BACKGROUND: Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. METHODS: We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. RESULTS: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. CONCLUSIONS: Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Changes in health-related quality of life (HRQoL) were evaluated in patients with chronic obstructive pulmonary disease (COPD) following treatment with placebo, salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler. Patients completed the disease-specific St. George's Respiratory Questionnaire (SGRQ) and the Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 16 wk of treatment. Data from 283 patients (95 patients in the placebo group and 94 in each salmeterol group) were available for HRQoL analysis. Apart from a small difference in ages, all treatment groups were well matched at baseline in terms of forced expiratory volume in one second (FEV1) and HRQoL scores. Compared with placebo, salmeterol 50 microg twice a day was associated with significant improvements in SGRQ "Total" and "Impacts" scores which exceeded the threshold for a clinically significant change. This was not seen with salmeterol 100 microg twice a day. Changes in SGRQ and SF-36 scores correlated. They also showed a weak but significant relationship with FEV1. This study has shown that a modest change in lung function may be associated with clinically significant gain in health and well-being in COPD patients.

Dynamic hyperinflation (DH) is a major pathophysiologic consequence of airflow limitation during exercise in patients with chronic obstructive pulmonary disease (COPD) and an important contributing factor to breathlessness. In this study we aimed to examine the effect of inhaled beta agonist therapy on DH during exercise in these patients and the relationship between changes in DH and breathlessness. In 13 COPD patients (mean age 65.1 +/- 2.0, FEV1 1.20 +/- 0.17, FEV1/FVC 40 +/- 3) we measured pulmonary function tests, exercise breathlessness by Borg score, and exercise flow volume and pressure volume loops on two separate days. Prior to testing, patients randomly received inhaled placebo or albuterol on the first test day and the alternative medication on the second test day. From measurements of exercise inspiratory capacity (IC), we calculated the end-expiratory and end-inspiratory lung volumes (EELV, EILV). We used esophageal pressure recordings to measure peak inspiratory esophageal pressure (Pesins) during exercise and this was related to the maximal capacity for pressure generation taking into account lung volume and airflow changes (Pcapi). Bronchodilator caused significant increase in both FEV1 and FVC (+0.23 and +0.51, p<0.01). Comparisons of breathlessness, exercise volumes, and pressures were made at the highest equivalent work load. There was a significant reduction in the peak exercise EELV/TLC (80 +/- 0.02% to 76 +/- 0.02%, p<0.05) while the peak EILV/TLC decreased by 2%(97 +/- 1% to 95 +/- 1%, p<0.05). The peak Pesins/Pcapi decreased (0.79 +/- 0.10 to 0.57 +/- 0.05, p<0.05), and the Pcapi - Pesins increased (7.4 +/- 3 to 13.0 +/- 3 cm H2O, p<0.05). There was significant improvement in neuroventilatory coupling for volume change (Pesins/Pcapi/VT/TLC 5.45 +/- 0.5 to 3.25 +/- 1.0, p<0.05). There was a significant reduction in breathlessness as measured by Borg score (4.5 +/- 0.7 to 3.1 +/- 0.5, p<0.05) and there was a significant correlation between delta Borg and delta EILV/TLC (r=0.771, p<0.01) with a trend for Pesins/Pcapi/VT/TLC (r=0.544, p=0.067). There was also a significant correlation between delta EELV/TLC and delta Pesins/Pcapi/VT/TLC (r=0.772, p<0.01). The relationships between delta Borg, delta resting volumes, and flow rates were not significant. We conclude that in patients with COPD, inhaled bronchodilator reduces exercise DH and improves inspiratory pressure reserve and neuroventilatory coupling. Changes in DH and neuroventilatory coupling were the main determinants of reduced breathlessness.

BACKGROUND: Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. METHODS: A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 microg once daily via dry-powder inhaler, compared with salmeterol, 50 microg bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 623 patients participated (tiotropium, n= 209; salmeterol, n = 213; and placebo, n = 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV(1)(mean, 1.08 +/- 0.37 L; percent predicted, 40 +/- 12%[+/- SD]). Compared with placebo treatment, the mean predose morning FEV(1) following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV(1)(0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p = 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium,- 5.14 U (p < 0.05 vs placebo); salmeterol,- 3.54 U (p = 0.4 vs placebo); and placebo,- 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). CONCLUSIONS: Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.

