review

Alternative Mechanisms for Long-Acting

2-Adrenergic Agonists in COPD*
Malcolm Johnson, PhD; and Stephen Rennard, MD, FCCP

2-Adrenergic agonists are commonly used as bronchodilators to treat patients with COPD. In
addition to prolonged bronchodilation, long-acting 2-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.
(CHEST 2001; 120:258 270)
Key words: COPD; formoterol; long-acting 2-adrenergic agonists; salmeterol
Abbreviations: cAMP cyclic adenosine monophosphate; CBF ciliary beat frequency; fMLP N-formyl-methionylleucyl-phenylalanine; IL interleukin; LABA long-acting 2-agonist; SABA short-acting 2-agonist; Mac-1
CD11b/CD18; PC phosphatidyl choline; PEF peak expiratory flow

Introduction: COPD Definition and

Etiology
OPD is defined as a syndrome characterized by
C 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 progres*From GlaxoSmithKline Research and Development (Dr. Johnson), Uxbridge, Middlesex, UK; and University of Nebraska
Medical Center (Dr. Rennard), Omaha, NB.
Dr. Johnson is Director of Respiratory Science for GlaxoSmithKline Research and Development, which markets a long-acting
2-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.
Manuscript received June 1, 2000; revision accepted December
15, 2000.
Correspondence to: Malcolm Johnson, PhD, GlaxoSmithKline
Research and Development, Stockley Park West, Uxbridge,
Middlesex UB11 1BT, United Kingdom; e-mail: mj0859@
glaxowellcome.co.uk
258

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

sively 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
Reviews

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

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.
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 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 2-Agonists in COPD:

Salmeterol and Formoterol
2-Adrenergic agonists are bronchodilators that
improve lung function, reduce symptoms, and protect against exercise-induced dyspnea in patients
with COPD.16 18 These agents induce bronchodilation by causing prolonged relaxation of airway
smooth muscle. Smooth-muscle relaxation is due to
2-adrenoceptormediated 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 2-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 2-adrenergic agonists, such as salbuCHEST / 120 / 1 / JULY, 2001

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

259

tamol, 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 2agonist (LABA) by virtue of prolonged specific binding to the 2-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 2-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 2-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 Charnie`re (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 2-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.

(12 g or 24 g).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 g,

Mechanisms of Airflow Limitation in

COPD: Effect of Salmeterol and
Formoterol
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 g
and 24 g, respectively), are effective in improving
airflow limitation in patients with COPD.28,29 In
1995, Cazzola and colleagues28 showed that salmeterol (50 g) induced a dose-independent bronchodilator response, which lasted longer than formoterol
260

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

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
Reviews

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.
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 2-adrenergic agonists is smoothmuscle, they also exert effects on other cells in the
airway with 2-adrenergic receptors which have been
implicated in the pathophysiology of COPD. For example, 2-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 2integrins (CD11a/CD18 and CD11b/CD18 [Mac-1])
and intercellular adhesion molecule-1.45 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 Nformyl-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, 2-adrenergic agonists also affect neutrophil accumulation.5355 In a clinical
study54 of patients with mild asthma, salmeterol (50
g 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 g 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
CHEST / 120 / 1 / JULY, 2001

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

261

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 M, inhibited tumor necrosis
factor-induced IL-8 release from human airway
smooth-muscle cells in vitro, and at 50 g bid for 3
months reduced BAL IL-8 concentrations in asthmatic patients receiving low-dose inhaled corticosteroids.55 Salmeterol, 0.1 to 10 M, 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 M,
caused concentration-related inhibition of fMLPinduced 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 2-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
262

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

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
Reviews

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 4,000; scale, 1 cm 2.5m). Bottom: scanning electron
micrograph of human nasal turbinate preincubated with salmeterol (4 107 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 4,000; scale, 1 cm 2.5 m). Reprinted with permission
from Dowling et al.65

