Long-acting Inhaled ₂-Agonist Therapy in Asthma

JOHAN C. KIPS and ROMAIN A. PAUWELS

Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium

	CONTENTS

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

Pharmacology of Long-acting Inhaled ₂-Agonists

Clinical Positioning in Adults

Clinical Positioning in Children

Additive Effect of LABA and ICS

Molecular Interactions between LABA and ICS

Differences between Formoterol and Salmeterol

Conclusion

The introduction of long-acting inhaled ₂-agonists has been a major therapeutic development, and has led to a fundamental reappraisal of ₂-agonist use in asthma management. This review attempts to highlight a few salient features that have emerged from the growing clinical experience with these products.

	PHARMACOLOGY OF LONG-ACTING INHALED 2-AGONISTS

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

Salmeterol and formoterol are two highly selective ₂-agonists with a bronchodilating effect lasting for at least 12 h after a single inhalation (1, 2). The molecular structure of both long-acting inhaled ₂-agonists (LABA) is, however, different (Figure 1). Salmeterol is the result of a specific research program designed to achieve prolonged duration of action by molecular modification of the short-acting ₂-agonists salbutamol. The resulting 25 Å molecule consists of the saligenin head of salbutamol that binds to the active site of the ₂-adrenergic receptor (₂AR), coupled to a long aliphatic side chain that profoundly increases the lipophilicity of the molecule. The concept has been proposed that the molecule diffuses laterally through the cell membrane to approach the ₂AR. The side chain then interacts with an auxiliary binding site (exo-site), a group of highly hydrophobic amino acids within the fourth domain of the ₂AR. Binding to the exo-site prevents dissociation of salmeterol from the ₂AR and allows the active saligenin head to repeatedly engage the active site of the receptor. This mechanism would account for the long duration of the effect but slow onset of action of salmeterol (3).

View larger version (35K): [in this window] [in a new window]   Figure 1.   Mode of action of 2-agonists based on the plasmalemma diffusion microkinetic theory (taken with permission from reference 4).

Formoterol, a formanilide substituted phenoethanolamine, was serendipitously found to be long-acting when given by inhalation. The length of the side chain and resulting lipophilicity of formoterol is intermediate between salmeterol and salbutamol. The plasmalemma diffusion microkinetic theory predicts that the moderate lipophilicity of formoterol allows it to enter the plasmalemma and to be retained. From this depot, the molecule diffuses slowly to activate the ₂AR over a prolonged period. Conversely, sufficient drug remains available in the aqueous biophase to allow immediate interaction with the active site of the receptor, accounting for its rapid onset of action. Formation of a depot within the plasmalemma seems to require high topical concentrations of formoterol in the bronchi. This is thought to explain why inhaled formoterol has a longer duration of action than when given orally, as the inhaled route achieves higher topical concentration in the periciliary fluid of the bronchi (4).

	CLINICAL POSITIONING IN ADULTS

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

Several studies have clearly established that monotherapy with ₂-agonists, either short-acting or long-acting, is clinically inferior to inhaled glucocorticosteroids (ICS) as maintenance treatment in persistent asthma (5). This is in line with current insight in the pathophysiology of asthma, identifying the disease as a chronic inflammatory disorder of the airways, and therefore recommending the use of "anti-inflammatory" controller medication as the basis of asthma treatment (10). Nevertheless, a substantial proportion of patients with more severe disease is insufficiently controlled with a low to moderate dose of ICS. For these patients, several therapeutic options exist. A first option consists of increasing the dose of ICS. However, it is increasingly recognized that clinical outcome measures such as symptoms, peak flow, or baseline FEV₁ display a flat dose- response relationship to the effect of inhaled steroids (11). This contrasts with the dose-dependent risk of systemic steroid activity. Hence, the clinical gain to be obtained from increasing the dose of steroids has to be balanced against the relatively higher risk of inducing side effects.

