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Glucocorticoid adrenoceptor combination

Robert Newton, Mark A Giembycz
In moderate-to-severe asthma, adding-on an inhaled long-acting β2 -adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides superior disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti-inflammatory/anti-asthma gene expression. In vitro, LABAs synergistically enhance the maximal expression of many glucocorticoid-induced genes. Other genes, including DUSP1 in human airways smooth muscle (ASM) and epithelial cells, are up-regulated additively by both drug classes...
September 20, 2016: British Journal of Pharmacology
Basma Fatima Anwar Husain, Ishira N Nanavaty, Swananda V Marathe, Rajeev Rajendran, Vidita A Vaidya
Adjunct α2-adrenoceptor antagonism is a potential strategy to accelerate the behavioral effects of antidepressants. Co-administration of the α2-adrenoceptor antagonist yohimbine hastens the behavioral and neurogenic effects of the antidepressant imipramine. We examined the transcriptional targets of short duration (7days), combination treatment of yohimbine and imipramine (Y+I) within the adult rat hippocampus. Using microarray and qPCR analysis we observed functional enrichment of genes involved in intracellular signaling cascades, plasma membrane, cellular metal ion homeostasis, multicellular stress responses and neuropeptide signaling pathways in the Y+I transcriptome...
August 3, 2015: Progress in Neuro-psychopharmacology & Biological Psychiatry
Mark A Giembycz, Robert Newton
Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid...
2015: F1000Prime Reports
T Joshi, M Johnson, R Newton, M A Giembycz
BACKGROUND AND PURPOSE: Inhaled glucocorticoid (ICS)/long-acting β2 -adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism...
May 2015: British Journal of Pharmacology
Hawazen BinMahfouz, Bibhusana Borthakur, Dong Yan, Tresa George, Mark A Giembycz, Robert Newton
Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting β2-adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICSs alone. Using models of cAMP- and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared with inhibiting either PDE alone...
January 2015: Molecular Pharmacology
Jana Franke, Getu Abraham
Altered airway cell proliferation plays an important role in the pathogenesis of human bronchial asthma and chronic obstructive pulmonary disease (COPD) as well as the equine recurrent airway obstruction (RAO) with consistent changes, i.e. narrowing the airway wall, explained by proliferation and differentiation of fibroblasts. In permanent cell lines, it has been suggested that β2-adrenoceptor agonists and glucocorticoids regulate cell proliferation via the β2-adrenoceptor pathway; indeed, no study was carried out in fresh isolated primary equine bronchial fibroblasts (EBF)...
October 15, 2014: European Journal of Pharmacology
Mark A Giembycz, Robert Newton
Current international guidelines recommend that roflumilast be added on to an inhaled corticosteroid/long-acting β2-adrenoceptor agonist (LABA) combination therapy in high-risk patients with severe, bronchitic chronic obstructive pulmonary disease who have frequent acute exacerbations. This article presents evidence that a glucocorticoid, LABA, and phosphodiesterase (PDE) 4 inhibitor in combination can interact in a complex manner to induce a panel of genes that could act collectively to suppress inflammation and improve lung function...
March 2014: Clinics in Chest Medicine
Neil S Holden, Tresa George, Christopher F Rider, Ambika Chandrasekhar, Suharsh Shah, Manminder Kaur, Malcolm Johnson, David P Siderovski, Richard Leigh, Mark A Giembycz, Robert Newton
In asthma and chronic obstructive pulmonary disease (COPD) multiple mediators act on Gαq-linked G-protein-coupled receptors (GPCRs) to cause bronchoconstriction. However, acting on the airway epithelium, such mediators may also elicit inflammatory responses. In human bronchial epithelial BEAS-2B cells (bronchial epithelium + adenovirus 12-SV40 hybrid), regulator of G-protein signaling (RGS) 2 mRNA and protein were synergistically induced in response to combinations of long-acting β2-adrenoceptor agonist (LABA) (salmeterol, formoterol) plus glucocorticoid (dexamethasone, fluticasone propionate, budesonide)...
January 2014: Journal of Pharmacology and Experimental Therapeutics
Thunicia Moodley, Sylvia M Wilson, Taruna Joshi, Christopher F Rider, Pawan Sharma, Dong Yan, Robert Newton, Mark A Giembycz
Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized...
April 2013: Molecular Pharmacology
Ann Allen, Philippe J Bareille, Vicki M Rousell
BACKGROUND: Fluticasone furoate (FF; GW685698) is a novel inhaled corticosteroid that is active at 24 h and under development for once-daily administration in combination with the long-acting β(2)-adrenoceptor agonist vilanterol (GW642444) for chronic obstructive pulmonary disease and asthma. In vitro studies examining the respiratory tissue-binding properties of corticosteroids showed FF to have the largest cellular accumulation and slowest rate of efflux compared with other clinically used inhaled corticosteroids, consistent with greater tissue retention...
January 2013: Clinical Pharmacokinetics
Bart G J Dekkers, Adnan Pehlic, Raissa Mariani, I Sophie T Bos, Herman Meurs, Johan Zaagsma
Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to increased airway narrowing in asthma. Increased ASM mass may be caused by exposure to mitogens, including platelet-derived growth factor (PDGF) and collagen type I, which induce a proliferative, hypocontractile ASM phenotype. In contrast, prolonged exposure to insulin induces a hypercontractile phenotype. Glucocorticosteroids and β₂-adrenoceptor agonists synergize to increase glucocorticosteroid receptor translocation in ASM cells; however, the impact of this synergism on phenotype modulation is unknown...
September 2012: Journal of Pharmacology and Experimental Therapeutics
Charlotte K Billington, Oluwaseun O Ojo, Raymond B Penn, Satoru Ito
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...
February 2013: Pulmonary Pharmacology & Therapeutics
Stacey L Tannheimer, Eric A Sorensen, Aaron C Haran, Christopher N Mansfield, Clifford D Wright, Michael Salmon
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)...
April 2012: Pulmonary Pharmacology & Therapeutics
Neil S Holden, Matthew J Bell, Christopher F Rider, Elizabeth M King, David D Gaunt, Richard Leigh, Malcolm Johnson, David P Siderovski, Scott P Heximer, Mark A Giembycz, Robert Newton
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...
December 6, 2011: Proceedings of the National Academy of Sciences of the United States of America
Long P Nguyen, Bhupinder Singh, Adedoyin A Okulate, Victoria Y Alfaro, Michael J Tuvim, Burton F Dickey, Richard A Bond
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...
February 2012: Naunyn-Schmiedeberg's Archives of Pharmacology
Katie J Ryan, Eadaoin W Griffin, Thomas J Connor
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...
March 2011: Journal of Neuroimmunology
Lars Schwabe, Martin Tegenthoff, Oliver Höffken, Oliver T Wolf
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...
June 16, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Gustavo Nino, Aihua Hu, Judith S Grunstein, Michael M Grunstein
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...
May 2010: Journal of Allergy and Clinical Immunology
Robert Newton, Richard Leigh, Mark A Giembycz
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...
February 2010: Pharmacology & Therapeutics
Esmaeil Mortaz, Mehdi Vaezi Rad, Malcolm Johnson, Danielle Raats, Frans P Nijkamp, Gert Folkerts
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...
September 2008: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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