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 2-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
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
2-adrenergic receptors by LABAs may increase
CHEST / 120 / 1 / JULY, 2001

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

263

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-foldlower 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.
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 pro-

Figure 4. Effect of salmeterol on pyocyanin-induced ciliary beat

slowing. Salmeterol was present throughout the experiment.
Salmeterol alone () had no effect on baseline CBF compared to
control CBF in medium 199 alone (f) at any of the concentrations (a, top: 1 107M; b, middle: 2 107M; c, bottom: 4
107M). At the latter concentration, salmeterol () significantly
(p 0.05) reduced ciliary slowing and ciliary dyskinesia (#)
produced by pyocyanin (20 g/mL) (F) and was also able to delay
the appearance of epithelial disruption (*) by 1 h. Reprinted with
permission from Kanthakumar et al.77
264

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

duction 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 g 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 -adrenergic and -adrenergic receptors are present on submucosal gland
mucous cells. However, available studies do not
report consistent effects of 2-adrenergic agonists on
mucus viscosity and glycoprotein secretion. Some
studies show increased viscosity and secretions83 85
and some no effect.86,87 There is a growing body
of literature that supports the role of 2-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
Reviews

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.
2-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 2-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. 2Adrenergic 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 2-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.

cently 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 2-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 g and 100 g 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 g 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
LABAs vs Ipratropium Bromide
Several studies16,108,109 have compared salmeterol
with ipratropium bromide in terms of safety and

Clinical Efficacy of LABAs in Patients

With COPD
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. 2-Adrenergic agonists are recommended in treatment guidelines, as
they improve lung function, reduce symptoms, and
protect against exercise-induced dyspnea. The re-

Figure 5. Reduction in St. Georges Respiratory Questionnaire

(SGRQ) total score over 6 weeks with salmeterol treatment.
Adapted from and reprinted with permission from Jones and
Bosh.105
CHEST / 120 / 1 / JULY, 2001

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

265

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
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 g and 24 g bid, with the
recommended dose of ipratropium bromide, 40 g
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 g 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

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
266

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

Van Noord and colleagues115 examined the effect

of the combination of salmeterol, 50 g bid, and
ipratropium bromide, 40 g 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 broReviews

mide 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 g bid, and theophylline (titrated to 10
to 20 g/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 g and 24 g, 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 g,
50 g, and 75 g) and formoterol (12 g, 24 g, and
36 g) 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
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.
ACKNOWLEDGMENT: 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.

References
1 Standards for the diagnosis and care of patients with chronic
obstructive pulmonary disease (COPD) and asthma. Am Rev
Respir Dis 1987; 136:225244
2 Chronic bronchitis, asthma and pulmonary emphysema: a
statement by the committee on diagnostic standards for
non-tuberculous respiratory disease. Am Rev Respir Dis
1962; 85:762768
3 Murray CJ, Lopez AD. Alternative projections of mortality
and disability by cause 1990 2020: global burden of disease
study. Lancet 1997; 349:1498 1504
4 Nagai A, West WW, Thurlbeck WM. The National Institutes
of Health Intermittent Positive-Pressure Breathing Trial:
pathology studies; ii. correlation between morphologic findings, clinical findings, and evidence of expiratory air-flow
obstruction. Am Rev Respir Dis 1985; 132:946 953
5 Hale KA, Ewing SL, Gosnell BA, et al. Lung disease in
long-term cigarette smokers with and without chronic air-flow
obstruction. Am Rev Respir Dis 1984; 130:716 721
6 Thurlbeck WM. Pathophysiology of chronic obstructive pulmonary disease. Clin Chest Med 1990; 11:389 403
7 Snider GL. Chronic obstructive pulmonary disease: a definition and implications of structural determinants of airflow
obstruction for epidemiology. Am Rev Respir Dis 1989;
140:S3S8
8 Speizer FE, Tager IB. Epidemiology of chronic mucus
hypersecretion and obstructive airways disease. Epidemiol
Rev 1979; 1:124 142
9 Leeder SR. Role of infection in the cause and course of chronic
bronchitis and emphysema. J Infect Dis 1975; 131:731742
10 Thom TJ. International comparisons in COPD mortality. Am
Rev Respir Dis 1989; 140:S27S34
11 Manfreda J, Mao Y, Litven W. Morbidity and mortality from
chronic obstructive pulmonary disease. Am Rev Respir Dis
1989; 140:S19 S26
CHEST / 120 / 1 / JULY, 2001

