[Show abstract][Hide abstract] ABSTRACT: PURPOSE OF REVIEW:
Obesity has significant impact on asthma incidence and manifestations. The purpose of the review is to discuss recent observations regarding the association between obesity and asthma focusing on underlying mechanisms, clinical presentation, response to therapy and effect of weight reduction.
Clinical and epidemiological studies indicate that obese patients with asthma may represent a unique phenotype, which is more difficult to control, less responsive to asthma medications and by that may have higher healthcare utilization. A number of common comorbidities have been linked to both obesity and asthma, and may, therefore, contribute to the obese-asthma phenotype. Furthermore, recently published studies indicate that even a modest weight reduction can improve clinical manifestations and outcome of asthma.
Compared with normal-weight patients, obese and overweight patients with asthma have poorer asthma control and respond less to corticosteroid therapy. Future studies focusing on the mechanism underlying both obesity and asthma including the obese-asthma phenotype are required to better characterize the link between the conditions and target the management of this patient group.
Current Opinion in Pulmonary Medicine 11/2014; · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases.
Respiratory medicine 06/2014; · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BackgroundCRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses.Objective
To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses.Methods
In this 3-center, double-blind, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1,000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test.ResultsFifteen subjects completed the study per protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared to placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response versus time curve (AUC(3-10h)) by on average 25.6% (p=0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (p=0.0029. There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments.Conclusion & Clinical RelevanceSetipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study we investigated the single- and multiple-dose tolerability and pharmacokinetics of setipiprant, an orally active, potent, and selective CRTH2 antagonist.This randomized, double-blind, placebo-controled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of 8 subjects each. Additionally, the impact of food on the pharmacokinetics was investigated in one dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables, plasma and urine levels of setipiprant were determined.Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration setipiprant was rapidly absorbed, and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose.In this entry-into humans study, setipiprant showed good tolerability and a favorable pharmacokinetic profile, thus warranting its development in the treatment of inflammatory disorders.This article is protected by copyright. All rights reserved.
Fundamental and Clinical Pharmacology 04/2014; · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review will discuss methodologies and applicability of key inflammatory models of respiratory disease in proof of concept or proof of efficacy clinical studies. In close relationship with these models, induced sputum and inflammatory cell counts will be addressed for phenotype-directed drug development. Additionally, important regulatory aspects regarding noninvestigational medicinal products used in bronchial challenges or clinical inflammatory models of respiratory disease will be highlighted.
The recognition of an ever increasing number of phenotypes and endotypes within conditions such as asthma and chronic obstructive pulmonary disease urges phenotyping of study populations already in early clinical phases of drug development. Apart from the choice of a relevant disease model, recent studies show that especially targeted therapies need to be tested in well defined disease subsets for adequate efficacy assessment. Noninvasive biomarkers, especially sputum inflammatory cell counts, aid phenotyping and are useful outcome measures for novel, targeted therapies.
Disease phenotyping becomes increasingly important for efficient and cost-effective drug development and subsequent disease management. Inflammatory models of respiratory disease combined with sputum biomarkers are important tools in this approach.
Current opinion in pulmonary medicine 11/2013; · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug.
Between February, 2009, and January, 2013, we undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned (1:1:1) to receive an inhaled dose of RPL554 (0·003 mg/kg or 0·009 mg/kg) or placebo by a computer-generated randomisation table. Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 (three received 0·009 mg/kg and three received 0·018 mg/kg) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 (0·018 mg/kg) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection. Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 (0·018 mg/kg) for 6 consecutive days in a single-blind (patients masked), placebo-controlled study in 12 men with clinically stable asthma. The safety and bronchodilator effect of RPL554 (0·018 mg/kg) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD. In study 4, a placebo-controlled crossover trial, the effect of RPL554 (0·018 mg/kg) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men. In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment. Analyses were by intention to treat. All trials were registered with EudraCT, numbers 2008-005048-17, 2011-001698-22, 2010-023573-18, and 2012-000742-34.
Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups. Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s (FEV1) and provocative concentration of methacholine causing a 20% fall in FEV1 (PC20MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV1 increase at 1 h of 520 mL (95% CI 320-720; p<0·0001), which was a 14% increase from placebo, and increased the PC20MCh by 1·5 doubling doses (95% CI 0·63-2·28; p=0·004) compared with placebo. The primary endpoint of study 2 was maximum FEV1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV1 from placebo on day 1 (555 mL, 95% CI 442-668), day 3 (505 mL, 392-618), and day 6 (485 mL, 371-598; overall p<0·0001). A secondary endpoint of study 3 (patients with COPD) was the increase from baseline in FEV1. RPL554 produced bronchodilation with a mean maximum FEV1 increase of 17·2% (SE 5·2). In healthy individuals (study 4), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 (0·018 mg/kg) did not significantly reduce the percentage of neutrophils in sputum (80·3% in the RPL554 group vs 84·2% in the placebo group; difference -3·9%, 95% CI -9·4 to 1·6, p=0·15), since RPL554 significantly reduced neutrophils (p=0·002) and total cells (p=0·002) to a similar degree.
