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  1. Article: Antigen-induced bronchial hyperresponsiveness in the rabbit is not dependent on M(2)-receptor dysfunction.

    Patel, H J / Douglas, G J / Herd, C M / Spina, D / Giembycz, M A / Barnes, P J / Belvisi, M G / Page, C P

    Pulmonary pharmacology & therapeutics

    1999  Volume 12, Issue 4, Page(s) 245–255

    Abstract: ... the increased release in ACh was not associated with an alteration in M(2)-receptor function. Thus, antigen ... induced bronchial hyperresponsiveness in the rabbit does not appear to depend upon M(2)-receptor ...

    Abstract We have assessed the effect of sensitization to allergen on airway smooth muscle responsiveness and acetylcholine (ACh) release from cholinergic nerves in tracheal preparations from rabbits immunized at birth to Alternaria tenuis and littermate control rabbits injected with saline. ACh release induced by EFS was significantly greater in tracheal preparations obtained from immunized rabbits compared with littermate controls. The ability of the muscarinic-receptor agonist, oxotremorine, to inhibit ACh release to EFS (4 Hz) was not altered by immunization. The contractile response evoked by electrical field stimulation (EFS), ACh and 5-hydroxytryptamine (5-HT) was not significantly altered in tracheal preparations from antigen immunized rabbits compared with littermate controls. Antigen challenge of immunized rabbits did not affect the release of ACh from isolated trachea following EFS, or the ability of oxotremorine to inhibit ACh release. Furthermore, antigen challenge of immunized rabbits failed to alter the contractile response to EFS or ACh, but reduced the contractile potency of 5-HT. These results demonstrate increased ACh release in tracheal preparations following immunization which had no functional consequence on airway smooth muscle responsiveness. Moreover, the increased release in ACh was not associated with an alteration in M(2)-receptor function. Thus, antigen-induced bronchial hyperresponsiveness in the rabbit does not appear to depend upon M(2)-receptor dysfunction.
    MeSH term(s) Acetylcholine/pharmacology ; Acetylcholine/secretion ; Allergens/immunology ; Animals ; Bronchial Hyperreactivity/immunology ; Cholinergic Fibers/physiology ; Disease Models, Animal ; Female ; Hypersensitivity/immunology ; Male ; Muscle, Smooth/immunology ; Rabbits ; Receptors, Muscarinic/physiology
    Chemical Substances Allergens ; Receptors, Muscarinic ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 1999
    Publishing country England
    Document type Journal Article
    ZDB-ID 1399707-5
    ISSN 1522-9629 ; 1094-5539
    ISSN (online) 1522-9629
    ISSN 1094-5539
    DOI 10.1006/pupt.1999.0204
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: α and β catalytic subunits of cAMP-dependent protein kinase regulate formoterol-induced inflammatory gene expression changes in human bronchial epithelial cells.

    Hamed, Omar / Joshi, Radhika / Mostafa, Mahmoud M / Giembycz, Mark A

    British journal of pharmacology

    2022  Volume 179, Issue 18, Page(s) 4593–4614

    Abstract: Background and purpose: It has been proposed that genomic mechanisms contribute to adverse effects often experienced by asthmatic subjects who take regular, inhaled β: Experimental approach: Gene expression changes were determined by RNA-sequencing. ... ...

