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Gene-environment interactions in the development of asthma and atopy.

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Gene-environment interactions in the development of asthma and atopy.

Expert Rev Respir Med. 2012 Jun;6(3):301-8

Authors: Custovic A, Marinho S, Simpson A

Abstract
Asthma is a complex multifactorial disorder involving a variety of different mechanisms. Little has changed in asthma treatment over the past five decades. There is evidence for a strong genetic component of asthma, but genetic studies have produced heterogeneous results with little replication, with most of the heritability remaining unexplained. The rapid increase in asthma prevalence over a short time period suggests that environmental exposures play an important role, but there is a considerable heterogeneity in the results describing the effect of different environmental exposures. There are many reasons for the lack of replication in genetic association studies and those of environmental exposures. These include the failure to consider that asthma may arise as a consequence of environmental factors, modulating the risk in genetically susceptible individuals via gene-environment interactions. In addition, many studies rely on oversimplified phenotypes often derived through aggregation of several heterogeneous conditions (e.g., 'physician-diagnosed asthma').

PMID: 22788944 [PubMed - in process]

Efficacy of anticholinergic drugs in asthma.

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Efficacy of anticholinergic drugs in asthma.

Expert Rev Respir Med. 2012 Jun;6(3):309-19

Authors: Novelli F, Malagrinò L, Dente FL, Paggiaro P

Abstract
Although bronchial hyperresponsiveness to cholinergic agents is a main feature of asthma, the role of anticholinergic drugs in chronic asthma management has been largely underestimated. Several single-dose studies comparing acute bronchodilation induced by ipratropium bromide with salbutamol have shown that salbutamol was more effective than ipratropium in asthma treatment. Recently, tiotropium has been studied in asthma, when added to low-dose inhaled corticosteroids in unselected moderate asthmatics or in patients with uncontrolled asthma, or patients with chronic obstructive pulmonary disease and history of asthma. Later, studies on patients with Arg/Arg β(2)-receptor polymorphism demonstrated a similar efficacy of tiotropium in comparison with salmeterol when both were added to low-dose inhaled corticosteroids. Further long-term studies are currently in progress, for the evaluation of the efficacy of tiotropium on clinical asthma control, and on the rate and severity of asthma exacerbations, as well as the potential modification of inflammatory mechanisms and varying efficacy in specific asthma phenotypes (such as smoking asthmatics).

PMID: 22788945 [PubMed - in process]

Past, present and future uses of methacholine testing.

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Past, present and future uses of methacholine testing.

Expert Rev Respir Med. 2012 Jun;6(3):321-9

Authors: Davis BE, Cockcroft DW

Abstract
Methacholine challenge testing is a valuable diagnostic and research tool used by clinicians to assist in the diagnosis of asthma, and by researchers to understand disease pathophysiology and assess novel therapeutic efficacy. The use of methacholine challenge in asthma relates to its direct effect on airway smooth muscle (i.e., bronchoconstriction) as a measure of airway hyperresponsiveness, a cardinal feature of asthma. Airway hyperresponsiveness has been documented in other airway disorders, including chronic obstructive pulmonary disease, cystic fibrosis and allergic rhinitis; however, there is little clinical application of methacholine challenge in these conditions as a diagnostic or disease management tool. The authors will review the aspects of methacholine challenge testing, as they relate to asthma, and point out its usefulness in clinical research. A brief review of past (historical) uses and speculation as to the future uses of methacholine challenge will also be discussed.

PMID: 22788946 [PubMed - in process]

The treatment of asthma in obesity.

The world is facing an unprecedented epidemic of obesity. This epidemic has led to major changes in the epidemiology of common diseases such as asthma. Obesity is a major risk factor for new-onset asthma.

This article will discuss the role of mechanical and metabolic factors, as well as obesity-related comorbidities, in both causing airway disease and also affecting response to therapy in obese asthmatics. Asthma in obese individuals probably includes a spectrum of disease with at least two distinct phenotypes: early-onset allergic disease complicated by obesity and late-onset disease developing in the setting of obesity.

