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(Chest. 2001;120:258-270.)
© 2001 American College of Chest Physicians

Alternative Mechanisms for Long-Acting ß2-Adrenergic Agonists in COPD*

Malcolm Johnson, PhD and Stephen Rennard, MD, FCCP

* From GlaxoSmithKline Research and Development (Dr. Johnson), Uxbridge, Middlesex, UK; and University of Nebraska Medical Center (Dr. Rennard), Omaha, NB.

Correspondence to: Malcolm Johnson, PhD, GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, Middlesex UB11 1BT, United Kingdom; e-mail: mj0859{at}glaxowellcome.co.uk


   Abstract
TOP
 Abstract
Introduction: COPD Definition...
 Long-Acting ß2...
 Mechanisms of Airflow Limitation...
 Clinical Efficacy of LABAs...
 Conclusion
 References
 
ß2-Adrenergic agonists are commonly used as bronchodilators to treat patients with COPD. In addition to prolonged bronchodilation, long-acting ß2-agonists (LABAs) exert other effects that may be of clinical relevance. These include inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as nonsmooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa, and attenuation of neutrophil recruitment and activation. This review details the possible alternative mechanisms of action of the LABAs, salmeterol and formoterol, in COPD.

Key Words: COPD • formoterol • long-acting ß2-adrenergic agonists • salmeterol


   Introduction: COPD Definition and Etiology
TOP
 Abstract
 Introduction: COPD Definition...
Long-Acting ß2...
 Mechanisms of Airflow Limitation...
 Clinical Efficacy of LABAs...
 Conclusion
 References
 
COPD is defined as a syndrome characterized by abnormal test results of expiratory flow, which do not change markedly over periods of several months of observation.1 It is a general term that describes diseases associated with respiratory obstruction (eg, chronic bronchitis) and loss of elastic lung recoil (eg, emphysema). COPD is characterized by breathlessness on physical exertion, and progressively deteriorating lung function, which may lead to respiratory failure, cough, and sputum production. Chronic bronchitis is defined clinically as a persistent cough, with sputum production present on most days for 3 months in 2 consecutive years. Emphysema is defined as a permanent enlargement of any part of the gas exchanging structure of the lung, accompanied by destruction of respiratory tissue without marked fibrosis.2 While COPD is currently the sixth-leading cause of death, with approximately 3 million deaths per year worldwide, it is expected to be the fifth-leading cause of death in the year 2020.3

At least three mechanisms are involved in the development of airflow limitation in COPD (Fig 1 ). Firstly, structural alterations such as goblet cell metaplasia, inflammation, smooth-muscle hypertrophy, and particularly fibrosis can narrow the airway lumen and reduce airflow. Secondly, destruction of alveolar walls can reduce alveolar attachments and decrease lung elastic recoil. With loss of elastic recoil, there is decreased driving pressure, and with attempts at forced exhalation, small airways collapse.4 5 Thirdly, airflow limitation in COPD cannot be explained entirely on a structural basis, and other mechanisms such as chronic bronchitis, peribronchiolar inflammation, and fibrosis of the small airways may contribute. In emphysema, loss of elastic lung recoil due to alveolar wall destruction plays the major role.6 Many patients with COPD have both lesions. All patients with COPD also have some degree of airflow limitation, some of which may be due to smooth-muscle contraction.



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  		Figure 1. Potential mechanisms involved in the development of airflow limitation in COPD.

 
The most significant cause of COPD is cigarette smoking,7 although there are other environmental and occupational etiologic factors (15 to 20% of COPD patients are lifelong nonsmokers). Smoking causes an accelerated decline in lung function with age. Between 20% to 30% of smokers who experience a more rapid decline in lung function become symptomatic.8 Epidemiologic studies show that children of smokers have a higher incidence of respiratory infections, particularly in the first year of life, which represents a major risk factor for the subsequent development of COPD.9 Therefore, morbidity and mortality from COPD may reflect the smoking patterns in various countries.10 11 12 13 Differences in morbidity and mortality from COPD may also be partially explained by national differences in diagnosis and genetic susceptibility.14 15


   Long-Acting ß2-Agonists in COPD: Salmeterol and Formoterol
TOP
 Abstract
 Introduction: COPD Definition...
 Long-Acting ß2...
Mechanisms of Airflow Limitation...
 Clinical Efficacy of LABAs...
 Conclusion
 References
 
