Alternative Mechanisms for Long-Acting b2-Adrenergic Agonists in COPD*

8/9/2019 Alternative Mechanisms for Long-Acting b2-Adrenergic Agonists in COPD*

1/13

Alternative Mechanisms for Long-Acting2-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. Inaddition to prolonged bronchodilation, long-acting 2-agonists (LABAs) exert other effects thatmay be of clinical relevance. These include inhibition of airway smooth-muscle cell proliferationand inflammatory mediator release, as well as nonsmooth-muscle effects, such as stimulation ofmucociliary transport, cytoprotection of the respiratory mucosa, and attenuation of neutrophilrecruitment and activation. This review details the possible alternative mechanisms of action ofthe LABAs, salmeterol and formoterol, in COPD. (CHEST 2001; 120:258 270)

Key words: COPD; formoterol; long-acting 2-adrenergic agonists; salmeterol

Abbreviations:cAMP cyclic adenosinemonophosphate; CBF ciliary beatfrequency;fMLP N-formyl-methionyl-leucyl-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

COPD is defined as a syndrome characterized byabnormal test results of expiratory flow, which

do not change markedly over periods of severalmonths of observation.1 It is a general term thatdescribes diseases associated with respiratory ob-struction (eg, chronic bronchitis) and loss of elasticlung recoil (eg, emphysema). COPD is characterizedby breathlessness on physical exertion, and progres-

sively deteriorating lung function, which may lead torespiratory failure, cough, and sputum production.Chronic bronchitis is defined clinically as a persistentcough, with sputum production present on most daysfor 3 months in 2 consecutive years. Emphysema is

defined as a permanent enlargement of any part ofthe gas exchanging structure of the lung, accompa-nied by destruction of respiratory tissue withoutmarked fibrosis.2 While COPD is currently thesixth-leading cause of death, with approximately 3million deaths per year worldwide, it is expected tobe the fifth-leading cause of death in the year 2020.3

At least three mechanisms are involved in thedevelopment of airflow limitation in COPD (Fig 1).Firstly, structural alterations such as goblet cellmetaplasia, inflammation, smooth-muscle hypertro-phy, and particularly fibrosis can narrow the airwaylumen and reduce airflow. Secondly, destruction of

alveolar walls can reduce alveolar attachments anddecrease lung elastic recoil. With loss of elasticrecoil, there is decreased driving pressure, and withattempts at forced exhalation, small airways col-lapse.4,5 Thirdly, airflow limitation in COPD cannotbe explained entirely on a structural basis, and othermechanisms such as chronic bronchitis, peribron-chiolar inflammation, and fibrosis of the small air-

ways may contribute. In emphysema, loss of elastic

*From GlaxoSmithKline Research and Development (Dr. John-son), Uxbridge, Middlesex, UK; and University of NebraskaMedical Center (Dr. Rennard), Omaha, NB.Dr. Johnson is Director of Respiratory Science for GlaxoSmith-Kline Research and Development, which markets a long-acting2-agonist used in the treatment of bronchial asthma and COPD.Dr. Rennard is a Professor in the Pulmonary and Critical CareMedicine Section of the Department of Internal Medicine at the

University of Nebraska Medical Center; he currently has anumber of relationships with companies that provide productsand/or services relevant to outpatient management of COPD.These relationships include medical education programs andperforming funded research both at basic and clinical levels. Hedoes not own stock in any pharmaceutical company.Manuscript received June 1, 2000; revision accepted December15, 2000.Correspondence to: Malcolm Johnson, PhD, GlaxoSmithKlineResearch and Development, Stockley Park West, Uxbridge,Middlesex UB11 1BT, United Kingdom; e-mail: mj0859@

glaxowellco me.co.uk

review

258 Reviews

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


2/13

lung recoil due to alveolar wall destruction plays themajor role.6 Many patients with COPD have bothlesions. All patients with COPD also have somedegree of airflow limitation, some of which may bedue to smooth-muscle contraction.

The most significant cause of COPD is cigarettesmoking,7 although there are other environmentaland occupational etiologic factors (15 to 20% ofCOPD patients are lifelong nonsmokers). Smokingcauses an accelerated decline in lung function withage. Between 20% to 30% of smokers who experi-ence a more rapid decline in lung function becomesymptomatic.8 Epidemiologic studies show that chil-

dren of smokers have a higher incidence of respira-tory infections, particularly in the first year of life,which represents a major risk factor for the subse-quent development of COPD.9 Therefore, morbidityand mortality from COPD may reflect the smokingpatterns in various countries.1013 Differences inmorbidity and mortality from COPD may also bepartially explained by national differences in diagno-sis and genetic susceptibility.14,15

Long-Acting 2

-Agonists in COPD:

Salmeterol and Formoterol

2-Adrenergic agonists are bronchodilators thatimprove lung function, reduce symptoms, and pro-tect against exercise-induced dyspnea in patients

with COPD.1618 These agents induce bronchodila-tion by causing prolonged relaxation of airwaysmooth muscle. Smooth-muscle relaxation is due to2-adrenoceptormediated activation of adenylatecyclase in airway smooth muscle, which in turnincreases the concentration of intracellular cyclicadenosine monophosphate (cAMP).19 Albuterol, ashort-acting 2-agonist (SABA), is usually adminis-

tered through a metered-dose inhaler, dry powderdevice, or by nebulization, but is also available fororal administration. It has been used by patients overthe 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 broncho-dilator for use in COPD-related acute bronchospasmand bronchitis. The major drawback with the firstgeneration of2-adrenergic agonists, such as salbu-

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

CHEST / 120 / 1 / JULY, 2001 259



3/13

tamol, is in their short duration of action (4 to 6 h),requiring the drug to be administered several times aday. The need for a long-acting bronchodilator for usein bronchial asthma and COPD has been met with thedevelopment of salmeterol20 and formoterol.21

Salmeterol was designed to be a long-acting 2-agonist (LABA) by virtue of prolonged specific bind-ing to the 2-adrenergic receptor, and repeatedstimulation of the active site, leading to longerefficacy. Salmeterol, due to its lipophilic properties,partitions into the phospholipid membrane and dif-fuses laterally to approach the 2-adrenoceptorthrough the cell membrane.22 The side chain ofsalmeterol then binds to a discrete hydrophobicdomain within the fourth transmembrane region ofthe 2-adrenoceptor called the exosite, (amino acids149158).23 Binding to the exosite prevents themolecule from dissociating from the receptor. Thesaligenin head of salmeterol is then free to engageand disengage with the active site of the receptor bythe Charniere (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 toincrease the affinity of agonists for the 2-adrenergicreceptor. The exact mechanism by which formoterolexerts prolonged effects on lung function is un-known, but may involve interaction with the mem-brane lipid bilayer.25 A hypothesis has been pro-posed whereby formoterol, which is moderatelylipophilic, enters the plasmalemma and is retained asa depot. The drug is also able to reach the receptorfrom the aqueous phase, accounting for its rapidonset of action. Subsequently, it gradually leaches

out from the plasmalemma to activate the receptor,imparting a prolonged concentration-dependent air-

ways smooth-muscle relaxant effect.26 In vivo, bothsalmeterol and formoterol, at equivalent clinicaldoses, induce bronchodilation for at least 12 h.