Both phenotypes are distinct from asthma in lean individuals. Treatment of asthma in obesity needs to consider altered response to controller therapy, and the fact that mechanical factors, metabolic inflammation and other comorbidities are probably contributing to airway disease.

Future studies should focus on the development of therapies specifically tailored towards the treatment of asthma in obesity.

Effect of Once-Daily Fluticasone Furoate/Vilanterol on 24-Hour Pulmonary Function in Patients With Chronic Obstructive Pulmonary Disease: A Randomized, Three-Way, Incomplete Block, Crossover Study.

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Available inhaled corticosteroid/long-acting β(2)-agonist combinations for chronic obstructive pulmonary disease (COPD) require twice-daily administration. The combination of fluticasone furoate (FF) and vilanterol (VI) FF/VI is being developed in a novel dry powder inhaler for the treatment of COPD and asthma with the potential for once-daily dosing.

Results from Phase II studies have shown clinically and statistically significant improvements over placebo in trough (24-hour postdose) forced expiratory volume in 1 second (FEV(1)) after once-daily dosing with FF or VI (VI concurrently with an inhaled corticosteroid) in asthma and VI in COPD.

OBJECTIVES: This Phase III, multicenter, randomized, double-blind, placebo-controlled study was designed based on guidance from drug regulators with the goal of evaluating the 24-hour spirometric effect of once-daily FF/VI in patients with COPD.

METHODS: Patients (aged ≥40 years) who completed a 2-week placebo run-in period were randomized to 1 of 18 three-course sequences of placebo and 2 of 3 dose combinations of FF/VI (50/25 μg, 100/25 μg, and 200/25 μg), dosed once daily in the morning. Each 28-day treatment period was separated by a 2-week, single-blind, placebo washout period. The primary end point was time-adjusted (weighted mean) 0 to 24-hour FEV(1) (AUC) at the end of each 28-day treatment period (period days 28-29). Safety profile assessments included incidence of adverse events (AEs) (defined according to the Medical Dictionary for Regulatory Activities), 12-lead ECG outputs, vital signs (pulse rate, diastolic and systolic blood pressure) and clinical laboratory assessments (including fasting serum glucose and potassium) and 24-hour serum cortisol. The pharmacokinetics of FF and VI were assessed at the end of each 28-day treatment period with FF/VI.

RESULTS: Eighty-seven patients were screened; 54 completed run-in and were randomized to double-blind treatment. The mean patient age was 57.9 years, and 46% were male. The majority of patients were current smokers (83%) and were receiving short-acting β(2)-agonists within the 3 months before screening (63%). All 3 strengths of once-daily FF/VI demonstrated significantly higher 0 to 24-hour (period days 28-29) change from period baseline weighted mean FEV(1) than placebo: adjusted mean improvements from placebo in FEV(1) for FF/VI were 220 to 236 mL (all, P < 0.001). Improvements versus placebo in change from period baseline serial FEV(1) measures were observed at each time-point and with each strength of FF/VI over the 0 to 25-hour period (period days 28-29), indicating sustained bronchodilation. The overall incidence of on-treatment AEs was low (10%-12% with FF/VI; 4% with placebo); 2 serious AEs were reported during washout periods (1 AE after FF/VI 50/25 μg and 1 AE after placebo) but neither was considered treatment related. No serious AEs were reported during the treatment periods or during the follow-up period. No clinically or statistically significant differences from placebo were reported for serum glucose or potassium. No significant effects on vital signs, ECG, or 24-hour serial serum cortisol were reported. The extent of systemic exposure to FF and VI at steady state was low for all strengths of FF/VI.

CONCLUSIONS: FF/VI inhaled once daily in the morning for 28 days produced significant improvements in pulmonary function with a prolonged (>24 hours') duration of action in this population of patients with COPD. The combination was well tolerated. ClinicalTrials.gov identifier: NCT01072149.

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