ß2-Adrenergic agonists are bronchodilators that improve lung function, reduce symptoms, and protect against exercise-induced dyspnea in patients with COPD.16 17 18 These agents induce bronchodilation by causing prolonged relaxation of airway smooth muscle. Smooth-muscle relaxation is due to ß2-adrenoceptor–mediated activation of adenylate cyclase in airway smooth muscle, which in turn increases the concentration of intracellular cyclic adenosine monophosphate (cAMP).19 Albuterol, a short-acting ß2-agonist (SABA), is usually administered through a metered-dose inhaler, dry powder device, or by nebulization, but is also available for oral administration. It has been used by patients over the past 3 decades to treat and prevent symptoms, and was a major advance in therapy at the time. Thirty years later, it remains the standard bronchodilator for use in COPD-related acute bronchospasm and bronchitis. The major drawback with the first generation of ß2-adrenergic agonists, such as salbutamol, is in their short duration of action (4 to 6 h), requiring the drug to be administered several times a day. The need for a long-acting bronchodilator for use in bronchial asthma and COPD has been met with the development of salmeterol20 and formoterol.21

Salmeterol was designed to be a long-acting ß2-agonist (LABA) by virtue of prolonged specific binding to the ß2-adrenergic receptor, and repeated stimulation of the active site, leading to longer efficacy. Salmeterol, due to its lipophilic properties, partitions into the phospholipid membrane and diffuses laterally to approach the ß2-adrenoceptor through the cell membrane.22 The side chain of salmeterol then binds to a discrete hydrophobic domain within the fourth transmembrane region of the ß2-adrenoceptor called the exosite, (amino acids 149–158).23 Binding to the exosite prevents the molecule from dissociating from the receptor. The saligenin head of salmeterol is then free to engage and disengage with the active site of the receptor by the Charnière (hinge) principle, flexion being around the O atom in the side chain,24 leading to a long, concentration-independent duration of action.

Formoterol was developed among attempts to increase the affinity of agonists for the ß2-adrenergic receptor. The exact mechanism by which formoterol exerts prolonged effects on lung function is unknown, but may involve interaction with the membrane lipid bilayer.25 A hypothesis has been proposed whereby formoterol, which is moderately lipophilic, enters the plasmalemma and is retained as a depot. The drug is also able to reach the receptor from the aqueous phase, accounting for its rapid onset of action. Subsequently, it gradually leaches out from the plasmalemma to activate the receptor, imparting a prolonged concentration-dependent airways smooth-muscle relaxant effect.26 In vivo, both salmeterol and formoterol, at equivalent clinical doses, induce bronchodilation for at least 12 h.


   Mechanisms of Airflow Limitation in COPD: Effect of Salmeterol and Formoterol
TOP
 Abstract
 Introduction: COPD Definition...
 Long-Acting ß2...
 Mechanisms of Airflow Limitation...
Clinical Efficacy of LABAs...
 Conclusion
 References
 
Smooth-Muscle Effects of LABAs in Patients With COPD
Bronchodilation:
The aim of bronchodilator therapy in patients with COPD is to treat any airflow obstruction that is reversible.27 Both salmeterol and formoterol, administered at the recommended twice-daily doses for regular inhaled therapy (50 µg and 24 µg, respectively), are effective in improving airflow limitation in patients with COPD.28 29 In 1995, Cazzola and colleagues28 showed that salmeterol (50 µg) induced a dose-independent bronchodilator response, which lasted longer than formoterol (12 µg or 24 µg).28 However, in an earlier study,29 there was no significant difference in the duration of action of salmeterol and formoterol. Disparity in these results may be explained by differences in the severity of disease. Formoterol has also been shown to induce mean peak bronchodilation (increase in FEV1 over baseline values) more rapidly than salmeterol.28 In addition, a 1999 study by Celik et al30 showed that after 10 min, formoterol induced a clinically and statistically significant improvement in FEV1 compared with placebo, whereas salmeterol required 20 min to achieve a significant improvement. The duration of action of salmeterol and formoterol was > 12 h in both cases.30

Airway Smooth-Muscle Proliferation:
The clinical relevance of airway smooth-muscle proliferation in patients with COPD remains to be determined, but it may apply to mixed disease. The SABA, albuterol, inhibited human airway smooth-muscle cell proliferation in vitro induced by mitogens, such as thrombin,31 an effect that was mediated by an increase in cAMP.32 LABAs such as salmeterol and formoterol act via the same receptors, and so would be expected to be at least as effective as SABAs, with a longer duration of action. Indeed, salmeterol inhibited thrombin-induced DNA synthesis in human airway smooth-muscle cells in culture via an action on cyclin D1 (Fig 2 ).33 By inhibiting smooth-muscle proliferation, LABAs may have the capacity to limit the degree of airway remodeling and resulting obstruction, providing that effective concentrations are achieved in the lungs of COPD patients following inhalation of LABAs. In this regard, it is encouraging that human peripheral lung tissue concentrations of salmeterol, following an inhaled dose of 50 µg, exceed 10 pmol/g,34 a concentration similar to that shown to have antiproliferative activity in vitro.33 Furthermore, although carried out in asthmatic patients, a recent study35 has shown that salmeterol reduces the degree of ongoing angiogenesis, a recognized component of airway remodeling, a property not shared by corticosteroids.