OBJECTIVE: To examine the benefits of adding salmeterol compared with increasing dose of inhaled corticosteroids. DESIGN: Systematic review of randomised, double blind clinical trials. Independent data extraction and validation with summary data from study reports and manuscripts. Fixed and random effects analyses. SETTING: EMBASE, Medline, and GlaxoWellcome internal clinical study registers. MAIN OUTCOME MEASURES: Efficacy and exacerbations. RESULTS: Among 2055 trials of treatment with salmeterol, there were nine parallel group trials of >/=12 weeks with 3685 symptomatic patients aged >/=12 years taking inhaled steroid in primary or secondary care. Compared with response to increased steroids, in patients receiving salmeterol morning peak expiratory flow was greater at three months (difference 22.4 (95% confidence interval 15.0 to 30.0) litre/min, P<0.001) and six months (27.7 (19.0 to 36.4) litre/min, P<0.001). Forced expiratory volume in one second (FEV(1)) was also increased at three months (0.10 (0.04 to 0.16) litres, P<0.001) and six months (0.08 (0.02 to 0.14) litres, P<0.01), as were mean percentage of days and nights without symptoms (three months: days-12%(9% to 15%), nights-5%(3% to 7%); six months: days-15%(12% to 18%), nights-5%(3% to 7%); all P<0.001) and mean percentage of days and nights without need for rescue treatment (three months: days-17%(14% to 20%), nights-9%(7% to 11%); six months: days-20%(17 to 23%), nights-8%(6% to 11%); all P<0.001). Fewer patients experienced any exacerbation with salmeterol (difference 2.73%(0.43% to 5.04%), P=0. 02), and the proportion of patients with moderate or severe exacerbations was also lower (2.42%(0.24% to 4.60%), P=0.03). CONCLUSIONS: Addition of salmeterol in symptomatic patients aged 12 and over on low to moderate doses of inhaled steroid gives improved lung function and increased number of days and nights without symptoms or need for rescue treatment with no increase in exacerbations of any severity.

This randomized controlled trial examined the benefits of combining an inhaled corticosteroid, fluticasone propionate (F), with an inhaled long-acting beta(2)-agonist, salmeterol (S), to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease (COPD). A total of 691 patients with COPD received the combination of F and S (FSC), S (50 mcg), F (500 mcg), or placebo twice daily via the Diskus device for 24 weeks. A significantly greater increase in predose FEV(1) at the endpoint was observed after FSC (156 ml) compared with S (107 ml, p = 0.012) and placebo (-4 ml, p < 0.0001). A significantly greater increase in 2-hour postdose FEV(1) at the endpoint was observed after treatment with FSC (261 ml) compared with F (138 ml, p < 0.001) and placebo (28 ml, p < 0.001). There were greater improvements in the Transition Dyspnea Index with FSC (2.1) compared with F (1.3, p = 0.033), S (0.9, p < 0.001), and placebo (0.4, p < 0.0001). The incidence of adverse effects (except for an increase in oral candidiasis with FSC and F) was similar among the treatment groups. We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo.

Angiogenesis and microvascular remodeling are known features of chronic inflammatory diseases such as asthma and chronic bronchitis, but the mechanisms and consequences of the changes are just beginning to be elucidated. In a model of chronic airway inflammation produced by Mycoplasma pulmonis infection of the airways of mice or rats, angiogenesis and microvascular remodeling create vessels that mediate leukocyte influx and leak plasma proteins into the airway mucosa. These vascular changes are driven by the immune response to the organisms. Plasma leakage results from gaps between endothelial cells, as well as from increased vascular surface area and probably other changes in the newly formed and remodeled blood vessels. Treatment with long-acting beta2 agonists can reduce but not eliminate the plasma occurring after infection. In addition to the elevated baseline leakage, the remodeled vessels in the airway mucosa are abnormally sensitive to substance P, but not to platelet-activating factor or serotonin, suggesting that the infection leads to a selective upregulation of NK1 receptors on the vasculature. The formation of new vessels and the remodeling of existing vessels are likely to be induced by multiple growth factors, including vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). VEGF increases vascular permeability, but Ang1 has the opposite effect. This feature is consistent with evidence that VEGF and Ang1 play complementary and coordinated roles in vascular growth and remodeling and have powerful effects on vascular function. Regulation of vascular permeability by VEGF and Ang1 may be their most rapid and potent actions in the adult, as these effects can occur independent of their effects on angiogenesis and vascular remodeling. The ability of Ang1 to block plasma leakage without producing angiogenesis may be therapeutically advantageous. Furthermore, because VEGF and Ang1 have additive effects in promoting angiogenesis but opposite effects on vascular permeability, they could be used together to avoid the formation of leaky vessels in therapeutic angiogenesis. Finally, the elucidation of the protective effect of Ang1 on blood vessel leakiness to plasma proteins raises the possibility of a new strategy for reducing airway edema in inflammatory airway diseases such as asthma and chronic bronchitis.