In four exploratory studies, inhaled RPL554 is an effective and well tolerated bronchodilator, bronchoprotector, and anti-inflammatory drug and further studies will establish the full potential of this new drug for the treatment of patients with COPD or asthma.
The lancet. Respiratory medicine. 11/2013; 1(9):714-27.
[Show abstract][Hide abstract] ABSTRACT: The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell-driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications.
The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recognition of asthma as a heterogeneous disease revealed different potential molecular targets and urged the development of targeted, customized treatment modalities. Evidence was provided for different inflammatory subsets of asthma and more recently, further refined to T helper (Th)2-high and Th2-low subphenotypes with different responsiveness to standard and targeted pharmacotherapy. Given these differences in immunology and pathophysiology, proof of concept studies of novel treatment modalities for asthma should be performed in adequate, well-defined phenotypes. In this review, we describe both existing and novel biomarkers of Th2-inflammation in asthma that can be applied to classify asthma subphenotypes in clinical studies and for treatment monitoring.
Current Allergy and Asthma Reports 08/2013; · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The current maintenance dose (10,000 AUeq/monthly) of a subcutaneous allergoid for house dust mite (HDM) immunotherapy has previously shown significant clinical efficacy in patients with HDM induced allergic rhinitis or rhinoconjunctivitis. In order to comply with the 2009 EMA guidelines on immunotherapy products, a study was conducted to evaluate the safety, tolerability and short-term treatment effects of up-dosing regimens with high doses (up to 40,000 AUeq) of allergoid HDM immunotherapy. METHODS: In total 48 patients with HDM-allergic rhinitis or rhinoconjunctivitis (29 M/19 F; 18--53 years) were included and enrolled into one of three up-dosing regimens (1:4:4): 1) a regular regimen with up-dosing to 40,000 AUeq followed by two maintenance doses (total duration 17 weeks), 2) an intermediate regimen (14 weeks) or 3) a fast regimen (11 weeks). Safety and tolerability were evaluated by monitoring of early and late local reactions and systemic reactions. In addition, short-term effects were assessed by conjunctival provocation test (CPT) and levels of serum allergen-specific IgE, IgG and IgG4. RESULTS: Thirty-nine patients completed the study according to protocol. No early local reactions occurred. Late local reactions (LLR) were observed in 12% of the injections. In total, 31 systemic reactions, all grade 1, were reported of which two needed oral antihistamine treatment. No grade 2 or higher systemic reactions were observed. Six patients (15%) did not reach the highest dose due to LLR and/or systemic reactions needing antihistamines (20% in the regular regimen, 16% in the intermediate regimen and 13% in the fast regimen). At the end of the study, an improvement in the CPT was observed in 82.1% of patients, indirectly indicating an early treatment effect at the current dose and higher doses. In addition, IgG4 immunoglobulin levels were significantly increased in all groups following treatment. CONCLUSIONS: In this open-label study, allergoid HDM immunotherapy in doses up to 40,000 AUeq was generally well tolerated and no clinically relevant safety issues were identified. In the safety aspects of the three up-dosing regimens no clinically relevant differences were encountered. Therefore, these dose ranges and up-dosing regimens can be safely included in future dose- finding efficacy studies.
Clinical and translational allergy. 05/2013; 3(1):16.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: GSK2190915, a potent 5-lipoxygenase-activating protein inhibitor, prevents the synthesis of leukotrienes and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). OBJECTIVE: To assess the effect of GSK2190915 on the allergen-induced asthmatic responses. METHODS: Nineteen eligible male subjects with mild asthma were enrolled in and completed this four-centre, double-blind, two-way crossover study (ClinicalTrials.gov NCT00748306). Subjects took GSK2190915 100 mg and placebo orally once daily for 5 days in randomized order. On Day 1 and 4 they had a methacholine challenge, on Day 3 they had an inhaled allergen challenge, and on Days 4 and 6 they had sputum induction. RESULTS: GSK2190915 attenuated the early (0-2 h) and late (4-10 h) asthmatic responses to inhaled allergen compared with placebo. There was a statistically significant attenuation of the early asthmatic response (EAR) by GSK2190915; treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) EAR was 0.408 L (0.205, 0.611). There was a statistically significant attenuation of the late asthmatic response (LAR) by GSK2190915; the treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) LAR was 0.229 L (0.041, 0.417). There was a statistically significant attenuation of allergen-induced sputum eosinophil count on Day 4 following GSK2190915: mean treatment difference (95% CI) between GSK2190915 and placebo was -9.95% (-18.15%, -1.77%). Compared with placebo, GSK2190915 100 mg reduced median sputum LTB(4) by > 90% on Days 4 and 6. There was no effect on methacholine PC(20) post allergen. GSK2190915 was generally well tolerated. CONCLUSION AND CLINICAL RELEVANCE: GSK2190915 shows potential as a treatment for patients with asthma.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Assessing patient's perspective provides useful information enabling a customized approach which has been advocated by current guidelines. In this multicentre cross-sectional study we evaluated personal viewpoints on allergen-specific immunotherapy (SIT) in patients treated with subcutaneous (SCIT) or sublingual (SLIT) immunotherapy. METHODS: A survey of 28 questions assessing patient's knowledge, perceptions, expectations and satisfaction was developed by an expert panel and was applied by physicians from allergology centres in patients with respiratory allergy treated with SIT. Treating physicians independently reported their satisfaction level regarding SIT for each patient. RESULTS: Fully completed surveys from 434 patients (55.3% male; 66.7% poly-sensitized, 74% SLIT) were analysed. Mean duration of SIT was 2.5 years with different allergens. Most patients acquired their SIT knowledge from their physician (95%) and consequently, their physicians' opinion in their choice to start with SIT was important. Most patients perceived SIT to be safe and easy to integrate into their daily routine. The main motivations for SIT were its supposed potential to alter the course of the disease (45.7%), less need of (28.2%), or dissatisfaction with current pharmacotherapy (19.3%). Both patients' and physicians' satisfaction was high (VAS-scores 74/100 and 78/100, respectively) and showed a significant correlation (SCIT: r=0.612; SLIT: r=0.608). No major difference was found in patients' answers based on the level of education. CONCLUSION: In this real life study evaluating different aspects of patient's perspective on SIT, the majority of patients had an adequate level of knowledge, perceptions, expectations and satisfaction about SIT, which corresponded well with the physician's perceptions and satisfaction. Our data warrant the use of patient's perspectives on chronic SIT treatment.