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

267

12 Feinleib M, Rosenberg HM, Collins JG, et al. Trends in

COPD morbidity and mortality in the United States. Am Rev
Respir Dis 1989; 140:S9 S18
13 Lebowitz MD. The trends in airway obstructive disease
morbidity in the Tucson epidemiologic study. Am Rev Respir
Dis 1989; 140:S35S41
14 Poller W, Faber JP, Scholz S, et al. Mis-sense mutation of
1-antichymotrypsin gene associated with chronic lung disease. Lancet 1992; 339:1538 1543
15 Poller W, Faber JP, Weidinger S, et al. A leucine-to-proline
substitution causes a defective 1-antichymotrypsin allele
associated with familial obstructive lung disease. Genomics
1993; 17:740 743
16 Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of
salmeterol xinafoate in the treatment of COPD. Chest 1999;
115:957965
17 Boyd G, Morice AH, Pounsford JC, et al. An evaluation of
salmeterol in the treatment of chronic obstructive pulmonary
disease (COPD). Eur Respir J 1997; 10:815 821
18 Maesen BLP, Westermann CJJ, Duurkens VAM, et al. Effects
of formoterol in apparently poorly reversible chronic obstructive
pulmonary disease. Eur Respir J 1999; 13:11031108
19 Lulich KM, Goldie RG, Paterson JW. -Adrenoceptor function in asthmatic bronchial smooth muscle. Gen Pharmacol
1988; 19:307311
20 Ullman A, Svedmyr N. Salmeterol, a new long acting inhaled
2-adrenoceptor agonist: comparison with albuterol in adult
asthmatic patients. Thorax 1988; 43:674 678
21 Hekking P, Maesen F, Greefhorst A, et al. Efficacy and
tolerability of inhaled formoterol compared with inhaled
albuterol over three months. In: Barnes P, Matthys H, eds.
Formoterol, a new generation 2-agonist. Toronto, Canada:
Hogrefe & Huber, 1990; 40 44
22 Rhodes DG, Newton R, Butler R, et al. Equilibrium and
kinetic studies of the interactions of salmeterol with membrane bilayers. Mol Pharmacol 1992; 42:596 602
23 Green SA, Spasoff AP, Coleman RA, et al. Sustained activation of a G protein-coupled receptor via anchored agonist
binding: molecular localization of the salmeterol exosite
within the 2-adrenergic receptor. J Biol Chem 1996; 271:
24029 24035
24 Johnson M. Salmeterol: a novel drug for the treatment of
asthma. Agents Actions Suppl 1991; 34:79 95
25 Anderson GP, Linden A, Rabe KF. Why are long-acting
2-adrenoceptor agonists long-acting? Eur Respir J 1994;
7:569 578
26 Waldeck B. Some pharmacodynamic aspects on long-acting
-adrenoceptor agonists. Gen Pharmacol 1996; 27:575580
27 Cochrane GM. Slow release theophyllines and chronic bronchitis. BMJ (Clin Res Ed) 1984; 289:16431644
28 Cazzola M, Matera MG, Santangelo G, et al. Salmeterol and
formoterol in partially reversible severe chronic obstructive
pulmonary disease: a dose-response study. Respir Med 1995;
89:357362
29 Cazzola M, Santangelo G, Piccolo A, et al. Effect of salmeterol and formoterol in patients with chronic obstructive
pulmonary disease. Pulm Pharmacol 1994; 7:103107
30 Celik G, Kayacan O, Beder S, et al. Formoterol and salmeterol in partially reversible chronic obstructive pulmonary
disease: a crossover, placebo-controlled comparison of onset
and duration of action. Respiration 1999; 66:434 439
31 Tomlinson PR, Wilson JW, Stewart AG. Inhibition by albuterol of the proliferation of human airway smooth muscle cells
grown in culture. Br J Pharmacol 1994; 111:641 647
32 Tomlinson PR, Wilson JW, Stewart AG. Salbutamol inhibits
the proliferation of human airway smooth muscle cells grown
in culture: relationship to elevated cAMP levels. Biochem
268