    Abstract Background and purpose: It has been proposed that genomic mechanisms contribute to adverse effects often experienced by asthmatic subjects who take regular, inhaled β
    Experimental approach: Gene expression changes were determined by RNA-sequencing. Gene silencing and genome editing were employed to explore the roles of β-arrestin-2 and PKA.
    Key results: The formoterol-regulated transcriptome in HBEC treated concurrently with TNFα was defined by 1480 unique gene expression changes. TNFα-induced transcripts modulated by formoterol were annotated with enriched gene ontology terms related to inflammation and proliferation, notably "GO:0070374~positive regulation of ERK1 and ERK2 cascade," which is an apparent β-arrestin-2 target. However, expression of the formoterol- and forskolin-regulated transcriptomes were highly rank-order correlated and the effects of formoterol on TNFα-induced inflammatory genes were abolished by an inhibitor of PKA. Furthermore, formoterol-induced gene expression changes in BEAS-2B bronchial epithelial cell clones deficient in β-arrestin-2 were comparable with those expressed by their parental counterparts. Contrariwise, gene expression was partially inhibited in clones lacking the α-catalytic subunit (Cα) of PKA and abolished following the additional knockdown of the β-catalytic subunit (Cβ) paralogue.
    Conclusions: The effects of formoterol on inflammatory gene expression in airway epithelia are mediated by PKA and involve the cooperation of PKA-Cα and PKA-Cβ.
    MeSH term(s) Adrenergic beta-2 Receptor Agonists/pharmacology ; Asthma/drug therapy ; Catalytic Domain ; Colforsin/pharmacology ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Epithelial Cells/metabolism ; Ethanolamines/metabolism ; Ethanolamines/pharmacology ; Formoterol Fumarate/pharmacology ; Gene Expression ; Humans ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; beta-Arrestins/metabolism ; beta-Arrestins/pharmacology ; beta-Arrestins/therapeutic use
    Chemical Substances Adrenergic beta-2 Receptor Agonists ; Ethanolamines ; Tumor Necrosis Factor-alpha ; beta-Arrestins ; Colforsin (1F7A44V6OU) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Formoterol Fumarate (W34SHF8J2K)
    Language English
    Publishing date 2022-07-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.15901
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  3. Article ; Online: Transcriptome-Level Interactions between Budesonide and Formoterol Provide Insight into the Mechanism of Action of Inhaled Corticosteroid/Long-Acting

    Mostafa, Mahmoud M / Rider, Christopher F / Wathugala, N Dulmini / Leigh, Richard / Giembycz, Mark A / Newton, Robert

    Molecular pharmacology

    2020  Volume 99, Issue 3, Page(s) 197–216

    Abstract: In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long- ... ...

    Abstract In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting
    MeSH term(s) Administration, Inhalation ; Adrenergic beta-2 Receptor Agonists/pharmacology ; Bronchi/cytology ; Bronchi/drug effects ; Bronchi/metabolism ; Budesonide/pharmacology ; Cell Line ; Drug Synergism ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Formoterol Fumarate/pharmacology ; Gene Expression Profiling/methods ; Gene Expression Regulation/drug effects ; Gene Ontology ; Gene Regulatory Networks/drug effects ; Glucocorticoids/pharmacology ; Humans ; Oligonucleotide Array Sequence Analysis
    Chemical Substances Adrenergic beta-2 Receptor Agonists ; Glucocorticoids ; Budesonide (51333-22-3) ; Formoterol Fumarate (W34SHF8J2K)
    Language English
    Publishing date 2020-12-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/molpharm.120.000146
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?

    Giembycz, M A

    British journal of pharmacology

    2008  Volume 155, Issue 3, Page(s) 288–290

    Abstract: PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most ... ...

    Abstract PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD-12-281 (aka GSK 842470), CDP840, CI-1018, D-4418, IC485, L-826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub-therapeutic or at the very bottom of the efficacy dose-response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many 'new(er)' PDE4 inhibitors in development are reported to have an improved therapeutic window including tetomilast, oglemilast, apremilast, ONO 6126, IPL-512602 and IPL-455903 (aka HT-0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti-inflammatory activity of PDE inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 inhibitors to suppress inflammation still remains a viable concept.
    MeSH term(s) Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/adverse effects ; Asthma/drug therapy ; Asthma/physiopathology ; Dose-Response Relationship, Drug ; Humans ; Inflammation/drug therapy ; Inflammation/physiopathology ; Maximum Tolerated Dose ; Phosphodiesterase 4 Inhibitors ; Phosphodiesterase Inhibitors/administration & dosage ; Phosphodiesterase Inhibitors/adverse effects ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Pulmonary Disease, Chronic Obstructive/physiopathology
    Chemical Substances Anti-Inflammatory Agents ; Phosphodiesterase 4 Inhibitors ; Phosphodiesterase Inhibitors
    Language English
    Publishing date 2008-07-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1038/bjp.2008.297
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  5. Article: A bronchoprotective role for

    George, Tresa / Chakraborty, Mainak / Giembycz, Mark A / Newton, Robert

    Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology

    2018  Volume 14, Page(s) 40

    Abstract: Background: Asthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and ...