Mechanisms of Airflow Limitation in

COPD: Effect of Salmeterol and

Formoterol

Smooth-Muscle Effects of LABAs in Patients WithCOPD

Bronchodilation: The aim of bronchodilator ther-

apy in patients with COPD is to treat any airflowobstruction that is reversible.27 Both salmeterol andformoterol, administered at the recommendedtwice-daily doses for regular inhaled therapy (50 gand 24 g, respectively), are effective in improvingairflow limitation in patients with COPD.28,29 In1995, Cazzola and colleagues28 showed that salmet-erol (50 g) induced a dose-independent broncho-dilator response, which lasted longer than formoterol

(12 g or 24 g).28 However, in an earlier study,29

there was no significant difference in the duration ofaction of salmeterol and formoterol. Disparity inthese results may be explained by differences in theseverity of disease. Formoterol has also been shownto induce mean peak bronchodilation (increase inFEV1over baseline values) more rapidly than salme-terol.28 In addition, a 1999 study by Celik et al30

showed that after 10 min, formoterol induced aclinically and statistically significant improvement inFEV1 compared with placebo, whereas salmeterolrequired 20 min to achieve a significant improve-ment. The duration of action of salmeterol andformoterol was 12 h in both cases.30

Airway Smooth-Muscle Proliferation: The clini-cal relevance of airway smooth-muscle proliferationin patients with COPD remains to be determined,but it may apply to mixed disease. The SABA,albuterol, inhibited human airway smooth-musclecell proliferationin vitro induced by mitogens, such

as thrombin,31 an effect that was mediated by anincrease in cAMP.32 LABAs such as salmeterol andformoterol act via the same receptors, and so wouldbe expected to be at least as effective as SABAs, witha longer duration of action. Indeed, salmeterol in-hibited thrombin-induced DNA synthesis in humanairway smooth-muscle cells in culture via an actionon cyclin D1 (Fig 2).33 By inhibiting smooth-muscleproliferation, LABAs may have the capacity to limitthe degree of airway remodeling and resulting ob-struction, providing that effective concentrations areachieved in the lungs of COPD patients followinginhalation of LABAs. In this regard, it is encouraging

that human peripheral lung tissue concentrations ofsalmeterol, following an inhaled dose of 50 g,

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

260 Reviews



4/13

exceed 10 pmol/g,34 a concentration similar to thatshown to have antiproliferative activity in vitro.33

Furthermore, although carried out in asthmatic pa-tients, a recent study35 has shown that salmeterolreduces the degree of ongoing angiogenesis, a rec-ognized component of airway remodeling, a propertynot shared by corticosteroids.

Airway Muscle Function: The pathophysiology ofCOPD may also have a systemic component.36 Sal-meterol affected the force of muscular contraction ofthe diaphragm and intercostal muscles in rats andconscious dogs.37,38 Both albuterol and salmeterolreduced the decline in diaphragm function duringsevere hypoxia in a rat model, with salmeterol dem-onstrating a longer duration of action.37 High sys-temic doses of salmeterol and albuterol increased thedepolarization of left costal and crural diaphragm,parasternal intercostal, and transversus abdominismuscles in the dog.39 The result is an increase inrespiratory muscle shortening and increased ventila-tion. These effects have been confirmed in lowerdoses in man.40 The effect of theophylline on respi-ratory muscle length and shortening have not beenstudied directly in an awake, intact mammal. How-ever, it is an interesting possibility that the LABAeffect and the presumed theophylline effect on thediaphragm, and other respiratory muscles, may beadditive. The benefit of the skeletal muscular effectsof LABAs in COPD could be a preservation ofdiaphragm structure and improvement of respiratorymuscle function, which may be particularly crucial atlater stages of the disease. The clinical relevance ofthese findings are still to be determined with respect

to inhaled LABAs, as they may not reach the targettissues at the relevant concentrations.

Nonsmooth-Muscle Effects of LABAs in PatientsWith COPD

Effect of LABAs on Neutrophils: Inflammation ofthe airways may also intermittently contribute toobstruction. This airway inflammation is caused byan influx of inflammatory cells, and release of medi-ators into the tissue.41 In patients with COPD, thereare increased numbers of monocytes and lymphocytes,particularly CD8 cells. Neutrophils are scarce in the

subepithelial area, but are present in the epitheliumand in the bronchial glands,42 as well as in the airwaylumen. BAL fluid and induced sputum from patients

with COPD contain increased numbers of neutrophils,which correlate with concentrations of the neutrophilchemoattractant, interleukin (IL)-8, although otherchemotaxins (eg, leukotriene B4) are also present.Markers of neutrophil activation, myeloperoxidase andelastase, have also been detected in the sputum of

COPD patients.41,43While the target effector tissue forbronchodilation by2-adrenergic agonists is smooth-muscle, they also exert effects on other cells in theairway with 2-adrenergic receptors which have beenimplicated in the pathophysiology of COPD. For ex-ample, 2-adrenergic receptors are present on neutro-phils,44 and LABAs have been shown to affect neutro-

phil numbers, activity, and function. Reduction inneutrophil number and function could therefore re-duce the severity of disease and degree of airflowobstruction in patients with COPD.

Neutrophil Adhesion: Adhesion of human neu-trophils is mediated by interactions between 2-integrins (CD11a/CD18 and CD11b/CD18 [Mac-1])and intercellular adhesion molecule-1.4547 Neutro-phil-endothelial cell adhesion is attenuated by agentsthat elevate cAMP through inhibition of neutrophilMac-1 cell surface expression.48 Salmeterol in-creased human neutrophil cAMP levels in a concen-

tration-dependent manner.49 In 1997, Bloemen andcoworkers50 showed that salmeterol inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP) stim-ulated human neutrophil adhesion to human airwayepithelial cells via Mac-1 inhibition. Both salmeterol51

and formoterol52 have been shown, in experimentalanimal models, to inhibit the adhesion of neutrophils tothe vascular endothelium, but the relevance of thesefindings to COPD patients is unclear.

Neutrophil Accumulation: In addition to theireffects on adhesion, 2-adrenergic agonists also af-fect neutrophil accumulation.5355 In a clinical

study54 of patients with mild asthma, salmeterol (50g bid for 6 weeks) treatment significantly reducedthe number of neutrophils in bronchial biopsies. Thiseffect was accompanied by significant reductions inserum E-selectin, an adhesion molecule involved inneutrophil recruitment, and in myeloperoxidase andlipocalin levels in BAL, markers of neutrophil acti-

vation.56 The addition of salmeterol, 50 g bid, tolow-dose inhaled corticosteroids also reduced neu-trophils in BAL (p 0.02) from asthmatic patients

with mild-to-moderate disease over 3 months.55 Atpresent, there are no published trials investigatingthe effect of formoterol on neutrophil accumulation

in man, although it is likely to have similar activity tosalmeterol. Whether LABAs will exhibit inhibitoryeffects on neutrophil accumulation in COPD re-mains to be determined.

Neutrophil Mediator Release/Activation: IL-8 maybe important in COPD pathophysiology because it isproduced and released in significant amounts byseveral types of airway cells, including epithelial

CHEST / 120 / 1 / JULY, 2001 261



5/13

cells, smooth-muscle cells, macrophages, and neu-trophils. It is a chemoattractant and an activator forneutrophils, and may result in a persistent inflamma-tory cycle, by establishing a positive feedback loop.Salmeterol, 0.01 to 0.1 M, inhibited tumor necrosisfactor-induced IL-8 release from human airwaysmooth-muscle cellsin vitro, and at 50 g bid for 3

months reduced BAL IL-8 concentrations in asth-matic patients receiving low-dose inhaled corticoste-roids.55 Salmeterol, 0.1 to 10 M, also caused down-regulation of neutrophil oxidative metabolism, andinhibition of respiratory burst (oxygen production) inresponse to fMLP, while albuterol was without effect.49

A later study verified that salmeterol, 1 to 100 M,caused concentration-related inhibition of fMLP-induced oxygen release from human neutrophils.57

Salmeterol also inhibited fMLP-induced oxidant pro-duction from calcium ionophore-activated neutrophils,and interfered with intracellular calcium flux, phospho-lipase A2 activity, and synthesis of platelet activating

factor. This may be relevant because platelet activatingfactor is associated with ciliary dysfunction, cytotoxicity,and impaired mucociliary clearance.58,59

While research on the effect of formoterol onneutrophil mediator release/activation in man is lim-ited,60 Anderson and colleagues60 showed that for-moterol treatment caused moderate inhibition ofactivated human neutrophil oxidant generation by asuperoxide scavenging mechanism, but unlike salme-terol, possessed weak membrane stabilizing proper-ties.60 In guinea pigs, formoterol has been shown toinhibit superoxide anion and hydrogen peroxide gener-ation from eosinophils.61,62 Therefore, LABAs have the

potential to decrease neutrophil activation in patientswith COPD and may be useful in controlling cytotoxicproperties of neutrophil-derived oxidants at sites ofinflammation within the airways. Whether inhalation isthe most appropriate means for delivery of agents forthis purpose is not known.

