < 0.05) in muscle from heat-stressed lambs. These findings demonstrate that heat stress impairs growth, metabolism, and well-being even when the impact of feed intake is eliminated by pair-feeding and that systemic inflammation and hypercatecholaminemia likely contribute to these deficits. Moreover, ractopamine improved muscle growth indicators without worsening the effects of heat stress.

[6]-Gingerol Ameliorates ISO-Induced Myocardial Fibrosis by Reducing Oxidative Stress, Inflammation, and Apoptosis through Inhibition of TLR4/MAPKs/NF-κB Pathway.

SCOPE: [6]-Gingerol is one of the primary pungent constituents of ginger. While [6]-gingerol has many pharmacological effects, its benefits for myocardial fibrosis, including its exact role and underlying mechanisms, remain largely unexplored. The present study is designed to characterize the cardio-protective effects of [6]-gingerol in myocardial fibrosis mice and possible underlying mechanisms. METHODS AND RESULTS: Mice are subcutaneously injected with isoproterenol (ISO, 10 mg kg-1 ) and gavaged with [6]-gingerol (10, 20 mg kg-1 day-1 ) for 14 days. Pathological alterations, fibrosis, oxidative stress, inflammation response, and apoptosis are examined. In ISO-induced myocardial fibrosis, [6]-gingerol treatment decreases the J-point, heart rate, cardiac weight index, left ventricle weight index, creatine kinase (CK), and lactate dehydrogenase serum levels, calcium concentration, reactive oxygen species, malondialdehyde, and glutathione disulfide (GSSG), and increases levels of superoxide dismutase, catalase, glutathione, and GSH/GSSG. Further, [6]-gingerol improved ISO-induced morphological pathologies, inhibited inflammation and apoptosis, and suppressed the toll-like receptor-4 (TLR4)/mitogen-activated protein kinases (MAPKs)/nuclear factor κB (NF-κB) signaling pathways. CONCLUSION: The protective effect of [6]-gingerol in mice with ISO-induced myocardial fibrosis may be related to the inhibition of oxidative stress, inflammation, and apoptosis, potentially through the TLR4/MAPKs/NF-κB signaling pathway.

Manipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling.

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.

Angiotensin (1-7) and Apelin co-therapy: New strategy for heart failure treatment of rats.

OBJECTIVE: Isoproterenol (ISO)-induced heart failure is a standardized model for the study of beneficial effects of various drugs. Both apelin and angiotensin 1-7 have a cardiac protective effect. We assumed that co-therapy with apelin and angiotensin 1-7 (Ang (1-7)) may have synergistic cardioprotective effects against isoproterenol-induced heart failure. Methods The animals were randomly assigned to one of eight groups of seven animals in each group as follows: (1) control I (saline; IP injection) (1) control II (saline; via mini-osmotic pump) (3) ISO (5 mg/ kg; IP), (4) Apelin (20µg/ kg; IP), (5) Ang (1-7) (30 µg/kg/day; via mini-osmotic pump), (6) Apelin+ISO, (7) Ang (1-7)+ISO, (8) Apelin+Ang (1-7)+ISO. Rat myocardial injury was induced by intraperitoneal injection of 5mg/kg of ISO for ten days. Apelin and Ang (1-7) were administered 30 minutes before ISO injection. RESULTS: A decrease in systolic blood pressure (SBP; p<0.001), diastolic blood pressure (DBP; p<0.05), left ventricular systolic pressure (LVSP; p<0.001), left ventricular contractility (dP / dt max; p<0.001), relaxation (dP / dt min; p<0.001) and an increase in left ventricular end-diastolic pressure (LVEDP; p<0.001) were observed in ISO-treated rats. Plasma LDH and myocardial and plasma MDA were higher in the ISO heart than in controls (P<0.001). Histopathological examination of cardiac tissue showed myocardial fibrosis and leukocyte infiltration in ISO-treated rats as compared to control. Co- therapy with apelin and Ang (1-7) was more effective than either agent used alone in restoring these parameters to that of control rats. CONCLUSION: The results of this study showed that the combination of apelin and ang (1-7) had a more cardioprotective effect than either used alone against ISO-induced heart failure, and co-therapy may be a useful treatment option for myocardial injuries and heart failure.

ß2-agonistas en asma: el extraño caso del Dr. Jekyll y Mr. Hyde / ß2-Agonists in Asthma: The Strange case of Dr. Jekyll and Mr. Hyde

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Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials.

BACKGROUND: Combinations of a long-acting muscarinic receptor antagonist (LAMA), long-acting ß-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstructive pulmonary disease (COPD) exacerbations on bronchodilator monotherapy. In this prespecified subgroup analysis, we assessed the efficacy and safety of the LAMA revefenacin in patients with COPD taking concomitant LABA, including ICS/LABA (LABA subgroup). METHODS: Efficacy data were obtained from two 12-week, replicate, placebo-controlled trials and safety data were pooled from the 12-week and a 52-week tiotropium-controlled trial. Patients received revefenacin 175 µg or placebo in the 12-week or tiotropium 18 µg in the 52-week studies. The efficacy endpoint was least squares (LS) mean change from baseline in trough forced expiratory volume in 1 second (FEV1). Clinical health outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ). RESULTS: Revefenacin produced similar improvements from baseline in trough FEV1 in the non-LABA and LABA subgroups [placebo-adjusted LS mean change (95% confidence interval) in day 85 trough FEV1, 150.9 (110.3-191.6) ml and 139.2 (82.9-195.5) ml; p < 0.0001 versus placebo]. Similar improvements were observed in SGRQ scores in the non-LABA and LABA subgroups [-3.3 (-5.4 to -1.2) and -3.4 (-6.3 to -0.6)]. Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse events reported in the LABA than the non-LABA subgroup. CONCLUSIONS: Once daily revefenacin for nebulization can be an effective and well-tolerated treatment for patients who require concomitant use of LABA with or without ICS. CLINICALTRIALS.GOV IDENTIFIERS: NCT02512510, NCT02459080, NCT02518139 The reviews of this paper are available via the supplemental material section.

Use of Antiasthmatic Drugs and the Risk of Type 1 Diabetes in Children: A Nationwide Case-Cohort Study.

Asthma has been reported to be associated with an increased risk of type 1 diabetes mellitus in childhood, but the reasons are unclear. We examined whether the use of antiasthmatic drugs was associated with the development of type 1 diabetes in childhood in a nationwide, register-based case-cohort study. We identified all children who were born January 1, 1995, through December 31, 2008, in Finland and diagnosed with type 1 diabetes by 2010 (n = 3,342). A 10% random sample from each birth-year cohort was selected as a reference cohort (n = 80,909). Information on all dispensed antiasthmatic drugs (Anatomical Therapeutic Chemical classification system code R03) during 1995-2009 was obtained, and associations between the use of antiasthmatic drugs and the development of type 1 diabetes were investigated using time-dependent and time-sequential Cox regression models. Dispensed inhaled corticosteroids and inhaled ß-agonists were associated with an increased risk of type 1 diabetes after adjusting for other antiasthmatic drugs, asthma, sex, and birth decade (hazard ratio = 1.29, 95% confidence interval: 1.09, 1.52, and hazard ratio = 1.22, 95% confidence interval: 1.07, 1.41, respectively). These findings suggest that children using inhaled corticosteroids or inhaled ß-agonists might be at increased risk of type 1 diabetes.