RGS5 gene and therapeutic response to short acting bronchodilators in paediatric asthma patients.

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RGS5 gene and therapeutic response to short acting bronchodilators in paediatric asthma patients.

Pediatr Pulmonol. 2012 Nov 28;

Authors: Labuda M, Laberge S, Brière J, Bérubé D, Krajinovic M

Abstract
Short-acting ?2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. Recent evidence demonstrated that prolonged exposure of cultured airway smooth muscle cells to ?2 agonists directly augments procontractile signaling pathways with the change in expression of regulator of G protein signaling 5 (RGS5). The aim of this study was to test whether genetic variants in RGS5 gene affect the response to short acting ?2-agonists. Bronchodilator responsiveness was assessed in 137 asthmatic children by % change in baseline forced expiratory volume in 1?sec (FEV(1) ) after administration of albuterol. The analyses were performed in patients with FEV(1) /FVC ratio below 0.9 (FVC-forced vital capacity, n?=?99). FEV(1) % change adjusted for baseline FEV(1) values was significantly different between genotypes of rs10917696 C/T polymorphism (P?=?0.008). The association remained significant with inclusion of age, sex, atopy, parental smoking, and controller medications into multivariate model (P?=?0.005). We also identified additive effect on the treatment outcome with previously published genetic variant G/A rs1544791 in phosphodiesterase 4 (PDE4D) gene. Carriers of two risk alleles (C and G) had adjusted mean % FEV(1) change value 4.6?±?1.3, while carriers of one and none of the risk alleles had 8.1?±?0.7% and 13.5?±?2.4%, respectively, P?=?0.001. Our work identifies a new genetic variant in RGS5 demonstrating additive effect with PDE4D, both implicated in modulation of asthma treatment. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.

PMID: 23193110 [PubMed – as supplied by publisher]

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Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation.

Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation.

Pharmacology. 2012;90(3-4):223-32

Authors: Kobayashi M, Kubo S, Shiraki K, Iwata M, Hirano Y, Ohtsu Y, Takahashi K, Shimizu Y

Abstract
We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-? production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an ?(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with ?(2) – adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

PMID: 23038661 [PubMed – in process]

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New therapeutic target for asthma, other lung disorders identified – Daily News & Analysis

New therapeutic target for asthma, other lung disorders identified
Daily News & Analysis
A researcher has discovered a molecule's previously unknown role as a major trigger for airway remodeling, which impairs lung function, making the molecule a promising therapeutic target for chronic asthma, chronic obstructive pulmonary disease (COPD)
LIGHT May Provide New Hope for Future Asthma Therapies, Researchers ClaimGenetic Engineering News
La Jolla Institute identifies new therapeutic target for asthma, COPD and ScienceBlog.com (blog)

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View full post on asthma – Google News

La Jolla Institute identifies new therapeutic target for asthma, COPD and … – EurekAlert (press release)

La Jolla Institute identifies new therapeutic target for asthma, COPD and
EurekAlert (press release)
The finding marks Dr. Croft's second major discovery with therapeutic potential for asthma. His previous finding, of a novel molecular mechanism driving lung inflammation, is the basis for a potential asthma treatment now in Phase II human clinical

and more »

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Research and Markets: Asthma: Modern Therapeutic Targets

Research and Markets: Asthma: Modern Therapeutic Targets

Research and Markets has announced the addition of the “Asthma: Modern Therapeutic Targets” book to their offering.

The care of an increasing number of adult and child patients with asthma has become a major task for clinicians, and a growing concern for public health physicians and health care administrators. At the same time, and in response to this situation, a considerable effort is being made in basic and clinical research to develop new treatments. This book looks into the future and assesses the possibilities of a number of new therapies for asthma under exploration and development. A group of distinguished international authors examine the potential of new agents working on various targets that are currently under evaluation, including autocoids and their inhibitors, enzyme-inhibitors, sensory nerves and sensory neuropeptides, and receptors in immunology Asthma: Modern Therapeutic Targets provides physicians with an appreciation of the future directions of treatment. It provides clinical pharmacologists and researchers with an up-to-date insight into advances in this exciting field. This book will also be a valuable tool for researchers in the pharmaceutical industry.

Benefits:

* Presents a comprehensive review of current treatment options
* Latest guidelines on clinical management reviewed from an international perspective
* Provides background on pharmacology and mechanisms of drug action
* Provides a key resource for individual patient care

Readership:

* Specialists in respiratory medicine, allergy and immunology
* General physicians
* Clinical pharmacologists
* Doctors in training

Key Topics Covered:

Section I: Autocoids and their receptors in airway diseases

* Adenosine receptors: novel molecular targets in asthma
* The role of transforming growth factors in asthma and their potential as a target for therapy
* The role of transcription factors in asthma: can we modify them for therapeutic purposes?
* Is IKK a feasible therapeutic target for allergic asthma?

Section II: Enzyme inhibitors

* Protease-activated receptors: targets for therapeutic intervention in asthma
* Nitric oxide synthase as a therapeutic target in asthma
* Metalloproteinases and asthma: untried potential for new therapeutic strategies

Section III: Sensory nerves and sensory neuropeptides

* Sensory neuropeptides as innovative targets in asthma
* Rationale for vanilloid receptor 1 antagonist-based therapies in asthma

Section IV: Receptors in immunology

* Anticytokines and cytokines as asthma therapy
* Tumour necrosis factor alpha and asthma
* Are chemokines viable targets for asthma?
* Antagonism of the chemokine receptor CCR3 as a potential therapeutic treatment for asthma

Author:

* R Polosa, Presidio Ospedaliero Ascoli-Tomaselli, Catania, Italy
* ST Holgate, Southampton General Hospital, Southampton, UK

For more information visit http://www.researchandmarkets.com/research/a7c5bf/asthma_modern_the

Contacts

Research and Markets
Laura Wood, Senior Manager,
press@researchandmarkets.com
U.S. Fax: 646-607-1907
Fax (outside U.S.): +353-1-481-1716

Pearl Therapeutics’ Bronchodilator Combination Therapeutic For COPD To Be Presented At The American Thoracic Society …

Pearl Therapeutics’ Bronchodilator Combination Therapeutic For COPD To Be Presented At The American Thoracic Society …
Pearl Therapeutics Inc., a company developing clinically differentiated double and triple combination therapies for the treatment of highly prevalent chronic respiratory diseases, announced four upcoming poster presentations at the Annual Meeting of the American Thoracic Society (ATS) to be held at the Ernest N. Morial Convention Center in New Orleans from May 14-19, 2010. Results from Pearl’s …

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