Neutrophil Apoptosis: Salmeterol and formot-erol, as well as other agents that elevate intracellularcAMP, may also regulate neutrophil apoptosis. Apo-ptosis, or programmed cell death, plays a crucial rolein the maintenance of cell homeostasis.63 Salmeterolinduced apoptosis in human neutrophils, the effects

being mediated by2-adrenergic receptor activation,and blocked by both the nonspecific antagonist, pro-pranolol, and the selective antagonist, ICI-118551.64

This is probably a LABA class effect, so although atpresent there are no published studies investigatingthe effect of formoterol on neutrophil apoptosis, it islikely to have a similar activity to salmeterol. The actionof salmeterol contrasts with glucocorticosteroids, whichblock apoptosis. When neutrophils fail to undergo

apoptosis and die by lysis, release of DNA and othercellular components may contribute adversely to thephysical properties of airway secretions.

Altogether, these data indicate that long-actingagents like salmeterol and formoterol increase cAMPin neutrophils and therefore inhibit adhesion, accu-mulation, activation, and induce apoptosis. The end

result is a possible reduction in the number andactivation status of neutrophils in airway tissue and inthe airway lumen.

Effect of LABAs on the Epithelium: Althoughevidence suggests that, unlike asthma, the epithe-lium is largely intact in COPD, epithelial dysfunctionmay still contribute to the disease. The epitheliumprovides an efficient physical barrier to the airway. Itprovides a first-line defense against irritants and patho-gens and preserves the integrity of the airway byfacilitating mucociliary clearance with associated coor-dinated ciliary beating. In addition, the epithelium

releases a range of cytokines and chemokines that candrive the inflammatory response.

Bacterial infection can damage the respiratoryepithelium directly and indirectly by release of tox-ins, proteases, oxidants, defensins, and other media-tors.65 66 Bacteria can release a number of patho-genic factors, which can damage the epithelium,including endotoxin, proteases, and moieties that canbind and inactivate cilia.67 In addition, bacteria canlead to recruitment of inflammatory cells throughthe direct release of chemotactic mediators,68

through the activation of complement and by acti-vating the release of chemotactic factors from airway

cells. Inflammatory cells, in turn, can release oxi-dants, proteases, and toxic peptides such as de-fensins. While the lung is protected by a variety ofantioxidants and antiproteases, it is likely that thesedefenses can be overcome by a locally intense in-flammatory response, thus setting the stage for tissuedamage. Acute viral infection can also cause damageof the epithelium, and initiate an inflammatoryresponse. Interestingly, some viruses can establishchronic latent infection when portions of the viralgenome persist in lung tissue.69 These conditionsmay also predispose to augmented inflammation.Epithelium, damaged by bacteria or by inflamma-

tion, is more easily colonized. Patients with stableCOPD are frequently colonized by bacteria such asunencapsulatedHaemophilus influenzae,Streptococ-cus pneumoniae, and Moraxella catarrhalis.70

Epithelial Protection: LABAs protect the respira-tory epithelium against the effects of microorgan-isms. Preincubation of human nasal turbinates withsalmeterol reduced Pseudomonas aeruginosa and

262 Reviews



6/13

H influenzae-induced epithelial damage65,71 (Fig 3),probably by maintaining intracellular cAMP concen-trations, which together with adenosine triphos-phate, are known to fall under these conditions.72

Reduction in epithelial damage was marked by adecrease in tight junction separation, epithelial strip-ping, and resultant exposure of collagen fibers andthe basement membrane, and preservation of thenumber of both ciliated and unciliated cells. Thiseffect was associated with a reduction in the totalnumber of bacteria adherent to the respiratory mu-

cosa, consistent with the observation that P aerugi-nosa and H influenzae preferentially adhere todamaged epithelial cell surfaces. In addition, thecytoprotective effects of salmeterol wereblocked by the selective 2-receptor antagonist,ICI 118551. Preincubation of tissue with bothsalmeterol (10 7M) and the corticosteroid flutica-sone propionate (10 7M) significantly inhibitedP aeruginosa-induced loss of ciliated cells in asynergistic manner.73

Furthermore, salmeterol protected the respiratoryepithelium against ultrastructural damage caused bythe P aeruginosa toxins, pyocyanin and elastase, as

evidenced by less cell projection (caused by separa-tion of tight junctions), loss of cilia, cytoplasmicblebbing, and mitochondrial damage with swellingand disruption of cristae.65 The effect of formoterolon epithelial protection has not been reported, but ifused in sufficient concentrations to increase cAMPover time, is likely to have similar activity. It isencouraging that the concentration range of salmet-erol for epithelial protective activity is similar to thatobserved in human peripheral lung tissue in vivo.34

If LABAs decrease bacterial colonization, theymay render patients less prone to acute bacterialexacerbations. A meta-analysis74 revealed that the

incidence of respiratory infections in a 16-week studyin COPD patients was 15% with placebo compared

with 8% with salmeterol (p 0.005).16 This wasconfirmed in a second study of salmeterol inCOPD,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 protec-tion against respiratory infections, perhaps by alter-ing the airway epithelium. Further investigation ofsuch an effect seems warranted.

Ciliary Beat Frequency: Effective mucociliarytransport depends on coordinated ciliary beating so

that particles (including bacteria) and debris arecarried out of the airways. Maintenance of ciliarybeating may attenuate P aeruginosa-induced andH influenzae-induced damage by preventing bacte-rial adherence, and reduce the concentration oftoxins in the microenvironment of the mucosal sur-face, thereby protecting against the development orpersistence of infection. Stimulation of epithelial2-adrenergic receptors by LABAs may increase

Figure 3. Top: scanning electron micrograph of human nasalturbinate tissue infected with P aeruginosa in vitro for 8 h.Bacteria are seen adhering to damaged epithelium and cellulardebris in preference to ciliated and unciliated epithelium. Mu-cosal damage is evidenced as cellular extrusion, and the presenceof dead cells, membrane damage, and cellular debris (origi-nal 4,000; scale, 1 cm 2.5m). Bottom: scanning electronmicrograph of human nasal turbinate preincubated with salmet-erol (4 107 mol/L) for 30 min prior to infection with P aerugi-

nosa in vitrofor 8 h. In comparison with Figure 3,top, there aresignificantly more ciliated cells and significantly less mucosaldamage. The mucosal damage is more patchy, interspersed

between the cilia. Epithelial damage is less extensive, with onlymild tight junction separation and cellular extrusion (origi-nal 4,000; scale, 1 cm 2.5 m). Reprinted with permissionfrom Dowling et al.65

CHEST / 120 / 1 / JULY, 2001 263



7/13

ciliary beat frequency (CBF) and mucociliary trans-port. Albuterol and salmeterol increased CBF inhuman nasal epithelial cells in culture, with salmet-erol increasing CBF at 100-foldlower concentra-tions than albuterol and its effect was sustained for15 to 20 h.75 A similar study with human bronchialepithelium revealed that, while albuterol induced atransient increase in CBF, salmeterol caused a sig-nificant and prolonged increase through 24 h post-exposure.76 At lower concentrations, salmeterol,

while having no effect itself, inhibited P aeruginosapyocyanin-induced reduction in CBF, and also theconcomitant fall in cAMP77 (Fig 4). At present, thereare no published accounts on the effect of formoterolon CBF, but as a LABA, it is likely to have similaractivity to salmeterol.