Chronic obstructive pulmonary disease (COPD) is a condition in which continuous bronchodilation may have clinical advantages. This study evaluated salmeterol, a beta-agonist bronchodilator with a duration of action substantially longer than that of short-acting beta-agonists, compared with ipratropium, an anticholinergic bronchodilator, and placebo in patients with COPD. Four hundred and five patients with COPD received either salmeterol 42 microg twice daily, ipratropium bromide 36 microg four times daily, or placebo for 12 wk in this randomized, double-blind, parallel-group study. Patients were stratified on the basis of bronchodilator response to albuterol (> 12% and > 200-ml improvement) and were randomized within each stratum. Bronchodilator response was measured over 12 h four times during the treatment period. Salmeterol provided similar maximal bronchodilatation to ipratropium but had a longer duration of action and a more constant bronchodilatory effect with no evidence of bronchodilator tolerance. Both active treatments were well tolerated. Salmeterol was an effective bronchodilator with a consistent effect over this 12-wk study in patients with COPD, including those "unresponsive" to albuterol. The long duration of action of salmeterol offers the advantage of twice daily dosing compared with the required four times a day dosing with ipratropium.

Myopathy complicating the therapy of severe asthma has been recently described in several case reports. Twenty-five consecutive patients admitted to the intensive care unit (ICU) at this hospital for mechanical ventilation for severe asthma were studied for the incidence of creatine kinase (CK) enzyme rise and for the development of clinical myopathy. Pharmacologic therapy was standardized, every patient receiving corticosteroids and aminophylline intravenously and salbutamol both nebulized and intravenously. Twenty-two patients received muscle relaxant therapy with vecuronium. In 19 of 25 (76%) of patients there was elevation of CK levels to a median of 1,575 U/L (range, 66 to 7,430) occurring 3.6 +/- 1.5 days after admission. In nine patients there was clinically detectable myopathy. The presence of either myopathy or CK enzyme rise was associated with a significant prolongation of ventilation time. Arterial blood gas measurements on admission to the ICU revealed a pH (mean +/- SD) of 7.07 +/- 0.21, a PaCO2 of 87.2 +/- 32.7, and a PaO2 (with a high FIO2) of 129 +/- 97 mm Hg; however, no correlation was found between the severity of initial metabolic disturbance and the subsequent development of myopathy. There was no association between the type of corticosteroid administered and the subsequent development of myopathy. Patients with myopathy had received a significantly higher total dose of vecuronium when compared with those who did not develop myopathy (p < 0.001, Kruskal Wallis test). We have therefore found a surprisingly high incidence of CK enzyme rise and myopathy in this group of mechanically ventilated patients with severe asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

We conducted a trial of inhaled salbutamol and orally administered theophylline in patients whose acute response to inhaled salbutamol was less than 25% of their baseline FEV1. Patients underwent 4 treatment periods, each of 2 wk duration, during which they received the following combinations: placebo-placebo, placebo-salbutamol, placebo-theophylline, and salbutamol-theophylline. The 19 patient who completed the study were all males with a mean age of 65 +/- 7.4 yr, mean FEV1 of 1.02 +/- 0.38, and mean VC of 2.73 +/- 0.19. Outcomes included twice-daily recordings of peak flow rates, spirometry, the distance patients could walk in 6 min, and clinical symptoms of dyspnea, fatigue, and emotional function. Clinically important and statistically significant differences between the 4 periods were noted on both physiologic and functional outcomes. For the group as a whole, improvement with inhaled salbutamol and orally administered theophylline was comparable, and additional benefit was gained from a combination of the 2 drugs. We conclude that both inhaled salbutamol and orally administered theophylline can improve airflow obstruction, functional exercise capacity, and quality of life in patients with primarily fixed air-flow limitation.