    Abstract Background: Asthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and inflammation. Common asthma therapeutics up-regulate expression of the regulator of G protein signalling (RGS), RGS2. As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase-activating protein in an acute neutrophilic model of lung inflammation.
    Methods: Wild type and
    Results: Lipopolysaccharide inhalation induced transient airways hyperreactivity (AHR) and neutrophilic lung inflammation. While AHR and inflammation was greatest 3 h post-LPS exposure, BAL neutrophils persisted for 24 h. At 3 h post-LPS inhalation, multiple inflammatory cytokines (CSF2, CSF3, IL6, TNF) and chemokines (CCL3, CCL4, CXCL1, CXCL2) were highly expressed in the BAL fluid, prior to declining by 24 h. Compared to wild type counterparts,
    Conclusions: While
    Language English
    Publishing date 2018-10-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2434973-2
    ISSN 1710-1492 ; 1710-1484
    ISSN (online) 1710-1492
    ISSN 1710-1484
    DOI 10.1186/s13223-018-0266-5
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  6. Article ; Online: Prostanoid Receptors of the EP

    Joshi, Radhika / Hamed, Omar / Yan, Dong / Michi, Aubrey N / Mostafa, Mahmoud M / Wiehler, Shahina / Newton, Robert / Giembycz, Mark A

    The Journal of pharmacology and experimental therapeutics

    2020  Volume 376, Issue 2, Page(s) 161–180

    Abstract: There is a clear, unmet clinical need to identify new drugs to treat individuals with asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) in whom current medications are either inactive or suboptimal. In ... ...

    Abstract There is a clear, unmet clinical need to identify new drugs to treat individuals with asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) in whom current medications are either inactive or suboptimal. In preclinical models, EP
    MeSH term(s) Aminopyridines/pharmacology ; Anti-Inflammatory Agents/pharmacology ; Benzamides/pharmacology ; Bronchi/cytology ; Cell Line ; Cyclic AMP/metabolism ; Cyclopropanes/pharmacology ; Dexamethasone/pharmacology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Humans ; Methyl Ethers/pharmacology ; Phosphodiesterase 4 Inhibitors/pharmacology ; Receptors, Prostaglandin E, EP4 Subtype/agonists ; Receptors, Prostaglandin E, EP4 Subtype/metabolism ; Response Elements ; Transcriptome
    Chemical Substances Aminopyridines ; Anti-Inflammatory Agents ; Benzamides ; Cyclopropanes ; Methyl Ethers ; ONO-AE1-329 ; PTGER4 protein, human ; Phosphodiesterase 4 Inhibitors ; Receptors, Prostaglandin E, EP4 Subtype ; Dexamethasone (7S5I7G3JQL) ; Cyclic AMP (E0399OZS9N) ; roflumilast N-oxide (F08MQ6CZCS)
    Language English
    Publishing date 2020-11-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.120.000196
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Bidirectional crosstalk via IL-6, PGE2 and PGD2 between murine myofibroblasts and alternatively activated macrophages enhances anti-inflammatory phenotype in both cells.

    Fernando, Maria R / Giembycz, Mark A / McKay, Derek M

    British journal of pharmacology

    2016  Volume 173, Issue 5, Page(s) 899–912

    Abstract: Background and purpose: Alternatively activated macrophages (AAMs) are important cells in the resolution of inflammation and tissue repair. We examined the impact of myofibroblasts, a vital cell in wound healing and tissue repair, on the development and ...