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  		Figure 2. Effect of salmeterol (SALM) on cell proliferation in thrombin (THR)-stimulated human cultured airway smooth muscle. Reprinted with permission from Harris et al.33

 
Airway Muscle Function:
The pathophysiology of COPD may also have a systemic component.36 Salmeterol affected the force of muscular contraction of the diaphragm and intercostal muscles in rats and conscious dogs.37 38 Both albuterol and salmeterol reduced the decline in diaphragm function during severe hypoxia in a rat model, with salmeterol demonstrating a longer duration of action.37 High systemic doses of salmeterol and albuterol increased the depolarization of left costal and crural diaphragm, parasternal intercostal, and transversus abdominis muscles in the dog.39 The result is an increase in respiratory muscle shortening and increased ventilation. These effects have been confirmed in lower doses in man.40 The effect of theophylline on respiratory muscle length and shortening have not been studied directly in an awake, intact mammal. However, it is an interesting possibility that the LABA effect and the presumed theophylline effect on the diaphragm, and other respiratory muscles, may be additive. The benefit of the skeletal muscular effects of LABAs in COPD could be a preservation of diaphragm structure and improvement of respiratory muscle function, which may be particularly crucial at later stages of the disease. The clinical relevance of these findings are still to be determined with respect to inhaled LABAs, as they may not reach the target tissues at the relevant concentrations.

Nonsmooth-Muscle Effects of LABAs in Patients With COPD
Effect of LABAs on Neutrophils:
Inflammation of the airways may also intermittently contribute to obstruction. This airway inflammation is caused by an influx of inflammatory cells, and release of mediators into the tissue.41 In patients with COPD, there are increased numbers of monocytes and lymphocytes, particularly CD8+ cells. Neutrophils are scarce in the subepithelial area, but are present in the epithelium and in the bronchial glands,42 as well as in the airway lumen. BAL fluid and induced sputum from patients with COPD contain increased numbers of neutrophils, which correlate with concentrations of the neutrophil chemoattractant, interleukin (IL)-8, although other chemotaxins (eg, leukotriene B4) are also present. Markers of neutrophil activation, myeloperoxidase and elastase, have also been detected in the sputum of COPD patients.41 43 While the target effector tissue for bronchodilation by ß2-adrenergic agonists is smooth-muscle, they also exert effects on other cells in the airway with ß2-adrenergic receptors which have been implicated in the pathophysiology of COPD. For example, ß2-adrenergic receptors are present on neutrophils,44 and LABAs have been shown to affect neutrophil numbers, activity, and function. Reduction in neutrophil number and function could therefore reduce the severity of disease and degree of airflow obstruction in patients with COPD.

Neutrophil Adhesion:
Adhesion of human neutrophils is mediated by interactions between ß2-integrins (CD11a/CD18 and CD11b/CD18 [Mac-1]) and intercellular adhesion molecule-1.45 46 47 Neutrophil-endothelial cell adhesion is attenuated by agents that elevate cAMP through inhibition of neutrophil Mac-1 cell surface expression.48 Salmeterol increased human neutrophil cAMP levels in a concentration-dependent manner.49 In 1997, Bloemen and coworkers50 showed that salmeterol inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulated human neutrophil adhesion to human airway epithelial cells via Mac-1 inhibition. Both salmeterol51 and formoterol52 have been shown, in experimental animal models, to inhibit the adhesion of neutrophils to the vascular endothelium, but the relevance of these findings to COPD patients is unclear.

Neutrophil Accumulation:
In addition to their effects on adhesion, ß2-adrenergic agonists also affect neutrophil accumulation.53 54 55 In a clinical study54 of patients with mild asthma, salmeterol (50 µg bid for 6 weeks) treatment significantly reduced the number of neutrophils in bronchial biopsies. This effect was accompanied by significant reductions in serum E-selectin, an adhesion molecule involved in neutrophil recruitment, and in myeloperoxidase and lipocalin levels in BAL, markers of neutrophil activation.56 The addition of salmeterol, 50 µg bid, to low-dose inhaled corticosteroids also reduced neutrophils in BAL (p < 0.02) from asthmatic patients with mild-to-moderate disease over 3 months.55 At present, there are no published trials investigating the effect of formoterol on neutrophil accumulation in man, although it is likely to have similar activity to salmeterol. Whether LABAs will exhibit inhibitory effects on neutrophil accumulation in COPD remains to be determined.