Effect of LABAs on the Production and Clearanceof Pulmonary Secretions

Production and Clearance of Mucus: During

exacerbations of COPD, the airways can be ob-structed by mucus as a result of altered production aswell as by defective mucociliary clearance.78 Bron-chial mucous glands are enlarged, gland ducts aredilated, and goblet cells are more numerous. Mem-branous bronchioles, 2 mm in diameter, are im-portant sites of airflow obstruction and show varyingdegrees of plugging with mucus and goblet cellmetaplasia.7 In addition, alterations in mucus rheol-ogy can occur, which renders the mucus difficult totransport. This combination of increased mucus pro-

duction and altered rheology causes mucus plugging,reduction in airway cross-sectional area and impair-ment of mucociliary clearance.

A study in healthy subjects showed that salmeterolincreased mucociliary transport by 37.6% and 60.5%compared with control subjects (p 0.001) andplacebo (p 0.02), respectively.79 Another study in

healthy subjects showed that 50 g of salmeterolimproved nasal mucociliary clearance by 21% com-pared with placebo (p 0.001).80 A clinical study inasthmatic patients indicated a modest enhancementof mucociliary function.81 Formoterol also signifi-cantly increased mucociliary clearance by 46% com-pared with placebo in 10 bronchitic patients after 6days.82

The efficiency of mucociliary clearance is alsoaffected by the amount and physical properties ofairway secretions. Submucosal glands and gobletcells contribute to airway secretions from both se-rous and mucous cells. Both -adrenergic and -ad-

renergic receptors are present on submucosal glandmucous cells. However, available studies do notreport consistent effects of2-adrenergic agonists onmucus viscosity and glycoprotein secretion. Somestudies show increased viscosity and secretions8385

and some no effect.86,87 There is a growing bodyof literature that supports the role of 2-adrenergicagonists in increasing mucus hydration, thereby possi-bly reducing viscosity and thus aiding effective muco-ciliary transport.88 However, mucus hydration will onlybe increased if the effect of LABAs on water move-ment is greater than on glycoprotein release.

Surfactant and Clearance of Alveolar Fluid: Al-teration in the amount and composition of surfactantin patients with COPD may be one of the mecha-nisms leading to decreased airflow. Prevention ofairway wall collapse by surfactant is important inmaintaining airway stability.89,90 In addition to itssurface activity, airway surfactant improves bronchialclearance and regulates airway liquid balance.91,92

Surfactant may also modulate the function of respi-ratory inflammatory cells. Its immunomodulatoryactivities include suppression of cytokine secretionand lymphocyte proliferation,93 and opsonization ofboth viruses and Gram-negative bacteria to facilitate

phagocytosis.94,95

A potential role of surfactant in COPD pathogen-esis is not yet clearly demonstrated. An alteration inmucociliary clearance and an impairment of antimi-crobial defense might be important surfactant re-lated factors in COPD. Cigarette smoke, an impor-tant risk factor for COPD, is known to adverselyeffect surfactant. In 1992, Lusuardi and colleagues96

showed there was a marked decrease (about sixfold

Figure4. Effect of salmeterol on pyocyanin-induced ciliary beatslowing. Salmeterol was present throughout the experiment.Salmeterol alone () had no effect on baseline CBF compared tocontrol CBF in medium 199 alone (f) at any of the concentra-tions (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 delaythe appearance of epithelial disruption (*) by 1 h. Reprinted withpermission from Kanthakumar et al.77

264 Reviews



8/13

to sevenfold) in the total phospholipid content ofpulmonary surfactant in BAL fluid in 20 nonasth-matic smokers with COPD compared with five non-smoker healthy control subjects. Phospholipid com-ponents such as phosphatidyl choline (PC) suppresslymphocyte and macrophage immune functions. In1997, Anzueto and colleagues97 showed that aerosol-ized surfactant improved pulmonary function andresulted in a dose-related improvement in mucocili-ary transport in patients with stable chronic bronchi-tis. Ambroxol, used as a mucolytic, is able to stimu-late surfactant release, but preliminary data showthat in COPD patients who smoke, drug dosageshigher than those usually employed to affect bron-chial mucus are necessary to obtain a significantincrease of surfactant phospholipids.2-Adrenergic agents enhance secretion of surfac-

tant/PC by type II epithelial cells. Salmeterol stim-ulated PC secretion (17 to 62%; effective concentra-tion causing a 50% increase in PC, 25 nmol/L) witha duration of action 6 h, which exceeds that of

other 2-adrenergic agonists tested to date.98 Thebenefit of enhanced PC secretion in COPD is verydifficult to examine directly, as changes in lung me-chanics may be related to a large number of factorsother than the activity of pulmonary surfactant. Moreinvestigations evaluating the potential benefits of mod-ulating surfactant secretion are needed.

Clearance (reabsorption) of alveolar fluid mayhelp to resolve airway obstruction in COPD. 2-Adrenergic agonists increase clearance by stimulat-ing intracellular cAMP, which in turn increasesapical sodium uptake and sodium/potassium-adeno-sine triphosphatase activity. Terbutaline stimulated

clearance of alveolar fluid through amiloride-sensi-tive and amiloride-insensitive pathways.99 Salmeterolincreased alveolar fluid clearance by 90 to 120% ofbasal values in human lung explants instilled withiso-osmolar albumin solution.100 Augmented fluidclearance with long-acting 2-adrenergic agonists,like salmeterol, could in theory contribute to resolu-tion of exacerbations of COPD, by improving edemaclearance. However, when administered via inhala-tion, they may not penetrate as far as the alveoli.

Clinical Efficacy of LABAs in Patients

With COPD

The aim of COPD treatment is to increase lungfunction, prevent disease progression, decreasesymptoms and exacerbations, and improve quality oflife.27,101 The role of currently available therapies inCOPD continues to be clarified. 2-Adrenergic ago-nists are recommended in treatment guidelines, asthey improve lung function, reduce symptoms, andprotect against exercise-induced dyspnea. The re-

cently drafted Global Initiative for Chronic Obstruc-tive Lung Disease guidelines recognize that bron-chodilator therapy is central to the symptomaticmanagement of COPD, and should be given on anas-needed basis or on a regular basis to prevent orreduce symptoms.102 Salmeterol and formoterol arepotent 2-agonists, characterized by a long durationof action when inhaled.103 Both have been shown torelieve symptoms for 12 h in adult asthmatic sub-

jects.104 The clinical efficacy of these two broncho-dilators in COPD has now also been established

Salmeterol vs Placebo

The efficacy and safety of 50 g and 100 g bid ofsalmeterol compared with placebo was studied in674 COPD patients over 16 weeks.17 FEV1 im-proved significantly in the salmeterol group com-pared with placebo (p 0.001), and significant re-

versibility to salmeterol compared with placebo waspresent in patients classified as not reversible to

albuterol at baseline. Treatment with salmeterolsignificantly improved daytime and nighttime symp-tom scores and improved breathlessness after a6-min walk. These clinical improvements were asso-ciated with a clinically significant improvement inhealth status (quality of life) with 50 g of salmet-erol, which correlated with patient and physicianassessments of treatment efficacy105 (Fig 5). Salme-terol also reduced dyspnea and hyperinflation andincreased airflow over 4 h in patients with symptom-atic COPD,106 as well as improving respiratory symp-toms and morning peak expiratory flow (PEF) insmokers with COPD.107

