Understanding how long-acting β2 -adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update.


:In moderate-to-severe asthma, adding an inhaled long-acting β2 -adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better 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 dual-specificity phosphatase 1(DUSP1) in human airways smooth muscle (ASM) and epithelial cells, are up-regulated additively by both drug classes. Synergy may also occur for LABA-induced genes, as illustrated by the bronchoprotective gene, regulator of G-protein signalling 2 (RGS2) in ASM. Such effects cannot be produced by either drug alone and may explain the therapeutic efficacy of ICS/LABA combination therapies. While the molecular basis of synergy remains unclear, mechanistic interpretations must accommodate gene-specific regulation. We explore the concept that each glucocorticoid-induced gene is an independent signal transducer optimally activated by a specific, ligand-directed, GR conformation. In addition to explaining partial agonism, this realization provides opportunities to identify novel GR ligands that exhibit gene expression bias. Translating this into improved therapeutic ratios requires consideration of GR density in target tissues and further understanding of gene function. Similarly, the ability of a LABA to interact with a glucocorticoid may be suboptimal due to low β2 -adrenoceptor density or biased β2 -adrenoceptor signalling. Strategies to overcome these limitations include adding-on a phosphodiesterase inhibitor and using agonists of other Gs-coupled receptors. In all cases, the rational design of ICS/LABA, and derivative, combination therapies requires functional knowledge of induced (and repressed) genes for therapeutic benefit to be maximized.


Br J Pharmacol


Newton R,Giembycz MA




Has Abstract


2016-12-01 00:00:00












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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Rozec B,Quang TT,Noireaud J,Gauthier C

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  • Contribution of Na+ -Ca2+ exchanger to pinacidil-induced relaxation in the rat mesenteric artery.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Tsang SY,Yao X,Wong CM,Au CL,Chen ZY,Huang Y

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  • Effects of inflammatory agents on endothelial lysosomal fragility and their inhibition by anti-inflammatory drugs.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Yoffe JR

    更新日期:1981-04-01 00:00:00

  • Pioglitazone opposes neurogenic vascular dysfunction associated with chronic hyperinsulinaemia.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Takatori S,Zamami Y,Yabumae N,Hanafusa N,Mio M,Egawa T,Kawasaki H

    更新日期:2008-04-01 00:00:00

  • Structure and function of midkine as the basis of its pharmacological effects.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章,评审


    authors: Muramatsu T

    更新日期:2014-02-01 00:00:00

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    pub_type: 杂志文章,评审


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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


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  • The activity of sodium cromoglycate analogues in human lung in vitro: a comparison with rat passive cutaneous anaphylaxis and clinical efficacy.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Church MK,Gradidge CF

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  • Apolipoprotein E favours the blunting by high-fat diet of prostacyclin receptor activation in the mouse aorta.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Cheng Y,Vanhoutte PM,Leung SWS

    更新日期:2018-09-01 00:00:00

  • A comparison of vasodilator activity of agents activating cyclic nucleotides with those inhibiting their metabolism in rabbit isolated ear artery.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Wood LM,Owen DA

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  • Endothelin converting enzyme (ECE) activity in human vascular smooth muscle.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Maguire JJ,Johnson CM,Mockridge JW,Davenport AP

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  • Pharmacological assessment of the duration of action of glycopyrrolate vs tiotropium and ipratropium in guinea-pig and human airways.

    abstract::1. Our study was aimed at investigating the duration of the bronchodilator action of the antimuscarinc drug glycopyrrolate compared to tiotropium and ipratropium. In the guinea-pig isolated trachea, the time (t1/2) necessary for a contractile response to carbachol (0.3 microM) to return to 50% recovery after washout o...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章


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  • Facilitation of noradrenaline release from sympathetic nerves in rat anococcygeus muscle by activation of prejunctional beta-adrenoceptors and angiotensin receptors.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Li CG,Majewski H,Rand MJ

    更新日期:1988-10-01 00:00:00

  • Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin-induced diabetic rats.