Neutrophil Mediator Release/Activation:
IL-8 may be important in COPD pathophysiology because it is produced and released in significant amounts by several types of airway cells, including epithelial cells, smooth-muscle cells, macrophages, and neutrophils. It is a chemoattractant and an activator for neutrophils, and may result in a persistent inflammatory cycle, by establishing a positive feedback loop. Salmeterol, 0.01 to 0.1 µM, inhibited tumor necrosis factor-{alpha}–induced IL-8 release from human airway smooth-muscle cells in vitro, and at 50 µg bid for 3 months reduced BAL IL-8 concentrations in asthmatic patients receiving low-dose inhaled corticosteroids.55 Salmeterol, 0.1 to 10 µM, also caused downregulation of neutrophil oxidative metabolism, and inhibition of respiratory burst (oxygen production) in response to fMLP, while albuterol was without effect.49 A later study verified that salmeterol, 1 to 100 µM, caused concentration-related inhibition of fMLP-induced oxygen release from human neutrophils.57 Salmeterol also inhibited fMLP-induced oxidant production from calcium ionophore-activated neutrophils, and interfered with intracellular calcium flux, phospholipase A2 activity, and synthesis of platelet activating factor. This may be relevant because platelet activating factor is associated with ciliary dysfunction, cytotoxicity, and impaired mucociliary clearance.58 59

While research on the effect of formoterol on neutrophil mediator release/activation in man is limited,60 Anderson and colleagues60 showed that formoterol treatment caused moderate inhibition of activated human neutrophil oxidant generation by a superoxide scavenging mechanism, but unlike salmeterol, possessed weak membrane stabilizing properties.60 In guinea pigs, formoterol has been shown to inhibit superoxide anion and hydrogen peroxide generation from eosinophils.61 62 Therefore, LABAs have the potential to decrease neutrophil activation in patients with COPD and may be useful in controlling cytotoxic properties of neutrophil-derived oxidants at sites of inflammation within the airways. Whether inhalation is the most appropriate means for delivery of agents for this purpose is not known.

Neutrophil Apoptosis:
Salmeterol and formoterol, as well as other agents that elevate intracellular cAMP, may also regulate neutrophil apoptosis. Apoptosis, or programmed cell death, plays a crucial role in the maintenance of cell homeostasis.63 Salmeterol induced apoptosis in human neutrophils, the effects being mediated by ß2-adrenergic receptor activation, and blocked by both the nonspecific antagonist, propranolol, and the selective antagonist, ICI-118551.64 This is probably a LABA class effect, so although at present there are no published studies investigating the effect of formoterol on neutrophil apoptosis, it is likely to have a similar activity to salmeterol. The action of salmeterol contrasts with glucocorticosteroids, which block apoptosis. When neutrophils fail to undergo apoptosis and die by lysis, release of DNA and other cellular components may contribute adversely to the physical properties of airway secretions.

Altogether, these data indicate that long-acting agents like salmeterol and formoterol increase cAMP in neutrophils and therefore inhibit adhesion, accumulation, activation, and induce apoptosis. The end result is a possible reduction in the number and activation status of neutrophils in airway tissue and in the airway lumen.

Effect of LABAs on the Epithelium:
Although evidence suggests that, unlike asthma, the epithelium is largely intact in COPD, epithelial dysfunction may still contribute to the disease. The epithelium provides an efficient physical barrier to the airway. It provides a first-line defense against irritants and pathogens and preserves the integrity of the airway by facilitating mucociliary clearance with associated coordinated ciliary beating. In addition, the epithelium releases a range of cytokines and chemokines that can drive the inflammatory response.

Bacterial infection can damage the respiratory epithelium directly and indirectly by release of toxins, proteases, oxidants, defensins, and other mediators.65 66 Bacteria can release a number of pathogenic factors, which can damage the epithelium, including endotoxin, proteases, and moieties that can bind and inactivate cilia.67 In addition, bacteria can lead to recruitment of inflammatory cells through the direct release of chemotactic mediators,68 through the activation of complement and by activating the release of chemotactic factors from airway cells. Inflammatory cells, in turn, can release oxidants, proteases, and toxic peptides such as defensins. While the lung is protected by a variety of antioxidants and antiproteases, it is likely that these defenses can be overcome by a locally intense inflammatory response, thus setting the stage for tissue damage. Acute viral infection can also cause damage of the epithelium, and initiate an inflammatory response. Interestingly, some viruses can establish chronic "latent" infection when portions of the viral genome persist in lung tissue.69 These conditions may also predispose to augmented inflammation. Epithelium, damaged by bacteria or by inflammation, is more easily colonized. Patients with stable COPD are frequently colonized by bacteria such as unencapsulated Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.70

Epithelial Protection:
LABAs protect the respiratory epithelium against the effects of microorganisms. Preincubation of human nasal turbinates with salmeterol reduced Pseudomonas aeruginosa and H influenzae-induced epithelial damage65 71 (Fig 3 ), probably by maintaining intracellular cAMP concentrations, which together with adenosine triphosphate, are known to fall under these conditions.72 Reduction in epithelial damage was marked by a decrease in tight junction separation, epithelial stripping, and resultant exposure of collagen fibers and the basement membrane, and preservation of the number of both ciliated and unciliated cells. This effect was associated with a reduction in the total number of bacteria adherent to the respiratory mucosa, consistent with the observation that P aeruginosa and H influenzae preferentially adhere to damaged epithelial cell surfaces. In addition, the "cytoprotective" effects of salmeterol were blocked by the selective ß2-receptor antagonist, ICI 118551. Preincubation of tissue with both salmeterol (10- 7M) and the corticosteroid fluticasone propionate (10- 7M) significantly inhibited P aeruginosa-induced loss of ciliated cells in a synergistic manner.73