LABAs vs Ipratropium Bromide

Several studies16,108,109 have compared salmeterolwith ipratropium bromide in terms of safety and

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 andBosh.105

CHEST / 120 / 1 / JULY, 2001 265



9/13

efficacy in a group of COPD patients. Salmeterolshowed a greater improvement in FEV1, and anextended time to first exacerbation compared withpatients receiving ipratropium bromide or place-bo.16,108 In those patients who showed reversibility toalbuterol, treatment with salmeterol resulted in aclinically and statistically significant improvement inFEV1. However, in those patients without reversibil-ity, treatment with salmeterol resulted in a statisti-cally but not clinically significant improvement inFEV1.16 When the two patient populations werecombined, the improvement in FEV1 afforded bysalmeterol was both clinically and statistically signif-icant.16 Patients treated with ipratropium bromideexperienced a trough in FEV1 after 6 h due to itsshorter duration of action, whereas patients receivingsalmeterol had a sustained improvement in FEV1over 12 h (Fig 6). Salmeterol also improved morningPEF, evening PEF, and nighttime shortness ofbreath (p 0.04) compared with ipratropium bro-mide.109 These beneficial effects were apparent in

those patients who were responsive as well as those

unresponsive to albuterol at baseline.108 Patientswith partially reversible COPD, pretreated withsalmeterol, were still able to respond normally toalbuterol for further bronchodilation when requiredfor rescue therapy.110

A number of studies have compared formoterolwith ipratropium bromide in COPD patients interms of quality of life, as well as clinical efficacy andsafety. In 2000, Dahl et al111 compared the efficacyand safety of 12 weeks of treatment with two doses ofinhaled formoterol, 12 g and 24 g bid, with therecommended dose of ipratropium bromide, 40 gqid, in 780 patients with COPD. In terms of improv-ing FEV1, both doses of formoterol were signifi-cantly superior to ipratropium bromide.111 In addi-tion, the onset of action of formoterol ( 5 min), wasfaster than that of ipratropium bromide, and theduration of action of formoterol lasted for at least12 h.111 Formoterol also significantly improvedCOPD patient quality of life112 and reduced thenumber of bad days (defined as 20% reduction

in PEF and/or at least double a symptom score)experienced by COPD patients compared with thosepatients treated with ipratropium bromide.112

LABAs vs Theophylline

Comparisons between LABAs and theophylline inCOPD patients are scarce. In the long-term treat-ment of patients with COPD, salmeterol was shownto be more effective than theophylline.113,114 Salme-terol, 50 g bid, was statistically more effective thanoral theophylline (dose titrated) in increasing themaximum value of morning PEF,113,114 and increas-

ing the percentage of days and nights without symp-toms.113 Salmeterol was also significantly superior totheophylline in reducing the need for additional albu-terol during the day and night, and increasing patientquality of life.113,114 However, it should be noted thatboth asthmatic and COPD patients were enrolled inthe study by Taccola et al.113 Although no studies arecurrently published that compared formoterol withtheophylline in the treatment of patients with COPD, itmay be assumed that as a LABA, formoterol wouldhave a similar activity to salmeterol.

Combination of LABAs With Ipratropium Bromideor Theophylline

Van Noord and colleagues115 examined the effectof the combination of salmeterol, 50 g bid, andipratropium bromide, 40 g qid, in patients withCOPD. They showed that ipratropium bromide andsalmeterol significantly improved FEV1to a greaterextent than salmeterol alone.115 However, patientsdid not experience any additional benefit in symp-tom control when salmeterol and ipratropium bro-

Figure6. FEV1change from baseline over 12 h with salmeterol,ipratropium, and placebo. The mean change from baseline in FEV1in the salmeterol group was significant (p 0.001) for each serialassessment at all visits. Significant differences in serial FEV1 be-tween salmeterol andipratropium treatment groups are indicated byasterisk. Reprinted with permission from Mahler et al.16

266 Reviews



10/13

mide were administered together.115 The combina-tion of formoterol and ipratropium bromide has alsobeen shown to be superior to formoterol alone inimproving mean peak FEV1in a group of 27 patients

with COPD.116 Beneficial effects are also observedwhen ipratropium bromide is combined with theSABA albuterol.117

The beneficial effects of the combination of sal-meterol, 42 g bid, and theophylline (titrated to 10to 20 g/mL) over 12 weeks of treatment hasrecently been shown in two large multicenter studies

with a total of 938 COPD patients.118 By week four,the combination of salmeterol and theophylline wassignificantly superior in improving FEV1than eithersalmeterol or theophylline alone, and this benefit

was maintained over the 12 weeks.118 In addition,significantly fewer patients in the combination grouphad exacerbations, and the transition dyspnea index wasalso significantly improved. At each 4-week period,albuterol use was significantly decreased in both the

combination and salmeterol-alone groups.118 Althoughno studies examining the combination of formoteroland theophylline have been published, it is likely thatformoterol would have similar activity to salmeterol.

Salmeterol vs Formoterol

Salmeterol and formoterol, administered at therecommended doses for regular inhaled therapy (ie,50 g and 24 g, respectively) by metered-doseinhaler were effective in improving airflow obstruc-tion in patients with COPD.29 Times to onset toimprove FEV1 by 15% were similar in both treat-

ment groups. In a later dose-ranging study, Cazzolaand colleagues28 showed that both salmeterol (25 g,50 g, and 75 g) and formoterol (12 g, 24 g, and36 g) induced an increase in FVC and FEV1 over12 h in patients with partially reversible, but severeCOPD. Formoterol induced a dose-related increasein these parameters and exhibited a faster onset ofaction than salmeterol. In addition, pretreatment

with either salmeterol or formoterol did not affectbronchodilator responses to albuterol in patients

with partially reversible COPD.119 In 1999, Maesenand coworkers18 also demonstrated that inhaled for-

moterol caused long-lasting, dose-dependent, lungfunction improvement (ie, FEV1, work of breathing,and airway resistance) in COPD patients poorlyreversible to terbutaline at baseline.

Side effects associated with the use of LABAsinclude elevated heart rate, decreased serum potas-sium concentrations and diastolic BP, as well asmusculoskeletal tremor.120 These side effects arepharmacologically predictable and dose-dependent.

Conclusion

LABAs, like salmeterol and formoterol, providesignificant clinical improvements in COPD despitethe limited reversibility of impaired lung function inthe disease. There are clinically significant increasesin lung function and decreased symptoms in COPDpatients, associated with a clinically significant im-

provement in health status. These benefits may beseen in patients who do not meet the defined criteriaof reversible when treated acutely with SABAs.The efficacy of LABAs in COPD may be explainedby more than bronchodilator effects. The additionaleffects on neutrophils, pulmonary epithelium, airwaysmooth muscle, and respiratory muscles may contrib-ute to the overall clinical efficacy in COPD and theassociated clinically relevant improvement in quality oflife. Treatment with LABAs may also reduce thenumbers of exacerbations and particularly decreaseseverity, and thus it is possibly that they may impact onthe overall cost of health care for COPD.

ACKNOWLEDGMENT: We thank Kate Komer for her invalu-able input, and Michael Spiro for carrying out an extensiveliterature search and compiling the data. We also thank Dr. RuthMurray for writing and editorial assistance.