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

Pharmacol 1995; 49:1809 1819

33 Harris T, Koutsoubos V, Guida E, et al. Salmeterol modulates
cell proliferation and cyclin D1 protein levels in thrombinstimulated human cultured airway smooth muscle via an
action independent of the 2-adrenoceptor [abstract]. Am J
Respir Crit Care Med 1999; 159:A530
34 Johnson M. Mechanisms of action of 2-adrenoceptor agonists. In: Busse WW, Holgate ST, eds. Asthma and rhinitis.
Oxford, UK: Blackwell, 2000; 15411557
35 Orsida B, Ward C, Li X, et al. Effect of a long acting
2-agonist over 3 months on airway wall vascular remodelling
in asthma. Am J Respir Crit Care Med 2001 (in press)
36 Polkey MI, Kyroussis D, Hamnegard CH, et al. Diaphragm
strength in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 1996; 154:1310 1317
37 van der Heijden HF, Heunks LM, Folgering H, et al.
2-Adrenoceptor agonists reduce the decline of rat diaphragm twitch force during severe hypoxia. Am J Physiol
1999; 276:L474 L480
38 Easton PA, Skjodt NM, Johnson M, et al. Salmeterol effect on
respiratory muscle in awake canines. Eur Respir J 1998;
28:451S
39 Kusuhara N, Rothwell BC, Easton PA. Effect of -adrenergics on respiratory muscle shortening and EMG activity in
awake canines [abstract]. Am J Respir Cell Mol Biol 1996;
153:A686
40 Easton P, Yokoba M, Hawes H, et al. Salbutamol effects on
parasternal muscle activity and ventilation in humans [abstract]. Am J Respir Crit Care Med 2000; 161:A117
41 Pesci A, Balbi B, Majori M, et al. Inflammatory cells and
mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12:380 386
42 Saetta M, Turato G, Facchini FM, et al. Inflammatory cells in
the bronchial glands of smokers with chronic bronchitis. Am J
Respir Crit Care Med 1997; 156:16331639
43 Hill AT, Bayley D, Stockley RA. The interrelationship of
sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 1999; 160:893 898
44 Szefler SJ, Edwards CK, Haslett C, et al. Effects of cell
isolation procedures and radioligand selection on the characterization of human leukocyte -adrenergic receptors. Biochem Pharmacol 1987; 36:1589 1597
45 Zimmerman GA, McIntyre TM. Neutrophil adherence to
human endothelium in vitro occurs by CD18 glycoproteindependent and -independent mechanisms. J Clin Invest 1988;
81:531537
46 Lo SK, Van Seventer GA, Levin SM, et al. Two leukocyte
receptors (CD11a/CD18 and CD11b/CD18) mediate transient adhesion to endothelium by binding to different ligands.
J Immunol 1989; 143:33253329
47 Tonnesen MG, Anderson DC, Springer TA, et al. Adherence
of neutrophils to cultured human microvascular endothelial
cells: stimulation by chemotactic peptides and lipid mediators
and dependence upon the MAC-1, LFA-1, p150,95 glycoprotein family. J Clin Invest 1989; 83:637 646
48 Derian CK, Santulli RJ, Rao PE, et al. Inhibition of chemotactic peptide-induced neutrophil adhesion to vascular endothelium by cAMP modulators. J Immunol 1995; 154:308 317
49 Ottonello L, Morone P, Dapino P, et al. Inhibitory effect of
salmeterol on the respiratory burst of adherent human neutrophils. Clin Exp Immunol 1996; 106:97102
50 Bloemen PG, van den Tweel MC, Henricks PA, et al.
Increased cAMP levels in stimulated neutrophils inhibit their
adhesion to human bronchial epithelial cells. Am J Physiol
1997; 272:L580 L587
51 Bolton PB, Lefevre P, McDonald DM. Salmeterol reduces
early- and late-phase plasma leakage and leukocyte adhesion in
Reviews