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  		Figure 3. Top: scanning electron micrograph of human nasal turbinate tissue infected with P aeruginosa in vitro for 8 h. Bacteria are seen adhering to damaged epithelium and cellular debris in preference to ciliated and unciliated epithelium. Mucosal damage is evidenced as cellular extrusion, and the presence of dead cells, membrane damage, and cellular debris (original x 4,000; scale, 1 cm = 2.5µm). Bottom: scanning electron micrograph of human nasal turbinate preincubated with salmeterol (4 x 10-7 mol/L) for 30 min prior to infection with P aeruginosa in vitro for 8 h. In comparison with Figure 3 , top, there are significantly more ciliated cells and significantly less mucosal damage. The mucosal damage is more patchy, interspersed between the cilia. Epithelial damage is less extensive, with only mild tight junction separation and cellular extrusion (original x 4,000; scale, 1 cm = 2.5 µm). Reprinted with permission from Dowling et al.65

 
Furthermore, salmeterol protected the respiratory epithelium against ultrastructural damage caused by the P aeruginosa toxins, pyocyanin and elastase, as evidenced by less cell projection (caused by separation of tight junctions), loss of cilia, cytoplasmic blebbing, and mitochondrial damage with swelling and disruption of cristae.65 The effect of formoterol on epithelial protection has not been reported, but if used in sufficient concentrations to increase cAMP over time, is likely to have similar activity. It is encouraging that the concentration range of salmeterol for epithelial protective activity is similar to that observed in human peripheral lung tissue in vivo.34

If LABAs decrease bacterial colonization, they may render patients less prone to acute bacterial exacerbations. A meta-analysis74 revealed that the incidence of respiratory infections in a 16-week study in COPD patients was 15% with placebo compared with 8% with salmeterol (p < 0.005).16 This was confirmed in a second study of salmeterol in COPD,16 where the incidence of bronchitis was 1% compared with 8% in the placebo group (p < 0.001). Thus, it appears that salmeterol offers some protection against respiratory infections, perhaps by altering the airway epithelium. Further investigation of such an effect seems warranted.

Ciliary Beat Frequency:
Effective mucociliary transport depends on coordinated ciliary beating so that particles (including bacteria) and debris are carried out of the airways. Maintenance of ciliary beating may attenuate P aeruginosa-induced and H influenzae-induced damage by preventing bacterial adherence, and reduce the concentration of toxins in the microenvironment of the mucosal surface, thereby protecting against the development or persistence of infection. Stimulation of epithelial ß2-adrenergic receptors by LABAs may increase ciliary beat frequency (CBF) and mucociliary transport. Albuterol and salmeterol increased CBF in human nasal epithelial cells in culture, with salmeterol increasing CBF at 100-fold–lower concentrations than albuterol and its effect was sustained for 15 to 20 h.75 A similar study with human bronchial epithelium revealed that, while albuterol induced a transient increase in CBF, salmeterol caused a significant and prolonged increase through 24 h postexposure.76 At lower concentrations, salmeterol, while having no effect itself, inhibited P aeruginosa pyocyanin-induced reduction in CBF, and also the concomitant fall in cAMP77 (Fig 4 ). At present, there are no published accounts on the effect of formoterol on CBF, but as a LABA, it is likely to have similar activity to salmeterol.



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  		Figure 4. Effect of salmeterol on pyocyanin-induced ciliary beat slowing. Salmeterol was present throughout the experiment. Salmeterol alone ({square}) had no effect on baseline CBF compared to control CBF in medium 199 alone ({blacksquare}) at any of the concentrations (a, top: 1 x 10-7M; b, middle: 2 x 10-7M; c, bottom: 4 x 10-7M). At the latter concentration, salmeterol ({circ}) significantly (p < 0.05) reduced ciliary slowing and ciliary dyskinesia (#) produced by pyocyanin (20 µg/mL) (•) and was also able to delay the appearance of epithelial disruption (*) by 1 h. Reprinted with permission from Kanthakumar et al.77

 
Effect of LABAs on the Production and Clearance of Pulmonary Secretions
Production and Clearance of Mucus:
During exacerbations of COPD, the airways can be obstructed by mucus as a result of altered production as well as by defective mucociliary clearance.78 Bronchial mucous glands are enlarged, gland ducts are dilated, and goblet cells are more numerous. Membranous bronchioles, < 2 mm in diameter, are important sites of airflow obstruction and show varying degrees of plugging with mucus and goblet cell metaplasia.7 In addition, alterations in mucus rheology can occur, which renders the mucus difficult to transport. This combination of increased mucus production and altered rheology causes mucus plugging, reduction in airway cross-sectional area and impairment of mucociliary clearance.

