Research

Efficacy and safety of AZD3199 vs formoterol in COPD: a randomized, double-blind study

Piotr Kuna, Yavor Ivanov, Vasily Ivanovich Trofimov, Takefumi Saito, Ola Beckman, Thomas Bengtsson, Carin Jorup andFrançois Maltais

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Respiratory Research 2013, 14:64 doi:10.1186/1465-9921-14-64

Published: 3 June 2013

Abstract (provisional)

Background

We investigated the efficacy and safety of AZD3199, a novel inhaled ultra-LABA, with the main aim of establishing a dose that would maintain 24-hour bronchodilation in patients with COPD.

Methods

Patients (n = 329) were randomized to AZD3199 (200, 400 or 800 mug o.d.), formoterol (9 mug b.i.d.) or placebo via Turbuhaler(R) in a parallel group study. The primary objective of the study was to compare the clinical efficacy of three doses of AZD3199 inhaled once daily with 9 mug formoterol twice daily and placebo, over a 4-week treatment period in adults with moderate-to-severe COPD. After 4 weeks, peak (0--4 h) and trough (24--26 h) forced expiratory volume in 1 second (FEV1) were assessed as the primary efficacy outcome variables.

Results

All AZD3199 doses significantly increased mean peak and trough FEV1 versus placebo (106--171 ml and 97--110 ml increases, respectively), but with no clear dose--response; the level of bronchodilation was comparable to or greater than that achieved with formoterol. Forced vital capacity (FVC) at peak bronchodilation also significantly increased with AZD3199 versus placebo (153--204 ml). COPD symptom scores and reliever use were reduced with AZD3199, while FEV1 reversibility was unaltered. Adverse events were mild-to-moderate, with no safety concerns identified. Drug exposure was dose-proportional, but lower than predicted from healthy volunteers.

Conclusions

All three doses of AZD3199 produced 24-hour bronchodilation, but with no clear dose--response, suggesting that doses of 200 mug or less may be sufficient to maintain bronchodilation over 24 hours in patients with COPD. No safety concerns were identified. Further studies are required to determine the once-daily AZD3199 dose for COPD.

Trial registration: Clinicaltrials.gov: NCT00929708

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Research

Induction of immune tolerance and reduction of aggravated lung eosinophilia by co-exposure to Asian sand dust and ovalbumin for 14 weeks in mice

Miao He, Takamichi Ichinose, Seiichi Yoshida, Hirohisa Takano, Masataka Nishikawa, Guifan Sun and Takayuki Shibamoto

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Allergy, Asthma & Clinical Immunology 2013, 9:19 doi:10.1186/1710-1492-9-19

Published: 3 June 2013

Abstract (provisional)

Background

Atmospheric contamination caused by Asian sand-dust (ASD) storms aggravates asthma in both human adults and children. This study aims to investigate a series of manifestations in allergic airway disease caused by co-exposure to allergens and ASD for 6 weeks and 14 weeks.

Methods

CD-1 Mice were instilled intratracheally with 0.1 mg of ASD/mouse four times (6 weeks) or eight times (14 weeks) at 2-week intervals (total dose of 0.4 mg or 0.8 mg/mouse) with or without ovalbumin (OVA). The pathologic changes in the airway, cytological alteration in bronchoalveolar lavage fluid (BALF), and levels of inflammatory cytokines/chemokines in BALF, and OVA-specific IgE and IgG1 antibodies in serum were measured in the treated CD-1 mice.

Results

Four-time co-exposure to OVA and ASD aggravates allergic airway inflammation along with Th2-cytokine IL-13 and eosinophil-relevant cytokine/chemokines IL-5, Eotaxin and MCP-3 in BALF, and fibrous thickening of the subepithelial layer in the airway. On the other hand, eight-time co-exposure attenuates these changes along with a significant increase of TGF-beta1 in BALF. Adjuvant effects of ASD toward IgG1 and IgE production in sera were, however, still seen in the eight-time co-exposure.

Conclusions

These results indicate that the immune responses in airways are exacerbated by four-time co-exposure to ASD with OVA, but that there is a shift to suppressive responses in eight-time co-exposure, suggesting that the responses are caused by TGF-beta1-related immune tolerance.