References

1 Standards for the diagnosis and care of patients with chronicobstructive pulmonary disease (COPD) and asthma. Am RevRespir Dis 1987; 136:225244

2 Chronic bronchitis, asthma and pulmonary emphysema: astatement by the committee on diagnostic standards fornon-tuberculous respiratory disease. Am Rev Respir Dis1962; 85:762768

3 Murray CJ, Lopez AD. Alternative projections of mortality

and disability by cause 19902020: global burden of diseasestudy. Lancet 1997; 349:14981504

4 Nagai A, West WW, Thurlbeck WM. The National Institutesof Health Intermittent Positive-Pressure Breathing Trial:pathology studies; ii. correlation between morphologic find-ings, clinical findings, and evidence of expiratory air-flowobstruction. Am Rev Respir Dis 1985; 132:946953

5 Hale KA, Ewing SL, Gosnell BA, et al. Lung disease inlong-term cigarette smokers with and without chronic air-flowobstruction. Am Rev Respir Dis 1984; 130:716721

6 Thurlbeck WM. Pathophysiology of chronic obstructive pul-monary disease. Clin Chest Med 1990; 11:389403

7 Snider GL. Chronic obstructive pulmonary disease: a defini-tion and implications of structural determinants of airflowobstruction for epidemiology. Am Rev Respir Dis 1989;140:S3S8

8 Speizer FE, Tager IB. Epidemiology of chronic mucushypersecretion and obstructive airways disease. EpidemiolRev 1979; 1:124142

9 Leeder SR. Role of infection in the cause and course of chronicbronchitis and emphysema. J Infect Dis 1975; 131:731742

10 Thom TJ. International comparisons in COPD mortality. AmRev Respir Dis 1989; 140:S27S34

11 Manfreda J, Mao Y, Litven W. Morbidity and mortality fromchronic obstructive pulmonary disease. Am Rev Respir Dis1989; 140:S19S26

CHEST / 120 / 1 / JULY, 2001 267



11/13

12 Feinleib M, Rosenberg HM, Collins JG, et al. Trends inCOPD morbidity and mortality in the United States. Am RevRespir Dis 1989; 140:S9S18

13 Lebowitz MD. The trends in airway obstructive diseasemorbidity in the Tucson epidemiologic study. Am Rev RespirDis 1989; 140:S35S41

14 Poller W, Faber JP, Scholz S, et al. Mis-sense mutation of1-antichymotrypsin gene associated with chronic lung dis-ease. Lancet 1992; 339:15381543

15 Poller W, Faber JP, Weidinger S, et al. A leucine-to-prolinesubstitution causes a defective 1-antichymotrypsin alleleassociated with familial obstructive lung disease. Genomics1993; 17:740743

16 Mahler DA, Donohue JF, Barbee RA, et al. Efficacy ofsalmeterol xinafoate in the treatment of COPD. Chest 1999;115:957965

17 Boyd G, Morice AH, Pounsford JC, et al. An evaluation ofsalmeterol in the treatment of chronic obstructive pulmonarydisease (COPD). Eur Respir J 1997; 10:815821

18 Maesen BLP, Westermann CJJ, Duurkens VAM, et al. Effectsof formoterol in apparently poorly reversible chronic obstructivepulmonary disease. Eur Respir J 1999; 13:11031108

19 Lulich KM, Goldie RG, Paterson JW. -Adrenoceptor func-tion in asthmatic bronchial smooth muscle. Gen Pharmacol1988; 19:307311

20 Ullman A, Svedmyr N. Salmeterol, a new long acting inhaled2-adrenoceptor agonist: comparison with albuterol in adultasthmatic patients. Thorax 1988; 43:674678

21 Hekking P, Maesen F, Greefhorst A, et al. Efficacy andtolerability of inhaled formoterol compared with inhaledalbuterol 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 andkinetic studies of the interactions of salmeterol with mem-brane bilayers. Mol Pharmacol 1992; 42:596602

23 Green SA, Spasoff AP, Coleman RA, et al. Sustained activa-tion of a G protein-coupled receptor via anchored agonistbinding: molecular localization of the salmeterol exosite

within the 2-adrenergic receptor. J Biol Chem 1996; 271:2402924035

24 Johnson M. Salmeterol: a novel drug for the treatment ofasthma. Agents Actions Suppl 1991; 34:7995

25 Anderson GP, Linden A, Rabe KF. Why are long-acting2-adrenoceptor agonists long-acting? Eur Respir J 1994;7:569578

26 Waldeck B. Some pharmacodynamic aspects on long-acting-adrenoceptor agonists. Gen Pharmacol 1996; 27:575580

27 Cochrane GM. Slow release theophyllines and chronic bron-chitis. BMJ (Clin Res Ed) 1984; 289:16431644

28 Cazzola M, Matera MG, Santangelo G, et al. Salmeterol andformoterol in partially reversible severe chronic obstructivepulmonary disease: a dose-response study. Respir Med 1995;89:357362

29 Cazzola M, Santangelo G, Piccolo A, et al. Effect of salmet-erol and formoterol in patients with chronic obstructivepulmonary disease. Pulm Pharmacol 1994; 7:103107

30 Celik G, Kayacan O, Beder S, et al. Formoterol and salmet-erol in partially reversible chronic obstructive pulmonarydisease: a crossover, placebo-controlled comparison of onsetand duration of action. Respiration 1999; 66:434439

31 Tomlinson PR, Wilson JW, Stewart AG. Inhibition by albu-terol of the proliferation of human airway smooth muscle cellsgrown in culture. Br J Pharmacol 1994; 111:641647

32 Tomlinson PR, Wilson JW, Stewart AG. Salbutamol inhibitsthe proliferation of human airway smooth muscle cells grownin culture: relationship to elevated cAMP levels. Biochem

Pharmacol 1995; 49:1809181933 Harris T, Koutsoubos V, Guida E, et al. Salmeterol modulates

cell proliferation and cyclin D1 protein levels in thrombin-stimulated human cultured airway smooth muscle via anaction independent of the 2-adrenoceptor [abstract]. Am JRespir Crit Care Med 1999; 159:A530

34 Johnson M. Mechanisms of action of2-adrenoceptor ago-nists. 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 acting2-agonist over 3 months on airway wall vascular remodellingin asthma. Am J Respir Crit Care Med 2001 (in press)

36 Polkey MI, Kyroussis D, Hamnegard CH, et al. Diaphragmstrength in chronic obstructive pulmonary disease. Am JRespir Crit Care Med 1996; 154:13101317

37 van der Heijden HF, Heunks LM, Folgering H, et al.2-Adrenoceptor agonists reduce the decline of rat dia-phragm twitch force during severe hypoxia. Am J Physiol1999; 276:L474L480

38 Easton PA, Skjodt NM, Johnson M, et al. Salmeterol effect onrespiratory muscle in awake canines. Eur Respir J 1998;28:451S

39 Kusuhara N, Rothwell BC, Easton PA. Effect of-adrener-gics on respiratory muscle shortening and EMG activity inawake canines [abstract]. Am J Respir Cell Mol Biol 1996;

153:A68640 Easton P, Yokoba M, Hawes H, et al. Salbutamol effects on

parasternal muscle activity and ventilation in humans [ab-stract]. Am J Respir Crit Care Med 2000; 161:A117

41 Pesci A, Balbi B, Majori M, et al. Inflammatory cells andmediators in bronchial lavage of patients with chronic ob-structive pulmonary disease. Eur Respir J 1998; 12:380386

42 Saetta M, Turato G, Facchini FM, et al. Inflammatory cells inthe bronchial glands of smokers with chronic bronchitis. Am JRespir Crit Care Med 1997; 156:16331639

43 Hill AT, Bayley D, Stockley RA. The interrelationship ofsputum inflammatory markers in patients with chronic bron-chitis. Am J Respir Crit Care Med 1999; 160:893898