A study in healthy subjects showed that salmeterol increased mucociliary transport by 37.6% and 60.5% compared with control subjects (p = 0.001) and placebo (p = 0.02), respectively.79 Another study in healthy subjects showed that 50 µg of salmeterol improved nasal mucociliary clearance by 21% compared with placebo (p < 0.001).80 A clinical study in asthmatic patients indicated a modest enhancement of mucociliary function.81 Formoterol also significantly increased mucociliary clearance by 46% compared with placebo in 10 bronchitic patients after 6 days.82

The efficiency of mucociliary clearance is also affected by the amount and physical properties of airway secretions. Submucosal glands and goblet cells contribute to airway secretions from both serous and mucous cells. Both {alpha}-adrenergic and ß-adrenergic receptors are present on submucosal gland mucous cells. However, available studies do not report consistent effects of ß2-adrenergic agonists on mucus viscosity and glycoprotein secretion. Some studies show increased viscosity and secretions83 84 85 and some no effect.86 87 There is a growing body of literature that supports the role of ß2-adrenergic agonists in increasing mucus hydration, thereby possibly reducing viscosity and thus aiding effective mucociliary transport.88 However, mucus hydration will only be increased if the effect of LABAs on water movement is greater than on glycoprotein release.

Surfactant and Clearance of Alveolar Fluid:
Alteration in the amount and composition of surfactant in patients with COPD may be one of the mechanisms leading to decreased airflow. Prevention of airway wall collapse by surfactant is important in maintaining airway stability.89 90 In addition to its surface activity, airway surfactant improves bronchial clearance and regulates airway liquid balance.91 92 Surfactant may also modulate the function of respiratory inflammatory cells. Its immunomodulatory activities include suppression of cytokine secretion and lymphocyte proliferation,93 and opsonization of both viruses and Gram-negative bacteria to facilitate phagocytosis.94 95

A potential role of surfactant in COPD pathogenesis is not yet clearly demonstrated. An alteration in mucociliary clearance and an impairment of antimicrobial defense might be important surfactant related factors in COPD. Cigarette smoke, an important risk factor for COPD, is known to adversely effect surfactant. In 1992, Lusuardi and colleagues96 showed there was a marked decrease (about sixfold to sevenfold) in the total phospholipid content of pulmonary surfactant in BAL fluid in 20 nonasthmatic smokers with COPD compared with five nonsmoker healthy control subjects. Phospholipid components such as phosphatidyl choline (PC) suppress lymphocyte and macrophage immune functions. In 1997, Anzueto and colleagues97 showed that aerosolized surfactant improved pulmonary function and resulted in a dose-related improvement in mucociliary transport in patients with stable chronic bronchitis. Ambroxol, used as a mucolytic, is able to stimulate surfactant release, but preliminary data show that in COPD patients who smoke, drug dosages higher than those usually employed to affect bronchial mucus are necessary to obtain a significant increase of surfactant phospholipids.

ß2-Adrenergic agents enhance secretion of surfactant/PC by type II epithelial cells. Salmeterol stimulated PC secretion (17 to 62%; effective concentration causing a 50% increase in PC, 25 nmol/L) with a duration of action > 6 h, which exceeds that of other ß2-adrenergic agonists tested to date.98 The benefit of enhanced PC secretion in COPD is very difficult to examine directly, as changes in lung mechanics may be related to a large number of factors other than the activity of pulmonary surfactant. More investigations evaluating the potential benefits of modulating surfactant secretion are needed.

Clearance (reabsorption) of alveolar fluid may help to resolve airway obstruction in COPD. ß2-Adrenergic agonists increase clearance by stimulating intracellular cAMP, which in turn increases apical sodium uptake and sodium/potassium-adenosine triphosphatase activity. Terbutaline stimulated clearance of alveolar fluid through amiloride-sensitive and amiloride-insensitive pathways.99 Salmeterol increased alveolar fluid clearance by 90 to 120% of basal values in human lung explants instilled with iso-osmolar albumin solution.100 Augmented fluid clearance with long-acting ß2-adrenergic agonists, like salmeterol, could in theory contribute to resolution of exacerbations of COPD, by improving edema clearance. However, when administered via inhalation, they may not penetrate as far as the alveoli.