    Abstract Background and purpose: Alternatively activated macrophages (AAMs) are important cells in the resolution of inflammation and tissue repair. We examined the impact of myofibroblasts, a vital cell in wound healing and tissue repair, on the development and function of AAMs.
    Experimental approach: The interaction between AAMs and myofibroblasts was tested using conditioned medium from murine dermal myofibroblasts and bone marrow-derived macrophages. AAMs were differentiated with IL-4 and IL-13.
    Key results: Conditioned medium from myofibroblasts enhanced the expression of AAM markers, arginase 1 and Ym1 (chitinase-3-like 3) and the spontaneous production of IL-10, while suppressing LPS-induced nitric oxide production. IL-6 from the myofibroblasts contributed to the amplification of the AAM phenotype; the selective COX-2 inhibitor, NS-398, significantly reduced the ability of myofibroblasts to promote an AAM phenotype. Pharmacological analyses indicated that myofibroblast-derived IL-6 enhanced arginase activity and spontaneous IL-10 output, while PGE2 , via the EP4 receptor, enhanced arginase expression and LPS-evoked IL-10 production. PGD2 suppressed LPS-evoked nitric oxide via the DP1 receptor. Reciprocally, conditioned medium from macrophages treated with IL-4 + IL-13 and myofibroblast conditioned medium components, but not macrophages given IL-4 + IL-13 only, reduced myofibroblast migration, the expression of COX-2, and the production of PGE2 and PGD2 .
    Conclusions and implications: These findings define mechanisms by which myofibroblasts enhance an AAM phenotype, which can promote wound healing directly, and/or via feedback communication to the myofibroblast, subsequently down-regulating its capacity to promote AAM function. This is an important homeostatic regulatory pathway in wound healing that can also limit unwanted fibrosis.
    MeSH term(s) Animals ; Arginase/metabolism ; Cell Movement ; Cells, Cultured ; Coculture Techniques ; Cytokines/genetics ; Cytokines/metabolism ; Dinoprostone/metabolism ; Inflammation/metabolism ; Lectins/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/metabolism ; Macrophages/physiology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Myofibroblasts/metabolism ; Myofibroblasts/physiology ; Nitric Oxide/metabolism ; Phenotype ; Prostaglandin D2/metabolism ; Receptors, Prostaglandin/metabolism ; Receptors, Prostaglandin E, EP4 Subtype/metabolism ; beta-N-Acetylhexosaminidases/metabolism
    Chemical Substances Cytokines ; Lectins ; Lipopolysaccharides ; Ptger4 protein, mouse ; Receptors, Prostaglandin ; Receptors, Prostaglandin E, EP4 Subtype ; prostanoid D receptor 1, mouse ; Nitric Oxide (31C4KY9ESH) ; Chil3 protein, mouse (EC 3.2.1.52) ; beta-N-Acetylhexosaminidases (EC 3.2.1.52) ; Arg1 protein, mouse (EC 3.5.3.1) ; Arginase (EC 3.5.3.1) ; Dinoprostone (K7Q1JQR04M) ; Prostaglandin D2 (RXY07S6CZ2)
    Language English
    Publishing date 2016-02-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.13409
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  8. Article ; Online: An analysis of glucocorticoid receptor-mediated gene expression in BEAS-2B human airway epithelial cells identifies distinct, ligand-directed, transcription profiles with implications for asthma therapeutics.

    Joshi, T / Johnson, M / Newton, R / Giembycz, M

    British journal of pharmacology

    2015  Volume 172, Issue 5, Page(s) 1360–1378

    Abstract: Background and purpose: International asthma guidelines recommend that inhaled glucocorticoids be used as a monotherapy in all patients with mild to moderate disease because of their ability to suppress airways inflammation. Current evidence suggests ... ...