44 Szefler SJ, Edwards CK, Haslett C, et al. Effects of cellisolation procedures and radioligand selection on the charac-terization of human leukocyte -adrenergic receptors. Bio-

chem Pharmacol 1987; 36:1589159745 Zimmerman GA, McIntyre TM. Neutrophil adherence to

human endothelium in vitro occurs by CD18 glycoprotein-dependent and -independent mechanisms. J Clin Invest 1988;81:531537

46 Lo SK, Van Seventer GA, Levin SM, et al. Two leukocytereceptors (CD11a/CD18 and CD11b/CD18) mediate tran-sient adhesion to endothelium by binding to different ligands.J Immunol 1989; 143:33253329

47 Tonnesen MG, Anderson DC, Springer TA, et al. Adherenceof neutrophils to cultured human microvascular endothelialcells: stimulation by chemotactic peptides and lipid mediatorsand dependence upon the MAC-1, LFA-1, p150,95 glyco-protein family. J Clin Invest 1989; 83:637646

48 Derian CK, Santulli RJ, Rao PE, et al. Inhibition of chemo-tactic peptide-induced neutrophil adhesion to vascular endo-thelium by cAMP modulators. J Immunol 1995; 154:308317

49 Ottonello L, Morone P, Dapino P, et al. Inhibitory effect ofsalmeterol on the respiratory burst of adherent human neu-trophils. Clin Exp Immunol 1996; 106:97102

50 Bloemen PG, van den Tweel MC, Henricks PA, et al.Increased cAMP levels in stimulated neutrophils inhibit theiradhesion to human bronchial epithelial cells. Am J Physiol1997; 272:L580L587

51 Bolton PB, Lefevre P, McDonald DM. Salmeterol reducesearly- and late-phase plasma leakage and leukocyte adhesion in

268 Reviews



12/13

rat airways. Am J Respir Crit Care Med 1997; 155:1428143552 Bowden JJ, Sulakvelidze I, McDonald DM. Inhibition of

neutrophil and eosinophil adhesion to venules of rat tracheaby 2-adrenergic agonist, formoterol. J Appl Physiol 1994;77:397405

53 Radermecker MF, Louis R, Corhay JL, et al. Effect ofsalmeterol, theophylline and nedocromil sodium on neutro-phil chemotaxis in man. Allergy 1992; 47:48

54 Li D, Wang D, Venge P, et al. Comparison of the anti-

inflammatory effects of inhaled fluticasone propionate andsalmeterol in asthma: a placebo-controlled crossover study ofbronchial biopsies. Eur Respir J 1997; 25:444S

55 Ward C, Li X, Wang N, et al. Salmeterol reduces BAL IL-8levels in asthmatics on low dose inhaled corticosteroids. EurRespir J 1998; 28:380S

56 Faurschou P, Dahl R, Jeffery P, et al. Comparison of theanti-inflammatory effects of fluticasone and salmeterol inasthma: a placebo controlled, double blind, cross-over study

with bronchoscopy, bronchial methacholine provocation andlavage. Eur Respir J 1997; 25:243S

57 Nials AT, Coleman RA, Johnson M, et al. The duration ofaction of non-2-adrenoceptor mediated responses to salme-terol. Br J Pharmacol 1997; 120:961967

58 Klettke U, Luck W, Wahn U, et al. Platelet-activating factorinhibits ciliary beat frequency of human bronchial epithelial

cells. Allergy Asthma Proc 1999; 20:11511859 Ganbo T, Hisamatsu K, Nakazawa T, et al. Platelet activating

factor (PAF) effects on ciliary activity of human paranasalsinus mucosa in vitro. Rhinology 1991; 29:231237

60 Anderson R, Feldman C, Theron AJ, et al. Anti-inflammatory,membrane-stabilizing interactions of salmeterol with humanneutrophilsin vitro. Br J Pharmacol 1996; 117:13871394

61 Okada C, Sugiyama H, Eda R, et al. Effect of formoterol onsuperoxide anion generation from bronchoalveolar lavagecells after antigen challenge in guinea pigs. Am J Respir CellMol Biol 1993; 8:509517

62 Rabe KF, Giembycz MA, Dent G, et al. Salmeterol is acompetitive antagonist at -adrenoceptors mediating inhibi-tion of respiratory burst in guinea-pig eosinophils. Eur J Phar-macol 1993; 231:305308

63 Vaux DL, Haecker G, Strasser A. An evolutionary perspective

on apoptosis. Cell 1994; 76:77777964 Lee E, Smith J, Robertson T, et al. Salmeterol and inhibitors

of phosphodiesterase 4 (PDE-4) induce apoptosis in neutro-phils from asthmatics: -adrenergic receptor-mediated sal-meterol 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 salmet-erol on Pseudomonas aeruginosa infection of respiratorymucosa. Am J Respir Crit Care Med 1997; 155:327336

66 Read RC,Wilson R, Rutman A, et al. Interaction of nontype-ableHaemophilus influenzaewith human respiratory mucosa

in vitro. J Infect Dis 1991; 163:54955867 Munro NC, Barker A, Rutman A, et al. Effect of pyocyanin

and 1-hydroxyphenazine on in vivo tracheal mucus velocity.J Appl Physiol 1989; 67:316323

68 Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8(IL-8) and an inhibitory effect of erythromycin on IL-8release in the airways of patients with chronic airway diseases.Infect Immun 1994; 62:41454152

69 Matsuse T, Hayashi S, Kuwano K, et al. Latent adenoviralinfection in the pathogenesis of chronic airways obstruction.Am Rev Respir Dis 1992; 146:177184

70 Murphy TF, Sethi S. Bacterial infection in chronic obstructivepulmonary disease. Am Rev Respir Dis 1992; 146:10671083

71 Dowling RB, Johnson M, Cole PJ, et al. Effect of salmeterolonHaemophilus influenzaeinfection of respiratory mucosa in

vitro. Eur Respir J 1998; 11:869072 Kanthakumar K, Taylor G, Tsang KW, et al. Mechanisms of

action of Pseudomonas aeruginosa pyocyanin on humanciliary beat in vitro. Infect Immun 1993; 61:28482853

73 Dowling RB, Johnson M, Cole PJ, et al. Effect of fluticasonepropionate and salmeterol onPseudomonas aeruginosainfec-tion 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; 23:264S75 Rusznak C, Sapsford RJ, Devalia JL, et al. Influence of

albuterol and salmeterol on ciliary beat frequency of culturedhuman bronchial epithelial cells. Thorax 1991; 46:782P

76 Devalia JL, Sapsford RJ, Rusznak C, et al. The effects ofsalmeterol and albuterol on ciliary beat frequency of culturedhuman bronchial epithelial cells, in vitro. Pulm Pharmacol1992; 5:257263

77 Kanthakumar K, Cundell DR, Johnson M, et al. Effect ofsalmeterol on human nasal epithelial cell ciliary beating:inhibition of the ciliotoxin, pyocyanin. Br J Pharmacol 1994;112:493498

78 Vestbo J, Prescott E, Lange P. Association of chronic mucushypersecretion with FEV1 decline and chronic obstructivepulmonary disease morbidity: Copenhagen City Heart StudyGroup. Am J Respir Crit Care Med 1996; 153:15301535

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 clearanceand salmeterol. Clin Otolaryngol Allied Sci 1997; 22:6870

81 Hasani A, Toms N, OConnor J, et al. The effect of salmeterolxinafoate on lung mucociliary clearance in patients with stableasthma. 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 functionalsignificance of the sympathetic innervation of mucous glandsin the bronchi of man. J Physiol 1988; 403:211219