   Clinical Efficacy of LABAs in Patients With COPD
TOP
 Abstract
 Introduction: COPD Definition...
 Long-Acting ß2...
 Mechanisms of Airflow Limitation...
 Clinical Efficacy of LABAs...
Conclusion
 References
 
The aim of COPD treatment is to increase lung function, prevent disease progression, decrease symptoms and exacerbations, and improve quality of life.27 101 The role of currently available therapies in COPD continues to be clarified. ß2-Adrenergic agonists are recommended in treatment guidelines, as they improve lung function, reduce symptoms, and protect against exercise-induced dyspnea. The recently drafted Global Initiative for Chronic Obstructive Lung Disease guidelines recognize that bronchodilator therapy is central to the symptomatic management of COPD, and should be given on an as-needed basis or on a regular basis to prevent or reduce symptoms.102 Salmeterol and formoterol are potent ß2-agonists, characterized by a long duration of action when inhaled.103 Both have been shown to relieve symptoms for 12 h in adult asthmatic subjects.104 The clinical efficacy of these two bronchodilators in COPD has now also been established

Salmeterol vs Placebo
The efficacy and safety of 50 µg and 100 µg bid of salmeterol compared with placebo was studied in 674 COPD patients over 16 weeks.17 FEV1 improved significantly in the salmeterol group compared with placebo (p < 0.001), and significant reversibility to salmeterol compared with placebo was present in patients classified as not reversible to albuterol at baseline. Treatment with salmeterol significantly improved daytime and nighttime symptom scores and improved breathlessness after a 6-min walk. These clinical improvements were associated with a clinically significant improvement in health status (quality of life) with 50 µg of salmeterol, which correlated with patient and physician assessments of treatment efficacy105 (Fig 5 ). Salmeterol also reduced dyspnea and hyperinflation and increased airflow over 4 h in patients with symptomatic COPD,106 as well as improving respiratory symptoms and morning peak expiratory flow (PEF) in smokers with COPD.107



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  		Figure 5. Reduction in St. George’s Respiratory Questionnaire (SGRQ) total score over 6 weeks with salmeterol treatment. Adapted from and reprinted with permission from Jones and Bosh.105

 
LABAs vs Ipratropium Bromide
Several studies16 108 109 have compared salmeterol with ipratropium bromide in terms of safety and efficacy in a group of COPD patients. Salmeterol showed a greater improvement in FEV1, and an extended time to first exacerbation compared with patients receiving ipratropium bromide or placebo.16 108 In those patients who showed reversibility to albuterol, treatment with salmeterol resulted in a clinically and statistically significant improvement in FEV1. However, in those patients without reversibility, treatment with salmeterol resulted in a statistically but not clinically significant improvement in FEV1.16 When the two patient populations were combined, the improvement in FEV1 afforded by salmeterol was both clinically and statistically significant.16 Patients treated with ipratropium bromide experienced a trough in FEV1 after 6 h due to its shorter duration of action, whereas patients receiving salmeterol had a sustained improvement in FEV1 over 12 h (Fig 6 ). Salmeterol also improved morning PEF, evening PEF, and nighttime shortness of breath (p = 0.04) compared with ipratropium bromide.109 These beneficial effects were apparent in those patients who were responsive as well as those unresponsive to albuterol at baseline.108 Patients with partially reversible COPD, pretreated with salmeterol, were still able to respond normally to albuterol for further bronchodilation when required for rescue therapy.110



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  		Figure 6. FEV1 change from baseline over 12 h with salmeterol, ipratropium, and placebo. The mean change from baseline in FEV1 in the salmeterol group was significant (p < 0.001) for each serial assessment at all visits. Significant differences in serial FEV1 between salmeterol and ipratropium treatment groups are indicated by asterisk. Reprinted with permission from Mahler et al.16

 
A number of studies have compared formoterol with ipratropium bromide in COPD patients in terms of quality of life, as well as clinical efficacy and safety. In 2000, Dahl et al111 compared the efficacy and safety of 12 weeks of treatment with two doses of inhaled formoterol, 12 µg and 24 µg bid, with the recommended dose of ipratropium bromide, 40 µg qid, in 780 patients with COPD. In terms of improving FEV1, both doses of formoterol were significantly superior to ipratropium bromide.111 In addition, the onset of action of formoterol (< 5 min), was faster than that of ipratropium bromide, and the duration of action of formoterol lasted for at least 12 h.111 Formoterol also significantly improved COPD patient quality of life112 and reduced the number of "bad days" (defined as > 20% reduction in PEF and/or at least double a symptom score) experienced by COPD patients compared with those patients treated with ipratropium bromide.112

LABAs vs Theophylline
Comparisons between LABAs and theophylline in COPD patients are scarce. In the long-term treatment of patients with COPD, salmeterol was shown to be more effective than theophylline.113 114 Salmeterol, 50 µg bid, was statistically more effective than oral theophylline (dose titrated) in increasing the maximum value of morning PEF,113 114 and increasing the percentage of days and nights without symptoms.113 Salmeterol was also significantly superior to theophylline in reducing the need for additional albuterol during the day and night, and increasing patient quality of life.113 114 However, it should be noted that both asthmatic and COPD patients were enrolled in the study by Taccola et al.113 Although no studies are currently published that compared formoterol with theophylline in the treatment of patients with COPD, it may be assumed that as a LABA, formoterol would have a similar activity to salmeterol.