rat airways. Am J Respir Crit Care Med 1997; 155:1428 1435

52 Bowden JJ, Sulakvelidze I, McDonald DM. Inhibition of
neutrophil and eosinophil adhesion to venules of rat trachea
by 2-adrenergic agonist, formoterol. J Appl Physiol 1994;
77:397 405
53 Radermecker MF, Louis R, Corhay JL, et al. Effect of
salmeterol, theophylline and nedocromil sodium on neutrophil chemotaxis in man. Allergy 1992; 47:48
54 Li D, Wang D, Venge P, et al. Comparison of the antiinflammatory effects of inhaled fluticasone propionate and
salmeterol in asthma: a placebo-controlled crossover study of
bronchial biopsies. Eur Respir J 1997; 25:444S
55 Ward C, Li X, Wang N, et al. Salmeterol reduces BAL IL-8
levels in asthmatics on low dose inhaled corticosteroids. Eur
Respir J 1998; 28:380S
56 Faurschou P, Dahl R, Jeffery P, et al. Comparison of the
anti-inflammatory effects of fluticasone and salmeterol in
asthma: a placebo controlled, double blind, cross-over study
with bronchoscopy, bronchial methacholine provocation and
lavage. Eur Respir J 1997; 25:243S
57 Nials AT, Coleman RA, Johnson M, et al. The duration of
action of non-2-adrenoceptor mediated responses to salmeterol. Br J Pharmacol 1997; 120:961967
58 Klettke U, Luck W, Wahn U, et al. Platelet-activating factor
inhibits ciliary beat frequency of human bronchial epithelial
cells. Allergy Asthma Proc 1999; 20:115118
59 Ganbo T, Hisamatsu K, Nakazawa T, et al. Platelet activating
factor (PAF) effects on ciliary activity of human paranasal
sinus mucosa in vitro. Rhinology 1991; 29:231237
60 Anderson R, Feldman C, Theron AJ, et al. Anti-inflammatory,
membrane-stabilizing interactions of salmeterol with human
neutrophils in vitro. Br J Pharmacol 1996; 117:13871394
61 Okada C, Sugiyama H, Eda R, et al. Effect of formoterol on
superoxide anion generation from bronchoalveolar lavage
cells after antigen challenge in guinea pigs. Am J Respir Cell
Mol Biol 1993; 8:509 517
62 Rabe KF, Giembycz MA, Dent G, et al. Salmeterol is a
competitive antagonist at -adrenoceptors mediating inhibition of respiratory burst in guinea-pig eosinophils. Eur J Pharmacol 1993; 231:305308
63 Vaux DL, Haecker G, Strasser A. An evolutionary perspective
on apoptosis. Cell 1994; 76:777779
64 Lee E, Smith J, Robertson T, et al. Salmeterol and inhibitors
of phosphodiesterase 4 (PDE-4) induce apoptosis in neutrophils from asthmatics: -adrenergic receptor-mediated salmeterol activity and additive effects with PDE4 inhibitors
[abstract]. Am J Respir Cell Mol Biol 1999; 159:A329
65 Dowling RB, Rayner CF, Rutman A, et al. Effect of salmeterol on Pseudomonas aeruginosa infection of respiratory
mucosa. Am J Respir Crit Care Med 1997; 155:327336
66 Read RC, Wilson R, Rutman A, et al. Interaction of nontypeable Haemophilus influenzae with human respiratory mucosa
in vitro. J Infect Dis 1991; 163:549 558
67 Munro NC, Barker A, Rutman A, et al. Effect of pyocyanin
and 1-hydroxyphenazine on in vivo tracheal mucus velocity.
J Appl Physiol 1989; 67:316 323
68 Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8
(IL-8) and an inhibitory effect of erythromycin on IL-8
release in the airways of patients with chronic airway diseases.
Infect Immun 1994; 62:4145 4152
69 Matsuse T, Hayashi S, Kuwano K, et al. Latent adenoviral
infection in the pathogenesis of chronic airways obstruction.
Am Rev Respir Dis 1992; 146:177184
70 Murphy TF, Sethi S. Bacterial infection in chronic obstructive
pulmonary disease. Am Rev Respir Dis 1992; 146:10671083
71 Dowling RB, Johnson M, Cole PJ, et al. Effect of salmeterol
on Haemophilus influenzae infection of respiratory mucosa in

