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Background The dose-response relationship between two dose levels of fluticasone/formoterol ( flutiform ® , 100/10 μg and 500/20 μg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints). Methods Patients aged ≥18 years with forced expiratory volume in 1 s (FEV 1 ) ≥60% predicted and who required a dose of <60 mg AMP to elicit a 20% drop in FEV 1 (AMP PD 20 ) were randomised in this incomplete block, crossover study to receive 2 of 3 treatments b.i.d.: fluticasone/formoterol 500/20 μg (high dose), 100/10 μg (low dose) or placebo, during 2 periods of 28 ± 3 days each, separated by 2–3 weeks. AMP challenges were performed pre-dose and 12 h after last dose at the end of each treatment period. A series of post hoc analyses were performed only in patients allocated to both fluticasone/formoterol doses, who completed the study and had evaluable AMP PD 20 data for both treatments (“fluticasone/formoterol subgroup”). Changes in AMP PD 20 FEV 1 , percentage sputum eosinophils and FeNO levels (Day 1 vs Day 28) between treatments were compared by an analysis of covariance (ANCOVA). Results Sixty-two patients were randomised and 46 completed the study. Fifteen patients received both high- and low-dose fluticasone/formoterol ( post hoc subgroup). The difference in AMP PD 20 for the overall population was not statistically significant between high- and low-dose fluticasone/formoterol (LS mean fold difference: 1.3; p = 0.489), although both dose levels were superior to placebo: high-dose vs placebo LS mean fold difference: 4.4, p < 0.001; low-dose vs placebo LS mean fold difference: 3.5, p < 0.001. In the post hoc subgroup, the difference in AMP PD 20 between the doses was statistically significant in favour of the high-dose (LS mean fold difference: 2.4, p = 0.012). Other inflammatory parameters (sputum eosinophil counts and FeNO) showed small differences and statistically non-significant changes between high- and low-dose fluticasone/formoterol. Conclusions A significant dose-response was found between low- and high-dose fluticasone/formoterol in the post hoc subgroup (patients who received both doses), but not in the overall population, with the higher dose demonstrating a greater reduction in airway responsiveness to AMP. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Rationale Soluble inflammatory markers obtained from non-invasive airway sampling such as induced sputum may be useful biomarkers for targeted pharmaceutical interventions. However, before these soluble markers can be used as potential targets, their variability and reproducibility need to be established in distinct study populations. Objective This study aimed to assess the reproducibility of biomarkers obtained from induced sputum and serum in chronic smokers and non-smokers. Method Sputum and serum samples were obtained from 16 healthy non-smokers and 16 asymptomatic chronic smokers (for both groups: 8M/8F, 30–52 years, FEV 1 ≥80% pred.; ≥10 pack years for the smokers) on 2 separate visits 4–10 days apart. Soluble markers in serum and sputum were analysed by ELISA. The differences between smokers vs non-smokers were analysed with a t -test and variability was assessed on log-transformed data by a mixed model ANOVA. Results Analysable sputum samples could be obtained from all 32 subjects. In both study populations neutrophils and macrophages were the predominant cell types. Serum Pulmonary Surfactant Associated Protein D had favourable reproducibility criteria for reliability ratio (0.99), intra-subject coefficient of variation (11.2%) and the Bland Altman limits of agreement. Furthermore, chronic smokers, compared to non-smokers, had significantly higher sputum concentrations of IL-8 (1094.6 pg/mL vs 460.8 pg/mL, p = 0.006)), and higher serum concentrations of Pulmonary Surfactant Associated Protein D (110.9 pg/mL vs 64.7 pg/mL, p = 0.019), and lower concentrations of Serum Amyloid A (1352.4 pg/mL vs 2297.5 pg/mL, p = 0.022). Conclusion Serum Pulmonary Surfactant Associated Protein D proved to be a biomarker that fulfilled the criteria for reproducibility in both study groups. [ABSTRACT FROM AUTHOR]

Abstract: Non-adrenergic non-cholinergic (NANC) nerves release bronchoactive tachykinins such as substance P (SP) and neurokinin A (NKA) that can induce features of asthma. The airway response to NKA in humans closely resembles that of methacholine (M). Hence, we investigated the relationship between airway responsiveness to NKA and M in subjects with asthma. To this end, we analyzed baseline data of 27 subjects with mild persistent asthma (20F/7M) 19–46 y; FEV1 81–136% pred.; PC20FEV1 (M)&#60;80μmol/mL) participating in a proof-of-concept study. All subjects were non-smokers and asthma was controlled by on demand short-acting β2-agonists only. Dose-response curves to M (0.15–80μmol/mL) and NKA (3.4 (10−3)–0.88μmol/mL) were performed on two separate days, and airway response was measured by FEV1 until a ≥20% fall from baseline (PC20FEV1). Twenty-two subjects reached a PC20FEV1 on both occasions. The PC20FEV1 values of both agonists correlated significantly (Spearman''s r=−0.721; p=0.0002), and the relationship was given by 10log(PC20FEV1(NKA))=−1.36+ (0.60×10log(PC20FEV1(M)). We have demonstrated a significant relationship between airway responsiveness to NKA and methacholine in asthma. This suggests that both agonists may share common final pathways in causing bronchoconstriction in patients with mild persistent asthma. Based on our data and previous studies in asthma, it can be hypothesized that this direct NKA-induced bronchoconstrictor response may be mediated by predominant stimulation of the tachykinin NK-2 receptors on airway smooth muscle cells. [Copyright &y& Elsevier]