Anemia and hemoglobin serum levels are associated with exercise capacity and quality of life in chronic obstructive pulmonary disease.

BACKGROUND: Little is known about the relationship between hemoglobin concentrations, functional status and health related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD). Our aim was to investigate the prevalence of anemia and the association of hemoglobin with shortness of breath, exercise capacity, muscle strength and HRQL, in COPD patients. METHODS: A total of 105 COPD patients (77 males, 71.6 ± 9.2 years) were studied. Patients were classified as anemic and non anemic using the WHO criteria. We used the Medical Research Council Dyspnoea scale (MRCs) to measure shortness of breath. Exercise capacity was assessed using the six minute walking distance (6MWD) and the peak of VO2 during the maximal cycle ergometer test (VO2max). We used the Quadriceps and Handgrip strength assessment to determine muscle strength. The Saint George Respiratory Questionnaire was used to investigate HRQL. The physiological/functional characteristics of the two groups were compared. Regression models adjusting for confounders examined the independent association of anemia and of hemoglobin levels with clinical and functional outcomes. RESULTS: Anemic patients (12.3%) showed a significantly higher MRCs, a lower 6MWD, VO2max, and a worse quality of life. On the contrary, there was no difference in muscle strength between the two groups. In the regression models, hemoglobin was independently associated with reduced exercise capacity and HRQL. CONCLUSIONS: Anemia in COPD was a risk factor for poorer exercise capacity and quality of life, and these outcomes were linearly associated with hemoglobin. Our results should stimulate further research into exploring whether increasing hemoglobin has a beneficial effect on the outcomes in COPD.

The level of control of mild asthma in general practice: an observational community-based study.

OBJECTIVE: The aim of the present community-based study was to evaluate the level of asthma control in patients with mild asthma, regularly treated with inhaled steroids (ICS). METHOD: This observational cross-sectional study included patients registered in the general practitioner (GP) database and with at least three prescriptions of ICS in the last 12 months. Patients were asked to refer to the doctor's office for a standardised interview. The level of asthma control was self-measured by the patients using the Asthma Control Test (ACT)™ (Quality Metric, Inc.). RESULTS: The study included 950 asthmatic patients, referred by 540 GPs: 54.5% were females, mean age was 51 (±19.1) years; 59.5% were non-smokers, 22.5% were current smokers and 18.0% were former smokers; 81.1% of the patients were on ICS in the last 4 weeks. Only 38.6% of patients had a spirometry in the last 12 months. According to the ACT, 13.7% of the asthmatic patients were totally controlled, 51.0% well controlled, and 35.3% poorly controlled. Smoking habit, older age (>60) and living in Central or Southern Italy were associated with poorer control. In the last 12 months 4.5% of patients had an asthma-related hospitalisation, 5.3% an emergency visit and 18.9% a specialist visit. CONCLUSIONS: More than one of three patients had poor asthma control, despite being considered by their GPs as mild asthmatics and treated with ICS. Asthmatic patients need to be regularly re-evaluated. Treatment is often inadequate and should be targeted to improve control and reduce asthma morbidity (SAM104964).

Step-down compared to fixed-dose treatment with inhaled fluticasone propionate in asthma.

BACKGROUND: Inhaled corticosteroids (ICSs) are an effective treatment of asthma even when administered at a low dose. Once asthma is controlled, current guidelines recommend that the dose of ICS be reduced to the lowest possible and effective dose. Although the most appropriate strategy for the stepping down has not yet been defined, quantification of sputum eosinophils and bronchial hyperresponsiveness (BHR) are indeed measures of asthma control. OBJECTIVE: To compare the efficacy of step-down and fixed-dose strategies in the control of BHR to methacholine and eosinophilic inflammation patients with mild-to-moderate asthma. METHODS: We performed a double-blind, randomized study to compare inhaled fluticasone propionate (FP), 1,000 microg/d, then reduced to 200 microg/d (group 1; n = 18) to a fixed dose of FP, 200 microg/d (group 2; n = 17) administered for 6 weeks and then 8 weeks in reducing the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and sputum eosinophils in 35 patients. The duration of the efficacy was also followed subsequently after 8 weeks of placebo treatment. RESULTS: PD20 remarkably increased with both treatment strategies, but differences between groups were not significant. Sputum eosinophils (median values, percentage) at baseline and after each treatment period were not different (group 1, 16.4 to 1.0 to 2.7%; group 2, 16.7 to 2.8 to 2.8%, respectively). The percentages of patients in whom sputum eosinophilia was normalized (< or = 3%) were as follows: group 1, 69% and 60%; group 2, 50% and 57%. After placebo treatment, sputum eosinophils were still "normalized" in approximately one third of patients. CONCLUSION: Step-down and fixed-dose strategies with FP improved PD20 and sputum eosinophilia to a similar degree. The effect on sputum eosinophils persisted longer than that on methacholine.