Combination of LABAs With Ipratropium Bromide or Theophylline
Van Noord and colleagues115 examined the effect of the combination of salmeterol, 50 µg bid, and ipratropium bromide, 40 µg qid, in patients with COPD. They showed that ipratropium bromide and salmeterol significantly improved FEV1 to a greater extent than salmeterol alone.115 However, patients did not experience any additional benefit in symptom control when salmeterol and ipratropium bromide were administered together.115 The combination of formoterol and ipratropium bromide has also been shown to be superior to formoterol alone in improving mean peak FEV1 in a group of 27 patients with COPD.116 Beneficial effects are also observed when ipratropium bromide is combined with the SABA albuterol.117

The beneficial effects of the combination of salmeterol, 42 µg bid, and theophylline (titrated to 10 to 20 µg/mL) over 12 weeks of treatment has recently been shown in two large multicenter studies with a total of 938 COPD patients.118 By week four, the combination of salmeterol and theophylline was significantly superior in improving FEV1 than either salmeterol or theophylline alone, and this benefit was maintained over the 12 weeks.118 In addition, significantly fewer patients in the combination group had exacerbations, and the transition dyspnea index was also significantly improved. At each 4-week period, albuterol use was significantly decreased in both the combination and salmeterol-alone groups.118 Although no studies examining the combination of formoterol and theophylline have been published, it is likely that formoterol would have similar activity to salmeterol.

Salmeterol vs Formoterol
Salmeterol and formoterol, administered at the recommended doses for regular inhaled therapy (ie, 50 µg and 24 µg, respectively) by metered-dose inhaler were effective in improving airflow obstruction in patients with COPD.29 Times to onset to improve FEV1 by 15% were similar in both treatment groups. In a later dose-ranging study, Cazzola and colleagues28 showed that both salmeterol (25 µg, 50 µg, and 75 µg) and formoterol (12 µg, 24 µg, and 36 µg) induced an increase in FVC and FEV1 over 12 h in patients with partially reversible, but severe COPD. Formoterol induced a dose-related increase in these parameters and exhibited a faster onset of action than salmeterol. In addition, pretreatment with either salmeterol or formoterol did not affect bronchodilator responses to albuterol in patients with partially reversible COPD.119 In 1999, Maesen and coworkers18 also demonstrated that inhaled formoterol caused long-lasting, dose-dependent, lung function improvement (ie, FEV1, work of breathing, and airway resistance) in COPD patients poorly reversible to terbutaline at baseline.

Side effects associated with the use of LABAs include elevated heart rate, decreased serum potassium concentrations and diastolic BP, as well as musculoskeletal tremor.120 These side effects are pharmacologically predictable and dose-dependent.


   Conclusion
TOP
 Abstract
 Introduction: COPD Definition...
 Long-Acting ß2...
 Mechanisms of Airflow Limitation...
 Clinical Efficacy of LABAs...
 Conclusion
References
 
LABAs, like salmeterol and formoterol, provide significant clinical improvements in COPD despite the limited reversibility of impaired lung function in the disease. There are clinically significant increases in lung function and decreased symptoms in COPD patients, associated with a clinically significant improvement in health status. These benefits may be seen in patients who do not meet the defined criteria of "reversible" when treated acutely with SABAs. The efficacy of LABAs in COPD may be explained by more than bronchodilator effects. The additional effects on neutrophils, pulmonary epithelium, airway smooth muscle, and respiratory muscles may contribute to the overall clinical efficacy in COPD and the associated clinically relevant improvement in quality of life. Treatment with LABAs may also reduce the numbers of exacerbations and particularly decrease severity, and thus it is possibly that they may impact on the overall cost of health care for COPD.


   Acknowledgements
 
We thank Kate Komer for her invaluable input, and Michael Spiro for carrying out an extensive literature search and compiling the data. We also thank Dr. Ruth Murray for writing and editorial assistance.


   Footnotes
 
Abbreviations: cAMP = cyclic adenosine monophosphate; CBF = ciliary beat frequency; fMLP = N-formyl-methionyl-leucyl-phenylalanine; IL = interleukin; LABA = long-acting ß2-agonist; SABA = short-acting ß2-agonist; Mac-1 = CD11b/CD18; PC = phosphatidyl choline; PEF = peak expiratory flow

Dr. Johnson is Director of Respiratory Science for GlaxoSmithKline Research and Development, which markets a long-acting ß2-agonist used in the treatment of bronchial asthma and COPD. Dr. Rennard is a Professor in the Pulmonary and Critical Care Medicine Section of the Department of Internal Medicine at the University of Nebraska Medical Center; he currently has a number of relationships with companies that provide products and/or services relevant to outpatient management of COPD. These relationships include medical education programs and performing funded research both at basic and clinical levels. He does not own stock in any pharmaceutical company.

Received for publication June 1, 2000. Accepted for publication December 15, 2000.


   References
TOP
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 Introduction: COPD Definition...
 Long-Acting ß2...
 Mechanisms of Airflow Limitation...
 Clinical Efficacy of LABAs...
 Conclusion
 References
 

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