Glucocorticoid adrenoceptor combination

Agonists activating β(2)-adrenoceptors (β(2)ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac...

The phosphodiesterase 4 inhibitor (PDE4i) roflumilast has been approved in the US and EU for treatment of GOLD stage 3 and 4 chronic obstructive pulmonary disease (COPD). Inhaled β2 adrenoceptor agonist bronchodilators and anti-inflammatory glucocorticosteroids are also used as standard of care in COPD. We investigated the anti-inflammatory interaction of roflumilast in combination with long-acting β2 agonists (LABA), salmeterol or formoterol, or a glucocorticosteroid, dexamethasone, on cytokine production from LPS-stimulated human primary peripheral blood mononuclear cells (PBMC)...

In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling...

Glucocorticosteroids are the mainstay treatment for chronic asthma; however, adverse effects can limit their usefulness. We previously determined in experimental asthma that chronic administration of β₂-adrenoceptor inverse agonists reduced airway hyperresponsiveness and indexes of inflammation. However, the effect of co-administration of glucocorticosteroids with β₂-adrenoceptor inverse agonists is unknown. Therefore, we evaluated the anti-inflammatory effect of co-administration of dexamethasone, a glucocorticosteroid, and nadolol, a β₂-inverse agonist, in a murine asthma model...

Systemic administration of the β(2)-adrenoceptor agonist clenbuterol induces expression of IL-1β and its negative regulators, interleukin-1 receptor antagonist (IL-1ra) and the interleukin-1 type II decoy receptor (IL-1RII) in rat brain. Clenbuterol also increases central expression of the broad spectrum anti-inflammatory cytokine interleukin-10 (IL-10) and its downstream signalling molecule, suppressor of cytokine signalling-3 (SOCS-3). Here we examine the impact of combined treatment with clenbuterol (0...

Stress modulates instrumental action in favor of habitual stimulus-response processes that are insensitive to changes in outcome value and at the expense of goal-directed action-outcome processes. The neuroendocrine mechanism underlying this phenomenon is unknown. Here, we tested the hypothesis that concurrent glucocorticoid and noradrenergic activity bias instrumental behavior toward habitual performance. To this end, healthy men and women received hydrocortisone, the alpha2-adrenoceptor antagonist yohimbine or both orally before they were trained in two instrumental actions leading to two distinct food outcomes...

BACKGROUND: Chronic use of long-acting beta2-adrenergic receptor agonists (LABAs), resulting in beta2-adrenergic receptor desensitization, has been associated with increased asthma morbidity. When LABAs are used in combination with inhaled glucocorticoids, however, asthma control is improved, raising the following question: Do glucocorticoids inhibit the proasthmatic mechanism that mediates altered contractility in LABA-exposed airway smooth muscle (ASM)? OBJECTIVE: This study aimed to identify the potential protective role and mechanism of action of glucocorticoids in mitigating the effects of prolonged LABA exposure on ASM constrictor and relaxation responsiveness...

Glucocorticoids are widely used to treat various inflammatory lung diseases. Acting via the glucocorticoid receptor (GR), they exert clinical effects predominantly by modulating gene transcription. This may be to either induce (transactivate) or repress (transrepress) gene transcription. However, certain individuals, including those who smoke, have certain asthma phenotypes, chronic obstructive pulmonary disease (COPD) or some interstitial diseases may respond poorly to the beneficial effects of glucocorticoids...

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte. In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils. Human neutrophils were preincubated with salmeterol or FP or the combination...

Inhaled long-acting beta(2)-adrenoceptor agonists and glucocorticoids form the mainstay of maintenance treatment of asthma and chronic obstructive pulmonary disease (COPD), usually given as a combination inhaler. Most patients will have good asthma control if they comply with this therapy, although it is generally less effective in COPD. The traditional dogma has been that these agents act on distinct components of disease pathophysiology with beta(2) agonists acting on the bronchospastic component and glucocorticoids acting on the inflammatory component...

There is unequivocal evidence that the combination of an inhaled corticosteroid (ICS) -- i.e. glucocorticoid -- and an inhaled long-acting beta(2)-adrenoceptor agonist (LABA) is superior to each component administered as a monotherapy alone in the clinical management of asthma. Moreover, Calverley and colleagues (Lancet 2003, 361: 449-456; N Engl J Med 2007, 356: 775-789) reporting for the 'TRial of Inhaled STeroids ANd long-acting beta(2)-agonists (TRISTAN)' and 'TOwards a Revolution in COPD Health (TORCH)' international study groups also demonstrated the superior efficacy of LABA/ICS combination therapies over ICS alone in the clinical management of chronic obstructive pulmonary disease...