    Abstract Background and purpose: International asthma guidelines recommend that inhaled glucocorticoids be used as a monotherapy in all patients with mild to moderate disease because of their ability to suppress airways inflammation. Current evidence suggests that the therapeutic benefit of glucocorticoids is due to the transactivation and transrepression of anti-inflammatory and pro-inflammatory genes respectively. However, the extent to which clinically relevant glucocorticoids are equivalent in their ability to modulate gene expression is unclear.
    Experimental approach: A pharmacodynamics investigation of glucocorticoid receptor (GR)-mediated gene transactivation in BEAS-2B human airway epithelial cells was performed using a glucocorticoid response element luciferase reporter coupled with an analysis of glucocorticoid-inducible genes encoding proteins with anti-inflammatory and adverse-effect potential.
    Key results: Using transactivation as a functionally relevant output, a given glucocorticoid displayed a unique, gene expression 'fingerprint' where intrinsic efficacy and GR density were essential determinants. We showed that depending on the gene selected for analysis, a given glucocorticoid can behave as an antagonist, partial agonist, full agonist or even 'super agonist'. In the likely event that different, tissue-dependent gene expression profiles are reproduced in vivo, then the anti-inflammatory and adverse-effect potential of many glucocorticoids currently available as asthma therapeutics may not be equivalent.
    Conclusions and implications: The generation of gene expression 'fingerprints' in target and off-target human tissues could assist the rational design of GR agonists with improved therapeutic ratios. This approach could identify compounds that are useful in the management of severe asthma and other inflammatory disorders where systemic exposure is desirable.
    MeSH term(s) Asthma/drug therapy ; Asthma/genetics ; Asthma/metabolism ; Cells, Cultured ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Glucocorticoids/chemistry ; Glucocorticoids/metabolism ; Glucocorticoids/pharmacology ; Humans ; Ligands ; Molecular Structure ; Receptors, Glucocorticoid/agonists ; Receptors, Glucocorticoid/metabolism ; Response Elements/genetics ; Structure-Activity Relationship
    Chemical Substances Glucocorticoids ; Ligands ; Receptors, Glucocorticoid
    Language English
    Publishing date 2015-01-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.13014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far.

    Giembycz, M A

    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace

    2002  Volume 57, Issue 1, Page(s) 48–64

    Abstract: The beginning of the 1990s saw the synthesis and evaluation of orally-active, second generation phosphodiesterase (PDE) inhibitors that have high specificity for the PDE4 subtype. In vitro and in vivo studies established that this class of compounds ... ...

    Abstract The beginning of the 1990s saw the synthesis and evaluation of orally-active, second generation phosphodiesterase (PDE) inhibitors that have high specificity for the PDE4 subtype. In vitro and in vivo studies established that this class of compounds suppresses the activity of many pro-inflammatory and immune cells indicating that they may be effective in the treatment of airway inflammatory diseases. In this article we review the development status of the most advanced and extensively studied PDE4 inhibitors for asthma and chronic obstructive pulmonary disease.
    MeSH term(s) Aminopyridines/adverse effects ; Aminopyridines/metabolism ; Aminopyridines/therapeutic use ; Asthma/drug therapy ; Asthma/enzymology ; Benzamides/adverse effects ; Benzamides/metabolism ; Benzamides/therapeutic use ; Bronchodilator Agents/adverse effects ; Bronchodilator Agents/metabolism ; Bronchodilator Agents/pharmacokinetics ; Bronchodilator Agents/therapeutic use ; Carboxylic Acids ; Cyclohexanecarboxylic Acids ; Cyclopropanes ; Drug Interactions ; Humans ; Nitriles ; Phosphodiesterase Inhibitors/chemical synthesis ; Phosphodiesterase Inhibitors/classification ; Phosphodiesterase Inhibitors/therapeutic use ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Pulmonary Disease, Chronic Obstructive/enzymology
    Chemical Substances Aminopyridines ; Benzamides ; Bronchodilator Agents ; Carboxylic Acids ; Cyclohexanecarboxylic Acids ; Cyclopropanes ; Nitriles ; Phosphodiesterase Inhibitors ; Roflumilast (0P6C6ZOP5U) ; Cilomilast (8ATB1C1R6X)
    Language English
    Publishing date 2002-02
    Publishing country Italy
    Document type Journal Article ; Review
    ZDB-ID 1160940-0
    ISSN 1122-0643 ; 1120-0391
    ISSN 1122-0643 ; 1120-0391
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease.