Respiratory medicine 12/2012; · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 5-lipoxygenase metabolites of arachidonic acid, leukotrienes B4, C4, D4 and E4, are potent pro-inflammatory mediators that are implicated in the pathophysiology of asthma. Therefore, many antileukotriene compounds have been developed. Two major categories of these drugs are presently under investigation in patients with asthma: (a) leukotriene D4 receptor antagonists, which block the effects of cysteinyl leukotrienes at the receptor site; (b) leukotriene biosynthesis inhibitors, which prevent the formation of both cysteinyl leukotrienes and leukotriene B4. Both categories provide clinically relevant protection against bronchoconstrictor stimuli, such as exercise, cold dry air, and aspirin (acetylsalicylic acid). Unexpectedly, in allergen inhalation studies, leukotriene receptor antagonists have been shown to be more effective than the biosynthesis inhibitors.
Consequently, owing to their favourable pharmacokinetic profile, potent antileukotriene drugs represent a potential first-line treatment in the management of certain types of asthma such as exercise and aspirin-induced asthma. However, the definite place in therapy of both categories of drugs will depend on the results of long term treatment in the various subgroups of asthmatic patients in comparison with and in addition to present antiasthma medication.
[Show abstract][Hide abstract] ABSTRACT: Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FE(NO) ) is a simple, non-invasive and cost-effective online test applicable in both adults and children. In addition to symptoms and lung function measurements, FE(NO) reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive T helper 2 type airway inflammation in asthmatic patients. FE(NO) can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes.
The scope of this review is to provide an overview of the most important clinical studies using FE(NO) in asthma management and to summarise the implications of FE(NO) measurements in clinical practice.
In several studies, FE(NO) measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FE(NO) can aid asthma diagnosis, identify patients at risk of exacerbation and support customized treatment decisions. A simple and reliable tool to quantify peripheral nitric oxide will further aid to identify patients with small airways inflammation.
The Clinical Respiratory Journal 08/2012; 6(4):193-207. · 1.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Asthma and COPD are chronic inflammatory airway disorders with systemic manifestations. The two diseases have different airway inflammation, features of airway remodelling with subsequent pathophysiology and clinical presentation. The international management guidelines recommend stepwise pharmacotherapy depending on disease control and÷or disease stage, comprising relievers and overall uniform controller treatment, despite the heterogeneity across the conditions and treatment response. Despite effective medications per se, still too many patients remain uncontrolled and no treatment can definitely cure either of the conditions. This overview includes currently recommended pharmacotherapeutic options with novel and future treatment targets.
The Netherlands Journal of Medicine 12/2011; 69(11):486-99. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Roflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed.
[Show abstract][Hide abstract] ABSTRACT: Respiratory sensitization provides a case study for a new approach to chemical safety evaluation, as the prevalence of respiratory sensitization has increased considerably over the last decades, but animal and/or human experimental/predictive models are not currently available. Therefore, the goal of a working group was to design a road map to develop an ASAT approach for respiratory sensitisers. This approach should aim at (i) creating a database on respiratory functional biology and toxicology, (ii) applying data analyses to understand the multi-dimensional sensitization response, and how this predisposes to respiratory inflammation and irritation, and (iii) building a systems model out of these analyses, adding pharmacokinetic-pharmacodynamic modeling to predict respiratory responses to low levels of sensitisers. To this end, the best way forward would be to follow an integrated testing approach. Experimental research should be targeted to (i) QSAR-type approaches to relate potential as a respiratory sensitizer to its chemical structure, (ii) in vitro models and (iii) in vitro-in vivo extrapolation/validation.
Toxicology in Vitro 05/2011; 25(7):1251-8. · 3.21 Impact Factor