vitro. Eur Respir J 1998; 11:86 90

72 Kanthakumar K, Taylor G, Tsang KW, et al. Mechanisms of
action of Pseudomonas aeruginosa pyocyanin on human
ciliary beat in vitro. Infect Immun 1993; 61:2848 2853
73 Dowling RB, Johnson M, Cole PJ, et al. Effect of fluticasone
propionate and salmeterol on Pseudomonas aeruginosa infection of the respiratory mucosa in vitro. Eur Respir J 1999;
14:363369
74 James MH, Johnson M. Effect of salmeterol on respiratory
tract infections. Eur Respir J 1996; 23:264S
75 Rusznak C, Sapsford RJ, Devalia JL, et al. Influence of
albuterol and salmeterol on ciliary beat frequency of cultured
human bronchial epithelial cells. Thorax 1991; 46:782P
76 Devalia JL, Sapsford RJ, Rusznak C, et al. The effects of
salmeterol and albuterol on ciliary beat frequency of cultured
human bronchial epithelial cells, in vitro. Pulm Pharmacol
1992; 5:257263
77 Kanthakumar K, Cundell DR, Johnson M, et al. Effect of
salmeterol on human nasal epithelial cell ciliary beating:
inhibition of the ciliotoxin, pyocyanin. Br J Pharmacol 1994;
112:493 498
78 Vestbo J, Prescott E, Lange P. Association of chronic mucus
hypersecretion with FEV1 decline and chronic obstructive
pulmonary disease morbidity: Copenhagen City Heart Study
Group. Am J Respir Crit Care Med 1996; 153:1530 1535
79 Chambers CB, Corrigan BW, Newhouse MT. Salmeterol (S)
speeds mucociliary transport (MCT) in healthy subjects
[abstract]. Am J Respir Cell Mol Biol 1999; 159:A636
80 Tay HL, Armoogum N, Tan LK. Nasal mucociliary clearance
and salmeterol. Clin Otolaryngol Allied Sci 1997; 22:68 70
81 Hasani A, Toms N, OConnor J, et al. The effect of salmeterol
xinafoate on lung mucociliary clearance in patients with stable
asthma. Eur Respir J 1998; 12(Suppl28):180S
82 Melloni B, Germouty J. The influence of a new agonist:
formoterol on mucociliary function. Rev Mal Respir 1992;
9:503507
83 Pack RJ, Richardson PS, Smith IC, et al. The functional
significance of the sympathetic innervation of mucous glands
in the bronchi of man. J Physiol 1988; 403:211219
84 Phipps RJ, Williams IP, Richardson PS, et al. Sympathomimetic drugs stimulate the output of secretory glycoproteins
from human bronchi in vitro. Clin Sci 1982; 63:2328
85 Leikauf GD, Ueki IF, Nadel JA. Autonomic regulation of
viscoelasticity of cat tracheal gland secretions. J Appl Physiol
1984; 56:426 430
86 Boat TF, Kleinerman JI. Human respiratory tract secretions:
2. Effect of cholinergic and adrenergic agents on in vitro
release of protein and mucous glycoprotein. Chest 1975;
67:32S34S
87 Shelhamer JH, Marom Z, Kaliner M. Immunologic and
neuropharmacologic stimulation of mucous glycoprotein release from human airways in vitro. J Clin Invest 1980;
66:1400 1408
88 Wanner A, Salathe M, ORiordan TG. Mucociliary clearance in
the airways. Am J Respir Crit Care Med 1996; 154:1868 1902
89 Otis DR Jr, Johnson M, Pedley TJ, et al. Role of pulmonary
surfactant in airway closure: a computational study. J Appl
Physiol 1993; 75:13231333
90 Kamm RD, Schroter RC. Is airway closure caused by a liquid
film instability? Respir Physiol 1989; 75:141156
91 Bredenberg CE, Paskanik AM, Nieman GF. High surface
tension pulmonary edema. J Surg Res 1983; 34:515523
92 Schurch S, Gehr P, Im Hof V, et al. Surfactant displaces
particles toward the epithelium in airways and alveoli. Respir
Physiol 1990; 80:1732
93 Borron P, Veldhuizen RA, Lewis JF, et al. Surfactant associated protein-A inhibits human lymphocyte proliferation and
CHEST / 120 / 1 / JULY, 2001