    Giembycz, M A

    Expert opinion on investigational drugs

    2002  Volume 10, Issue 7, Page(s) 1361–1379

    Abstract: Cilomilast (Ariflo, SB-207499) is an orally-active, second generation phosphodiesterase (PDE) inhibitor that may be effective in the treatment of asthma and chronic obstructive pulmonary disease (COPD). It has high selectivity for the cyclic AMP-specific, ...

    Abstract Cilomilast (Ariflo, SB-207499) is an orally-active, second generation phosphodiesterase (PDE) inhibitor that may be effective in the treatment of asthma and chronic obstructive pulmonary disease (COPD). It has high selectivity for the cyclic AMP-specific, or PDE4, isoenzyme that predominates in pro-inflammatory and immune cells and is ten-fold more selective for PDE4D than for PDE4A, B and C. In vitro, cilomilast suppresses the activity of many pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD and is highly active in animal models of these diseases. Cilomilast demonstrates a markedly improved side effect profile over the archetypal PDE4 inhibitor, rolipram, which has been attributed to its inability to discriminate between the high affinity rolipram binding site and the catalytic domain of the enzyme, and the fact that it is negatively charged which at physiological pH should limit its penetration in to the CNS. In humans cilomilast is rapidly absorbed after oral administration, providing dose-proportional systemic exposure up to 4 mg, completely bioavailable, has a half-life of approximately 7 h and is subject to negligible first pass hepatic metabolism. Cilomilast is extensively metabolised with decyclopentylation, acyl glucuronidation and 3-hydroxylation of the cyclopentyl ring representing the principal routes. Most of the drug is excreted in the urine (approximately 90%) and faeces (6 - 7%) with unchanged cilomilast accounting for less than 1% of the administered dose. Cilomilast has been evaluated in Phase I, Phase II and Phase III trials and dose-response experiments have demonstrated a clinically significant increase in lung function and a perceived improvement in quality of life in patients with COPD. Trials of cilomilast in asthma have been less impressive although a trend towards improved lung function has been reported. Cilomilast is safe and well-tolerated at doses up to 15 mg in both short- and long-term dosing trials with a low incidence of adverse effects. No evidence for drug-drug interactions with commonly prescribed medications for COPD and asthma such as digoxin, corticosteroids, salbutamol, theophylline or warfarin has been found. Moreover, the pharmacokinetics of cilomilast are essentially the same in smokers and non-smokers, indicating that no dose adjustments of cilomilast will be required in patients with COPD. Thus, cilomilast displays a promising clinical profile in the treatment of inflammatory airway diseases, in particular COPD and the results of further Phase III trials are awaited with interest.
    MeSH term(s) 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors ; Bronchodilator Agents/administration & dosage ; Bronchodilator Agents/metabolism ; Bronchodilator Agents/therapeutic use ; Carbon Radioisotopes ; Carboxylic Acids ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cyclohexanecarboxylic Acids ; Drug Interactions ; Drug Tolerance ; Humans ; Lung Diseases, Obstructive/drug therapy ; Lung Diseases, Obstructive/metabolism ; Male ; Nitriles ; Phosphodiesterase Inhibitors/administration & dosage ; Phosphodiesterase Inhibitors/metabolism ; Phosphodiesterase Inhibitors/therapeutic use
    Chemical Substances Bronchodilator Agents ; Carbon Radioisotopes ; Carboxylic Acids ; Cyclohexanecarboxylic Acids ; Nitriles ; Phosphodiesterase Inhibitors ; Cilomilast (8ATB1C1R6X) ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; PDE4A protein, human (EC 3.1.4.17) ; PDE4D protein, human (EC 3.1.4.17)
    Language English
    Publishing date 2002-01-28
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1182884-5
    ISSN 1744-7658 ; 1354-3784 ; 0967-8298
    ISSN (online) 1744-7658
    ISSN 1354-3784 ; 0967-8298
    DOI 10.1517/13543784.10.7.1361
    Database MEDical Literature Analysis and Retrieval System OnLINE

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