Inhaled corticosteroids are more effective in COPD patients when used with LABA than with SABA.

Adding long-acting beta agonists (LABA) to inhaled corticosteroids (ICS) has been associated with beneficial effects in COPD patients in randomized controlled trials and observational studies. However, it is not known whether adding short-acting beta agonists (SABA) to ICS instead of LABA will be similarly effective in COPD. We compared the effectiveness of combination therapies involving ICS with LABA versus ICS with SABA in reducing risk of re-hospitalization or death among COPD patients within a year of discharge from a first COPD hospitalization. Using the UK General Practice Research Database, we obtained 437 pairs of patients who either used ICS plus LABA or ICS plus SABA, each pair having been matched on disease severity. We found that 12.1% of patients prescribed ICS with LABA experienced re-hospitalization or death within 12 months compared with 18.1% among those given ICS with SABA. In multivariate analyses, we found a 38% risk reduction (P<0.007) among patients given ICS with LABA relative to those given ICS with SABA. Models stratified by SABA use generated a risk reduction of 35% (P=0.02) among those given ICS and LABA with SABA in the 90-day period, and of 49% (P<0.05) among those given ICS and LABA without any SABA compared with the combination users of ICS and SABA. We conclude that in moderate to severe COPD patients, the combined use of ICS with LABA is more effective in reducing the risk of re-hospitalization or death than the combined use of ICS with SABA.

Exacerbations as a starting point of pro-active chronic obstructive pulmonary disease management.

Chronic obstructive pulmonary disease (COPD) exacerbations could represent an opportunity for pro-active COPD management rather than mere treatment if previously unknown disease is discovered; the extent of underdiagnosis and undertreatment of COPD in patients attending an emergency department (ED) with an exacerbation is not known. During 2002, we recalled 131 COPD patients in stable conditions, 4-8 weeks after they had attended the ED or been discharged from our University Hospital (North-West of Italy). Information on diagnosis and management prior to the ED attendance were collected; spirometry and arterial blood gas analyses were performed. One-third of patients had never been diagnosed and treated even though 83% of them had moderate-to-very-severe COPD and about 30% already had respiratory failure. Only 20% had received information on the nature of the disease and none had received a written action plan. Only 60% were receiving long-acting bronchodilators and 41% of patients with respiratory failure were receiving long-term oxygen. A substantial number of undiagnosed and untreated patients with moderate-to-very-severe COPD came to our attention through an exacerbation. This enforces the importance of exacerbations as the starting point of pro-active COPD management and of the ED as a valuable sentinel to identify this subset of patients.

Clinical pharmacokinetics of salmeterol.