    abstract::1. Acetylcholine (ACh)-induced relaxation of aortic strips with endothelium and production of cyclic GMP between streptozotocin-induced diabetic and age-matched control rats were compared. 2. The concentration-response curve for ACh-induced relaxation was shifted to the right in diabetic rats. IC50 values for ACh were...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Kamata K,Miyata N,Kasuya Y

    更新日期:1989-06-01 00:00:00

  • Aldosterone does not mediate angiotensin II-induced atherosclerosis and abdominal aortic aneurysms.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Cassis LA,Helton MJ,Howatt DA,King VL,Daugherty A

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  • The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Miglio G,Rosa AC,Rattazzi L,Grange C,Collino M,Camussi G,Fantozzi R

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  • Role of putative neurotransmitters in the central gastric antisecretory effect of prostaglandin E2 in rats.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


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  • Different contributions of chemokine N-terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3.

    abstract:BACKGROUND AND PURPOSE:Chemokines and their receptors form an intricate interaction and signalling network that plays critical roles in various physiological and pathological cellular processes. The high promiscuity and apparent redundancy of this network makes probing individual chemokine/receptor interactions and fun...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Szpakowska M,Nevins AM,Meyrath M,Rhainds D,D'huys T,Guité-Vinet F,Dupuis N,Gauthier PA,Counson M,Kleist A,St-Onge G,Hanson J,Schols D,Volkman BF,Heveker N,Chevigné A

    更新日期:2018-05-01 00:00:00

  • Relative contributions of direct and indirect mechanisms mediating endothelin-induced contraction of guinea-pig trachea.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Hay DW,Hubbard WC,Undem BJ

    更新日期:1993-11-01 00:00:00

  • Inhibition by nitric oxide-donors of human polymorphonuclear leucocyte functions.

    abstract::1. The study was designed to test the hypothesis that nitric oxide (NO)-releasing compounds increase guanosine 3':5'-cyclic monophosphate (cyclic GMP) production in human polymorphonuclear leucocytes (PMNs) and concomitantly inhibit PMN functions, i.e. leukotriene B4 (LTB4) synthesis, degranulation, chemotaxis and sup...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Moilanen E,Vuorinen P,Kankaanranta H,Metsä-Ketelä T,Vapaatalo H

    更新日期:1993-07-01 00:00:00

  • Effects of the bradykinin antagonist, HOE 140, in experimental acute pancreatitis.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


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    更新日期:1992-10-01 00:00:00

  • Characterization of the ORL(1) receptor on adrenergic nerves in the rat anococcygeus muscle.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Ho M,Corbett AD,McKnight AT

    更新日期:2000-09-01 00:00:00

  • Subclassification of atrial and intestinal muscarinic receptors of the rat--direct binding studies with agonists and antagonists.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Brunner F

    更新日期:1989-06-01 00:00:00

  • Influence of the endothelium on contractile effects of 5-hydroxytryptamine and selective 5-HT agonists in canine basilar artery.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Connor HE,Feniuk W

    更新日期:1989-01-01 00:00:00

  • Adrenoceptors in the cat choledochoduodenal junction studied in situ.

    abstract::1. The effects of adrenaline, noradrenaline, isoprenaline and terbutaline (PINN), 1-(3,5-dihydroxyphenyl)-2(t-butylamino)-ethanol, on the sphincter of Oddi were studied in anaesthetized cats. Both adrenaline and noradrenaline (1-4 mug/kg) increased resistance to flow through the sphincter. This effect was blocked by d...

    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Liedberg G,Persson CG

    更新日期:1970-07-01 00:00:00

  • Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β-amyloid in ageing and Alzheimer's disease.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章,评审


    authors: Weinreb O,Amit T,Bar-Am O,Youdim MB

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  • Characterization of the tachykinin NK2 receptor in the human bronchus: influence of amastatin-sensitive metabolic pathways.

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: McMillan MR,Burnstock G,Haworth SG

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Yoon M,Lee H,Jeong S,Kim JJ,Nicol CJ,Nam KW,Kim M,Cho BG,Oh GT

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    journal_title:British journal of pharmacology

    pub_type: 杂志文章


    authors: Badawy AA,Evans M

    更新日期:1981-11-01 00:00:00