Biochemical modifications induced by a combination of anabolic compounds in target organs of male veal calves have been evaluated. Six male Friesian crossbred calves were treated with of 17beta-estradiol, dexamethasone sodium phosphate and clenbuterol or served as controls. beta-Adrenoceptors (beta-ARs) were measured in myocardium, lung, spleen, cerebral cortex, hippocampus, thalamus, hypothalamus, and hypophysis, glucocorticoid receptors (GRs) in the spleen and androgen receptors (AnRs) in the testis, by binding assay...

Asthma bronchiale, an inflammatory airway disease, imposes a significant health care problem worldwide. It is characterized by three critical phenotypic traits: intermittent and reversible bronchoconstriction, bronchial hyperresponsiveness and airway inflammation. Conventional therapy basically consists of beta(2)-adrenoceptor agonists in combination with glucocorticoids. Nevertheless, there is an urgent need for novel therapies, both for patients with uncontrollable disease symptoms and for those suffering from glucocorticoid-insensitive asthma...

Asthma incidence has climbed markedly in the past two decades despite an increased use of medications that suppress airway inflammation and repress contraction of smooth muscle that encircles the airways. Asthmatics exhibit episodes of airway inflammation that potentiates reversible airway smooth muscle spasm. A hallmark diagnostic symptom of asthma is airway hyperresponsiveness to inhaled non-allergic stimuli, such as methacholine, that directly induce airway smooth muscle contraction. Inhaled gluccocorticoids are used for first-line prevention of airway inflammation, and are frequently combined with inhaled beta2-adrenoceptor agonists that can effectively relax airway smooth muscle and restore airway conductance...

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used as maintenance therapy in patients with moderate to severe asthma or chronic obstructive pulmonary disease (COPD). The main effect of inhaled corticosteroids is thought to be mediated through suppression of airway inflammation, while long-acting beta2-adrenoceptor agonists are thought to work by inducing bronchodilation. However, there is emerging data to indicate that these two classes of drugs interact positively with each other, leading to added or perhaps synergistic benefits for patients...

Beta(2)-Agonists blunt the function of the beta-adrenoceptor G-protein adenylate cyclase-signalling system, whereas glucocorticoids reverse the agonist-mediated diminished beta-adrenergic responses; however, these effects have not been reported in vivo in calf lymphocytes. In this study, we first investigated the presence of the beta(2)-adrenergic receptors on calf lymphocytes, and second we tested the effects of either clenbuterol alone or in combination with dexamethasone on receptor expression and function (isoproterenol-induced intracellular adenosine 3',5'-cyclic monophosphate (cAMP) formation) in vivo...

None of the available drugs for chronic obstructive pulmonary disease is able to reduce the progressive decline in lung function which is the hallmark of this disease. Smoking cessation is the only intervention that has been shown so far to reduce disease progression. The current pharmacological therapy for chronic obstructive pulmonary disease is largely symptomatic and is based on bronchodilators including selective beta2-adrenoceptor agonists (short- and long-acting), anticholinergics, theophylline, or a combination of these drugs...

The use of a regular long-acting beta2-adrenoceptor agonists (beta2-agonists; LABA) is now established in asthma guidelines as the preferred option for second-line controller therapy in addition to inhaled corticosteroids. This has been driven by data showing beneficial effects of LABAs on exacerbation rates, in turn suggesting a putative corticosteroid-sparing effect. As LABAs are devoid of any clinically meaningful anti-inflammatory activity in vivo, their effects on exacerbations are presumably due to a diurnal stabilising effect on airway smooth muscle...

BACKGROUND: Increased airway smooth muscle bulk is a pathological feature of asthma. Asthma is well controlled by the combined inhalation of glucocorticoids and beta2-adrenoceptor agonists. The basic molecular mechanism of the interaction of the two drugs on proliferation of airway smooth muscle cells is yet to be identified. Our aim was to elucidate how glucocorticoids and beta2 agonists affect the growth of human bronchial airway smooth muscle cells. METHODS: We assessed the effect of formoterol and budesonide on the activation and function of transcription factors by immunohistochemistry, western blotting, DNA mobility shift assay, and a luciferase reporter gene assay...

The current concept of asthma therapy is based on a stepwise approach, depending on disease severity, and the aim is to reduce the symptoms that result from airway obstruction and inflammation, to prevent exacerbations and to maintain normal lung function. Beta2-adrenoceptor agonists and glucocorticoids are at present the most effective drugs for the treatment of airway obstruction and inflammation, with theophylline, leukotriene receptor antagonists and anticholinergics as second- or third-line therapy. There are, to date, no additional or newly developed drugs available that add substantially to the current strategies or even replace beta2-adrenoceptor agonists or glucocorticoids...