Salmeterol is an inhaled long-acting selective beta(2)-adrenoceptor agonist that is commercially available as the xinafoate (1-hydroxy-2-naphthoic acid) salt of the racemic mixture of the two optical isomers, (R)- and (S)-, of salmeterol. It acts locally in the lung through action on beta2 receptors. Limited data have been published on the pharmacokinetics of salmeterol. Moreover, there are no data on the extent to which inhaled salmeterol undergoes first-pass metabolism. This lack of information is most likely due to the very low plasma concentrations reached after inhalation of therapeutic doses of salmeterol and the problems in developing an analytical method that is sensitive enough to determine these concentrations. When salmeterol is inhaled, plasma concentrations of the drug often cannot be detected, even at 30 minutes after administration of therapeutic doses. Larger inhaled doses give approximately proportionally increased blood concentrations. Plasma salmeterol concentrations of 0.1 to 0.2 and 1 to 2 microg/L have been attained in healthy volunteers about 5 to 15 minutes after inhalation of a single dose of 50 and 400 microg, respectively. In patients who inhaled salmeterol 50microg twice daily for 10 months, a second peak concentration of 0.07 to 0.2 microg/L occurred 45 to 90 minutes after inhalation, probably because of the gastrointestinal absorption of the swallowed drug. Salmeterol xinafoate dissociates in solution to salmeterol and 1-hydroxy-2-naphthoic acid. These two compounds are then absorbed, distributed, metabolised and excreted independently. The xinafoate moiety has no apparent pharmacological activity, is highly protein bound (>99%), largely to albumin, and has a long elimination half-life of about 12 to 15 days in healthy individuals. For this reason, it accumulates in plasma during repeated administration, with steady-state concentrations reaching about 80 to 90 microg/L in patients treated with salmeterol 50microg twice daily for several months. The cytochrome P450 (CYP) isoform 3A4 is responsible for aliphatic oxidation of salmeterol base, which is extensively metabolised by hydroxylation with the major metabolite being alpha-hydroxysalmeterol, with subsequent elimination predominantly in the faeces. It has been demonstrated that 57.4% of administered radioactivity is recovered in the faeces and 23% in the urine; most is recovered between 24 and 72 hours after administration. Unchanged salmeterol accounts for <5% of the excreted dose in the urine. Since the therapeutic dose of salmeterol is very low, it is unlikely that any clinically relevant interactions will be observed as a consequence of the coadministration of salmeterol and other drugs, such as fluticasone propionate, that are metabolised by CYP3A. All the available data clearly show that at the recommended doses of salmeterol, systemic concentrations are low or even undetectable. This is an important point, because it has been demonstrated that the systemic effects of salmeterol are more likely to occur with higher doses, which lead to approximately proportionally increased blood concentrations.

A comparison between inhaled salmeterol and theophylline in the short-term treatment of stable chronic obstructive pulmonary disease.

BACKGROUND: International guidelines indicate that the long-acting bronchodilators play a key role in the treatment of patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the short term efficacy and safety of 50 and 100 microg bid inhaled salmeterol, compared with placebo and orally dose titrated slow-release theophylline in patients with stable COPD. METHODS: Thirteen patients (67+/-7 years, three females) with moderate-to-severe COPD (FEV1<70% predicted and >30% predicted) and with poor reversibility (post-bronchodilator FEV1<12% and <200 ml from pre-bronchodilator values) completed this single centre randomised, double-blind, double-dummy, four-phase cross-over clinical trial. Patients were randomised to treatment after a 2-week oral corticosteroid trial and a theophylline titration phase. Each treatment lasted 2 week with a 2-week washout period. Values at the end of treatments were compared. RESULTS: Inhaled salmeterol at both tested doses was better than placebo in improving lung function (FEV1, FVC, and morning PEF) of stable patients with moderate COPD over a period of 2 weeks. Although slight (about 170 ml, 150 ml, and 120 ml/min on average, for FEV1, FVC, and PEF, respectively) the improvement was significant. The effects seem to improve only slightly with the higher dose. Salmeterol appeared to be more effective than theophylline treatment when compared to placebo, as theophylline improved significantly, but less, the FEV1 (about 80 ml, on average) without affecting any of the other lung function variables. Salmeterol 100 microg was significantly better than theophylline in improving morning PEF. Four patients reported five adverse events while receiving placebo and 2 and 3 patients reported 2 and 3 adverse events, respectively, during salmeterol 50 microg and salmeterol 100 microg phases. None was considered drug related. Five patients experienced 13 adverse events with theophylline treatment, four of which were considered drug related. CONCLUSION: Inhaled salmeterol improves lung function in stable patients with moderate-to-severe and poorly reversible COPD. The magnitude of improvement in FEV1 observed in this study is similar to that found in longer and larger studies on similar populations of patients. In those studies, that improvement was associated with a better quality of life and less symptoms. Theophylline determined a smaller improvement in FEV1 with more unpleasant side effects that both doses of inhaled salmeterol, though there was no significant difference. It is concluded that salmeterol is an effective and well tolerated therapy, potentially preferable to theophylline, at least in the short-term management of stable COPD.

Nebulized fluticasone propionate vs. budesonide as adjunctive treatment in children with asthma exacerbation.