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Research

COPD and disease-specific health status in a working population

Koichi Nishimura, Satoshi Mitsuma, Atsuko Kobayashi, Mikako Yanagida, Kazuhito Nakayasu, Yoshinori Hasegawa andPaul W Jones

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Respiratory Research 2013, 14:61 doi:10.1186/1465-9921-14-61

Published: 2 June 2013

Abstract (provisional)

Background

It has been debated whether treatment should be started early in subjects with mild to moderate COPD. An impaired health status score was associated with a higher probability of being diagnosed with COPD as compared with undiagnosed COPD.

Purpose: To investigate the health status in a healthy working population, to determine reference scores for healthy non-smoking subjects, and to investigate the relationship between their health status and airflow limitation.

Methods

A total of 1333 healthy industrial workers aged >=40 years performed spirometry and completed the St. George's Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT).

Results

The prevalence of COPD defined by the fixed ratio of the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was 10.9%, and the prevalence defined by the Lower Limit of Normal was 5.0%. All SGRQ and CAT scores were skewed to the milder end. In 512 non-smoking subjects with normal spirometry, the mean SGRQ score was 5.7, and the mean CAT score was 5.8. In 145 people with COPD defined by the fixed ratio, the mean SGRQ score was 7.9, with a zero score in 6.9% of the subjects. Using the CAT, the mean score was 7.3, with 7.6% of the scores being zero. The scores in patients identified using the Lower Limit of Normal approach were: SGRQ 8.4 (13.4% had a score of zero) and CAT 7.4 (13.4% had a score of zero). Although the 95th percentiles of the Total, Symptoms, Activity, and Impact scores of the SGRQ and CAT sores were 13.8, 34.0, 23.4, 7.2 and 13.6 in the 512 healthy non-smoking subjects, respectively, they were also distributed under their upper limits in over 80% of the COPD subjects.

Conclusion

The COPD-specific health status scores in a working population were good, even in those with spirometrically diagnosed COPD. All scores were widely distributed in both healthy non-smoking subjects and in subjects with COPD, and the score distribution overlapped remarkably between these two groups. This suggests that symptom-based methods are not suitable screening tools in a healthy general population.

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Research article

Response of the airways and autonomic nervous system to acid perfusion of the esophagus in patients with asthma: a laboratory study

Dharshika Lakmali Amarasiri, Arunasalam Pathmeswaran, Hithanadura Janaka de Silva and Channa Dhammika Ranasinha

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BMC Pulmonary Medicine 2013, 13:33 doi:10.1186/1471-2466-13-33

Published: 2 June 2013

Abstract (provisional)

Background

Gastro-esophageal reflux disease (GERD) predisposes to airway disease through a vagally-mediated esophago-bronchial reflex. This study investigates this vagal response to esophageal acid perfusion.

Methods

40 asthmatics with mild stable asthma participated. Each subject underwent spirometry and autonomic function testing (valsalva maneuver, heart rate response to deep breathing and to standing from supine position) four times: a) before intubation, b) after intubation, and then immediately after perfusion with, in random order, c) concentrated lime juice solution (pH 2--3) and d) 0.9% saline. Subjects were blinded to the solution perfused.

Results

Asthmatics were of mean (SD) age 34.3 years (1.3), and 67.5% of them were females. pH monitoring demonstrated that 20 subjects had abnormal reflux and 20 did not. In each group 10 subjects had a positive GERD symptom score. Following perfusion with acid compared to saline, all subjects showed significant decreases in FEV1 and PEFR and significant increases in the mean valsalva ratio and heart rate difference on deep breathing from baseline values, but no changes in FVC or heart rate ratio on standing. There were no significant differences in any of the parameters between subjects with and without reflux.

Conclusions

Acid stimulation of the distal esophagus results in increased parasympathetic activity and concomitant broncho-constriction in asthmatics irrespective of their reflux state. This strengthens the hypothesis that GER triggers asthma-like symptoms through a vagally mediated esophago-bronchial reflex and encourages a possible role for anti-cholinergic drugs in the treatment of reflux-associated asthma.

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Research

Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides

Céline Pellaton, Yannick Perrin, Caroline Boudousquié, Nathalie Barbier, Jacqueline Wassenberg, Giampietro Corradin,Anne-Christine Thierry, Régine Audran, Christophe Reymond and François Spertini

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Clinical and Translational Allergy 2013, 3:17 doi:10.1186/2045-7022-3-17

Published: 1 June 2013

Abstract (provisional)

Background

Synthetic contiguous overlapping peptides (COPs) may represent an alternative to allergen extracts or recombinant allergens for allergen specific immunotherapy. In combination, COPs encompass the entire allergen sequence, providing all potential T cell epitopes, while preventing IgE conformational epitopes of the native allergen.