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

269

IL-2 production. Am J Respir Cell Mol Biol 1996; 15:115121

94 Benne CA, Benaissa-Trouw B, Van Strijp JA, et al. Surfactant
protein A, but not surfactant protein D, is an opsonin for
influenza A virus phagocytosis by rat alveolar macrophages.
Eur J Immunol 1997; 27:886 890
95 Pikaar JC, Voorhout WF, van Golde LM, et al. Opsonic
activities of surfactant proteins A and D in phagocytosis of
Gram-negative bacteria by alveolar macrophages. J Infect Dis
1995; 172:481 489
96 Lusuardi M, Capelli A, Carli S, et al. Role of surfactant in
chronic obstructive pulmonary disease: therapeutic implications. Respiration 1992; 59(suppl 1):28 32
97 Anzueto A, Jubran A, Ohar JA, et al. Effects of aerosolized
surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial. JAMA 1997; 278:1426 1431
98 Kumar V, Kresch M. Effects of salmeterol (S) on phosphatidylcholine (PC) secretion by type II cells. Pediatr Res 1996;
39:337A
99 Sakuma T, Okaniwa G, Nakada T, et al. Alveolar fluid
clearance in the resected human lung. Am J Respir Crit Care
Med 1994; 150:305310
100 Sakuma T, Folkesson H, Suzuki S, et al. Salmeterol increases alveolar epithelial fluid clearance in both in vitro and
ex vivo rat lungs, as well as in ex vivo human lungs. Am J
Respir Cell Mol Biol 1996; 153:A195
101 Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary
disease (COPD): The European Respiratory Society Task
Force. Eur Respir J 1995; 8:1398 1420
102 Global Initiative for Chronic Obstructive Lung Disease.
National Institutes of Health Report 2701A, 2001. Available
at: http://www.goldcopd.com. Accessed June 15, 2001
103 Jack D. The Lilly prize lecture: a way of looking at agonism
and antagonism; lessons from albuterol, salmeterol and
other -adrenoceptor agonists. Br J Clin Pharmacol 1991;
31:501514
104 Bartow RA, Brogden RN. Formoterol: an update of its
pharmacologic properties and therapeutic efficacy in the
management of asthma. Drugs 1998; 55:303322
105 Jones PW, Bosh TK. Quality of life changes in COPD
patients treated with salmeterol. Am J Respir Crit Care Med
1997; 155:12831289
106 Ramirez-Venegas A, Ward J, Lentine T, et al. Salmeterol
reduces dyspnea and improves lung function in patients with
COPD. Chest 1997; 112:336 340
107 Ulrik CS. Efficacy of inhaled salmeterol in the management
of smokers with chronic obstructive pulmonary disease: a
single center randomised, double blind, placebo controlled,
crossover study. Thorax 1995; 50:750 754
108 Anderson W, Wisniewski M, Rickard K. Pulmonary function
response to salmeterol and ipratropium in patients revers-