OBJECTIVES: To compare the effects of nebulized fluticasone propionate (FP) and nebulized budesonide (BUD) in addition to inhaled salbutamol in children with mild asthma exacerbation. METHODS: The study was a multicenter, randomized, single-blind, parallel group design. One hundred and sixty-eight children, aged 4-15 years, were randomly allocated to receive either nebulized FP (250 mcg) or nebulized BUD (500 mcg) twice daily for 10 days. On presentation, at the end of treatment, and after a 7-day follow-up, clinical assessment and pulmonary function measurements were performed. Daytime and nighttime asthma symptom scores, the use of rescue salbutamol, and morning/evening peak expiratory flow (PEF) values were recorded at home during the treatment period. Morning cortisol concentration (51 children) and overnight urinary cortisol excretion (30 children) were also measured in six centers at the start and at the end of the treatment. RESULTS: Improvement of morning PEF was significantly higher in patients treated with FP (p=0.032). The percentage of symptom-free nights was significantly higher in the BUD group (p=0.006), but no difference was found in symptom-free days. No intergroup difference was detected in the percentage of days/nights free from rescue medication and in pulmonary function tests performed in outpatient settings. There was no evidence of hypothalamo-pituitary-adrenal axis suppression. CONCLUSIONS: A short course of nebulized FP has the same effects as a double dose of nebulized BUD, when either drug is added to bronchodilator therapy in children with mild asthma exacerbation

Lung myofibroblasts as targets of salmeterol and fluticasone propionate: inhibition of alpha-SMA and NF-kappaB.

Lung myofibroblasts play a major role in the pathophysiology of asthma, contributing not only to tissue remodelling but also to airway inflammation. Nevertheless, only recently, attention has been focused on these cells as potential targets for anti-allergic drugs. Herein, we analysed the pharmacological response of lung myofibroblasts to beta2-agonists associated or not to inhaled corticosteroids, investigating their effects on (i) the constitutive and transforming growth factor-beta (TGF-beta)-induced expression of alpha-smooth muscle actin (alpha-SMA), the main functional marker of myofibroblastic differentiation and contractility; (ii) isometric contraction and (iii) tumour necrosis factor-alpha (TNF-alpha)-induced nuclear translocation of the pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB). The beta2-agonist salmeterol (SMl) has on human lung myofibroblasts new direct anti-contractile/anti-inflammatory effects that are amplified by the combined use of low concentrations of the glucocorticoid fluticasone propionate (FP). First, SMl and/or FP (10(-12) M) inhibits the constitutive and TGF-beta-induced expression of alpha-SMA. Second, the two drugs block the TNF-alpha-induced nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. Finally, SMl decreases TNF- alpha-induced production of the inflammatory cytokine IL-6. The complementary anti-inflammatory/ anti-contractile effects displayed by SMl and FP on lung myofibroblasts in vitro may be related to the improvement in lung function and symptom control obtained in vivo by the early use of low doses of glucocorticoids in combination with long-acting beta2-agonists.

Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone.

We conducted a randomized, double-blind, parallel-group study to assess the effect of 6 weeks treatment with low-dose (100 microg twice a day) or high-dose (500 microg twice a day) inhaled fluticasone propionate (FP) on the vascular component of airway remodeling in 30 patients with mild to moderate asthma. We also studied the effect on the inflammatory cells and the basement membrane thickness, and we compared findings from bronchial biopsies taken in patients with asthma with those in eight control subjects. Bronchial responsiveness to methacholine and asthma symptom score were measured before and after treatments. Eight patients in the low-dose FP group and eight patients in high-dose FP group completed the study. At baseline, patients with asthma showed an increase in the number of vessels and in vascular area as compared with control subjects. In the subjects with asthma, number of vessels correlated with vascular area (p < 0.01) and with number of mast cells (p < 0.01). Bronchial responsiveness to methacholine, asthma symptom score, and inflammatory cells decreased significantly after both low- and high-dose FP (p < 0.05). However, the number of vessels, the vascular area, and the basement membrane thickness decreased only after high-dose FP (p < 0.05). In conclusion, this study shows that in patients with mild to moderate asthma, high dose of inhaled FP given over 6 weeks can significantly affect airway remodeling by reducing both submucosal vascularity and basement membrane thickness.