84 Phipps RJ, Williams IP, Richardson PS, et al. Sympathomi-metic drugs stimulate the output of secretory glycoproteins

from human bronchiin vitro. Clin Sci 1982; 63:232885 Leikauf GD, Ueki IF, Nadel JA. Autonomic regulation of

viscoelasticity of cat tracheal g land secretions. J Appl Physiol1984; 56:426 430

86 Boat TF, Kleinerman JI. Human respiratory tract secretions:2. Effect of cholinergic and adrenergic agents on in vitrorelease of protein and mucous glycoprotein. Chest 1975;67:32S34S

87 Shelhamer JH, Marom Z, Kaliner M. Immunologic andneuropharmacologic stimulation of mucous glycoprotein re-lease from human airways in vitro. J Clin Invest 1980;66:14001408

88 Wanner A, Salathe M, ORiordan TG. Mucociliary clearance inthe airways. Am J Respir Crit Care Med 1996; 154:18681902

89 Otis DR Jr, Johnson M, Pedley TJ, et al. Role of pulmonarysurfactant in airway closure: a computational study. J ApplPhysiol 1993; 75:13231333

90 Kamm RD, Schroter RC. Is airway closure caused by a liquidfilm instability? Respir Physiol 1989; 75:141156

91 Bredenberg CE, Paskanik AM, Nieman GF. High surfacetension pulmonary edema. J Surg Res 1983; 34:515523

92 Schurch S, Gehr P, Im Hof V, et al. Surfactant displacesparticles toward the epithelium in airways and alveoli. RespirPhysiol 1990; 80:1732

93 Borron P, Veldhuizen RA, Lewis JF, et al. Surfactant associ-ated protein-A inhibits human lymphocyte proliferation and

CHEST / 120 / 1 / JULY, 2001 269



13/13

IL-2 production. Am J Respir Cell Mol Biol 1996; 15:11512194 Benne CA, Benaissa-Trouw B, Van Strijp JA, et al. Surfactant

protein A, but not surfactant protein D, is an opsonin forinfluenza A virus phagocytosis by rat alveolar macrophages.Eur J Immunol 1997; 27:886890

95 Pikaar JC, Voorhout WF, van Golde LM, et al. Opsonicactivities of surfactant proteins A and D in phagocytosis ofGram-negative bacteria by alveolar macrophages. J Infect Dis1995; 172:481489

96 Lusuardi M, Capelli A, Carli S, et al. Role of surfactant inchronic obstructive pulmonary disease: therapeutic implica-tions. Respiration 1992; 59(suppl 1):2832

97 Anzueto A, Jubran A, Ohar JA, et al. Effects of aerosolizedsurfactant in patients with stable chronic bronchitis: a prospec-tive randomized controlled trial. JAMA 1997; 278:14261431

98 Kumar V, Kresch M. Effects of salmeterol (S) on phosphati-dylcholine (PC) secretion by type II cells. Pediatr Res 1996;39:337A

99 Sakuma T, Okaniwa G, Nakada T, et al. Alveolar fluidclearance in the resected human lung. Am J Respir Crit CareMed 1994; 150:305310

100 Sakuma T, Folkesson H, Suzuki S, et al. Salmeterol in-creases alveolar epithelial fluid clearance in bothin vitroandex vivo rat lungs, as well as in ex vivo human lungs. Am J

Respir Cell Mol Biol 1996; 153:A195101 Siafakas NM, Vermeire P, Pride NB, et al. Optimal assess-

ment and management of chronic obstructive pulmonarydisease (COPD): The European Respiratory Society TaskForce. Eur Respir J 1995; 8:13981420

102 Global Initiative for Chronic Obstructive Lung Disease.National Institutes of Health Report 2701A, 2001. Availableat: http://www.goldcopd.com. Accessed June 15, 2001

103 Jack D. The Lilly prize lecture: a way of looking at agonismand antagonism; lessons from albuterol, salmeterol andother -adrenoceptor agonists. Br J Clin Pharmacol 1991;31:501514

104 Bartow RA, Brogden RN. Formoterol: an update of itspharmacologic properties and therapeutic efficacy in themanagement 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 Med1997; 155:12831289

106 Ramirez-Venegas A, Ward J, Lentine T, et al. Salmeterolreduces dyspnea and improves lung function in patients withCOPD. Chest 1997; 112:336340

107 Ulrik CS. Efficacy of inhaled salmeterol in the managementof smokers with chronic obstructive pulmonary disease: asingle center randomised, double blind, placebo controlled,crossover study. Thorax 1995; 50:750754

108 Anderson W, Wisniewski M, Rickard K. Pulmonary functionresponse to salmeterol and ipratropium in patients revers-

ible and non-reversible to anticholinergics and -agonists.Eur Respir J 1997; 25:104S

109 Bailey W, Yancey S, Rickard K, et al. Peak flow andsymptom monitoring in COPD: a 12-week comparison ofplacebo, Atrovent and Serevent [abstract]. Am J Respir CritCare Med 1997; 155:A34

110 Cazzola M, Vinciguerra A, Di Perna F, et al. Early revers-ibility to albuterol does not always predict bronchodilationafter salmeterol in stable chronic obstructive pulmonary

disease. Respir Med 1998; 92:10121016111 Dahl R, Greefhorst A, Nowak D, et al. Comparison of theefficacy and safety of inhaled formoterol and ipratropiumbromide in patients with COPD [abstract]. Am J Respir CritCare Med 2000; 161:A805

112 Greefhorst A, Dahl R, Nowak D, et al. Effect of inhaledformoterol and ipratropium bromide on quality of life, baddays and exacerbations in patients with COPD [abstract].Am J Respir Crit Care Med 2000; 161:A807

113 Taccola M, Bancalari L, Ghignoni G, et al. Salmeterol versusslow-release theophylline in patients with reversible obstructivepulmonary disease. Monaldi Arch Chest Dis 1999; 54:302306

114 Di Lorenzo G, Morici G, Drago A, et al. Efficacy, tolerabil-ity, and effects on quality of life of inhaled salmeterol andoral theophylline in patients with mild-to-moderate chronicobstructive pulmonary disease: SLMT02 Italian Study

Group. Clin Ther 1998; 20:11301148115 Van Noord J, De Munck D, Bantje T, et al. Efficacy and

safety of salmeterol and ipratropium bromide in patientswith chronic obstructive pulmonary disease [abstract]. Am JRespir Crit Care Med 1998; 157:A799

116 Sichletidis L, Kottakis J, Marcou S, et al. Bronchodilatoryresponses to formoterol, ipratropium, and their combinationin patients with stable COPD. Int J Clin Pract 1999;53:185188

117 Friedman M, Witek T Jr, Serby C, et al. Combinationbronchodilator therapy is associated with a reduction inexacerbations of COPD [abstract]. Am J Respir Crit CareMed 1996; 153:A126

118 Knobil K, Emmett A, Reilly D, et al. Combination therapywith salmeterol and theophylline for COPD [abstract]. Am JRespir Crit Care Med 2000; 161:A804

119 Cazzola M, Di Perna F, Noschese P, et al. Effects offormoterol, salmeterol or oxitropium bromide on airwayresponses to albuterol in COPD. Eur Respir J 1998; 11:13371341

120 Bennett J, Smyth E, Pavord I, et al. Systemic effects ofalbuterol and salmeterol in patients with asthma. Thorax1994; 49:771774

121 Rudiger J, Eickelberg O, Tamm M, et al. 2-adrenoceptoragonists inhibit cell proliferation by activation of P21 geneexpression [abstract]. Am J Respir Crit Care Med 1999;159:A445

270 Reviews

Alternative Mechanisms for Long-Acting b2-Adrenergic Agonists in COPD*

Documents

Transcript of Alternative Mechanisms for Long-Acting b2-Adrenergic Agonists in COPD*