Methods

Individual COPs were derived from the sequence of Bet v 1, the major allergen of birch pollen, and its known crystal structure, and designed to avoid IgE binding. Three sets of COPs were tested in vitro in competition ELISA and basophil degranulation assays. Their in vivo reactivity was determined by intraperitoneal challenge in rBet v 1 sensitized mice as well as by skin prick tests in volunteers with allergic rhinoconjunctivitis to birch pollen.

Results

The combination, named AllerT, of three COPs selected for undetectable IgE binding in competition assays and for the absence of basophil activation in vitro was unable to induce anaphylaxis in sensitized mice in contrast to rBet v 1. In addition no positive reactivity to AllerT was observed in skin prick tests in human volunteers allergic to birch pollen. In contrast, a second set of COPs, AllerT4-T5 displayed some residual IgE binding in competition ELISA and a weak subliminal reactivity to skin prick testing.

Conclusions

The hypoallergenicity of contiguous overlapping peptides was confirmed by low, if any, IgE binding activity in vitro, by the absence of basophil activation and the absence of in vivo induction of allergic reactions in mouse and human (ClinicalTrials.gov NCT01719133).

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The Journal of Allergy and Clinical Immunology
Volume 131, Issue 6 , Pages 1479-1490, June 2013

Endotypes and phenotypes of chronic rhinosinusitis: A PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology

• Cezmi A. Akdis, MD
, 
• Claus Bachert, MD, PhD
, 
• Cemal Cingi, MD
, 
• Mark S. Dykewicz, MD
, 
• Peter W. Hellings, MD
, 
• Robert M. Naclerio, MD
,
• Robert P. Schleimer, MD
, 
• Dennis Ledford, MD

Received 31 October 2012; received in revised form 11 February 2013; accepted 14 February 2013. published online 15 April 2013.

• Abstract
• Full Text
• PDF
• Images
• References

Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or “endotypes,” which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti–IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.

Key words: Chronic rhinosinusitis, endotypes, phenotypes, cytokines, biological agents, treatment, diagnosis, IgE, nasal polyps,pathophysiology

Abbreviations used: ARS, Acute rhinosinusitis, BAFF, B cell–activating factor of the TNF family, CRS, Chronic rhinosinusitis, CRSwNP,Chronic rhinosinusitis with nasal polyps, CRSsNP, Chronic rhinosinusitis without nasal polyps, CT, Computed tomography, EPOS, European Position Paper on Rhinosinusitis and Nasal Polyps, MMP, Matrix metalloproteinase, NP, Nasal polyp, SE, Staphylococcus aureusexotoxin/enterotoxin, STAT3, Signal transducer and activator of transcription 3, TIMP, Tissue inhibitor of metalloproteinases, TJ, Tight junction, TLR, Toll-like receptor, TRAIL, TNF-related apoptosis-inducing ligand

 

 Disclosure of potential conflict of interest: C. A. Akdis receives research support from Novartis, PREDICTA, the Swiss National Science Foundation, MeDALL, the Global Allergy and Asthma European Network, and the Christine Kühne-Center for Allergy Research and Education; has consulted for Actellion, Aventis, Stallergenes, and Allergopharma; is president of the European Academy of Allergy and Clinical Immunology; is a fellow and interest group member of the American Academy of Allergy, Asthma & Immunology (AAAAI); is a former committee member of the Global Allergy and Asthma European Network; and is the director of the Christine Kühne-Center for Allergy Research and Education. C. Bachert has received research support from Novartis and GlaxoSmithKline. M. S. Dykewicz has consultant arrangements with Boehringer Ingelheim, Ista, and Merck. R. M. Naclerio has received travel support from AAAAI; has board memberships with Merck, TEVA, and Sunovion; has received grants from TEVA, Johnson & Johnson, and Kalypsis; and has received payment for lectures from TEVA and Sunovion. R. P. Schleimer has consultant arrangements with Intersect ENT, GlaxoSmithKline, Allakos, and Aurasense; has received research support from the National Institutes of Health; and has received stock/stock options from Allakos. D. Ledford has received travel support from AAAAI; has consultant arrangements with Genentech; and has received payment for lectures from Meda and Genentech. The rest of the authors declare that they have no relevant conflicts of interest.

PII: S0091-6749(13)00367-9

doi:10.1016/j.jaci.2013.02.036

© 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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Volume 131, Issue 6 , Pages 1479-1490, June 2013