270

Downloaded From: http://journal.publications.chestnet.org/ on 02/08/2014

109

110

111

112

113
114

115

116

117

118
119

120
121

ible and non-reversible to anticholinergics and -agonists.

Eur Respir J 1997; 25:104S
Bailey W, Yancey S, Rickard K, et al. Peak flow and
symptom monitoring in COPD: a 12-week comparison of
placebo, Atrovent and Serevent [abstract]. Am J Respir Crit
Care Med 1997; 155:A34
Cazzola M, Vinciguerra A, Di Perna F, et al. Early reversibility to albuterol does not always predict bronchodilation
after salmeterol in stable chronic obstructive pulmonary
disease. Respir Med 1998; 92:10121016
Dahl R, Greefhorst A, Nowak D, et al. Comparison of the
efficacy and safety of inhaled formoterol and ipratropium
bromide in patients with COPD [abstract]. Am J Respir Crit
Care Med 2000; 161:A805
Greefhorst A, Dahl R, Nowak D, et al. Effect of inhaled
formoterol and ipratropium bromide on quality of life, bad
days and exacerbations in patients with COPD [abstract].
Am J Respir Crit Care Med 2000; 161:A807
Taccola M, Bancalari L, Ghignoni G, et al. Salmeterol versus
slow-release theophylline in patients with reversible obstructive
pulmonary disease. Monaldi Arch Chest Dis 1999; 54:302306
Di Lorenzo G, Morici G, Drago A, et al. Efficacy, tolerability, and effects on quality of life of inhaled salmeterol and
oral theophylline in patients with mild-to-moderate chronic
obstructive pulmonary disease: SLMT02 Italian Study
Group. Clin Ther 1998; 20:1130 1148
Van Noord J, De Munck D, Bantje T, et al. Efficacy and
safety of salmeterol and ipratropium bromide in patients
with chronic obstructive pulmonary disease [abstract]. Am J
Respir Crit Care Med 1998; 157:A799
Sichletidis L, Kottakis J, Marcou S, et al. Bronchodilatory
responses to formoterol, ipratropium, and their combination
in patients with stable COPD. Int J Clin Pract 1999;
53:185188
Friedman M, Witek T Jr, Serby C, et al. Combination
bronchodilator therapy is associated with a reduction in
exacerbations of COPD [abstract]. Am J Respir Crit Care
Med 1996; 153:A126
Knobil K, Emmett A, Reilly D, et al. Combination therapy
with salmeterol and theophylline for COPD [abstract]. Am J
Respir Crit Care Med 2000; 161:A804
Cazzola M, Di Perna F, Noschese P, et al. Effects of
formoterol, salmeterol or oxitropium bromide on airway
responses to albuterol in COPD. Eur Respir J 1998; 11:
13371341
Bennett J, Smyth E, Pavord I, et al. Systemic effects of
albuterol and salmeterol in patients with asthma. Thorax
1994; 49:771774
Rudiger J, Eickelberg O, Tamm M, et al. 2-adrenoceptor
agonists inhibit cell proliferation by activation of P21 gene
expression [abstract]. Am J Respir Crit Care Med 1999;
159:A445

Reviews