Instead of increasing the dose of steroids, an alternative option consists of adding another form of controller medication to an unchanged dose of ICS. To date, the combination of ICS with LABA has been most extensively investigated, starting with the two landmark studies by Greening and Woolcock. Greening and coworkers recruited 429 patients with mild to moderate disease severity, symptomatic despite treatment with beclomethasone dipropionate (BDP) 200 µg twice daily. The subjects were randomized to receive either a 2.5-fold higher dose of BDP (500 µg twice daily) or BDP 200 + salmeterol 50 µg for 6 mo. Adding salmeterol offered significantly better symptom and peak flow improvement than increasing the dose of steroids (12). The study by Woolcock and coworkers was conducted in 738 moderate to severe asthmatics, who were insufficiently controlled on a dose of 500 µg BDP twice daily or equivalent. Over a 6-mo treatment period, adding salmeterol 50 or 100 µg to BDP 500 µg twice daily clearly had a more rapid and pronounced beneficial effect on symptoms and baseline lung function than doubling the dose of ICS. In both groups taking salmeterol, morning peak flow improved with more than 45 L/min compared with a 16 L/min increase in the group taking BDP 1,000 µg twice daily (13). A striking observation is that the clinical benefit of adding ₂-agonists applies for LABA, but not for short-acting ₂-agonists, which offer no benefit in comparison to placebo when given as add-on in a four-times-a-day dosing regimen (14).

As for LABA, combining theophylline (17, 18) or cysteinyl leukotriene (CysLt₁) receptor antagonists (LTRA) (19) to inhaled steroids is also clinically advantageous. Relatively little is known on the effect of LABA as compared with these other forms of combination treatment. However, currently available data indicate that adding LABA offers a larger improvement than either theophylline (20) or LTRA (21). In mild asthmatics, the combination of salmeterol 50 µg with fluticasone propionate (FP) 100 µg twice daily provided better overall asthma control than montelukast 10 mg once daily added to FP 100 µg twice daily. Among other features, the difference in improvement of baseline FEV₁ was 0.14 L in favor of the salmeterol group (22). Based on these and other studies, it would therefore seem that LABA are the most effective form of "add-on" therapy, obtaining a clinical benefit that is superior to increasing the dose of ICS within a two- to fourfold range.

The safety of such an add-on approach has been an area of intense concern. As monotherapy with LABA is considered to have little or no anti-inflammatory effect in asthma, fear existed that despite offering significant symptomatic relief, adding LABA to an unchanged dose of ICS would insufficiently control the underlying inflammation, or might even mask its progression (23), resulting in the loss of long-term asthma control. This concern is not supported by current evidence. Eosinophil counts were shown not to be significantly different in induced sputum samples obtained throughout a 1-yr treatment period with either 100 µg budesonide + 9 µg formoterol twice daily or 400 µg budesonide twice daily (24). This is concordant with the observation that adding LABA does not result in an increase in clinical parameters of asthma instability, such as disease exacerbations (13, 25, 26). In a study that specifically addressed this issue, Pauwels and coworkers evaluated the add-on effect of formoterol 9 µg twice daily to a low (100 µg twice daily) or higher (400 µg twice daily) dose of budesonide in a group of 852 mild to moderate asthmatics. The primary outcome variable was the number of severe exacerbations over a 1-yr treatment, starting after a 1-mo run-in phase during which all patients were stabilized with 800 µg budesonide twice daily. Adding formoterol to either dose of budesonide not only improved symptoms and lung function, but also reduced the number of severe asthma exacerbations by 25%. In comparison to 200 µg budesonide, treatment with 800 µg had no different effect on baseline FEV₁, but showed a 50% reduction in the severe exacerbation rate (Figure 2) (27). Similarly, the results of a meta-analysis indicate that adding salmeterol in symptomatic asthma also has a significantly better effect on exacerbations than increasing the dose of steroids within a 2- or 2.5-fold range (28). Importantly, this beneficial effect only emerges from add-on studies with long-acting but not short-acting ₂-agonists (16, 26). In line with these observations, it has also been shown that adding LABA allows one to reduce the dose of ICS without losing asthma control in patients with mild to moderate asthma (29, 30). These various lines of evidence indicate that adding LABA to ICS is a clinically very effective and safe treatment option for patients with moderate to severe asthma.

View larger version (27K): [in this window] [in a new window]   Figure 2.   The effect of inhaled formoterol and budesonide on the yearly rate of severe exacerbations in asthma (adapted from reference 27). Treatment consisted of budesonide 100 µg + placebo twice daily (BUD200), budesonide 100 µg + formoterol 12 µg twice daily (BUD200+F), budesonide 400 µg + placebo twice daily (BUD800), or budesonide 400 µg + formoterol 12 µg twice daily (BUD800+F). Medication was inhaled by means of a Turbuhaler. The stated doses are the metered doses.

Implementing this treatment modality is further facilitated by the current development of formulations that combine both the LABA and the ICS in one inhaler. Formulations that have been developed include the combination of salmeterol 50 µg with FP 125, 250, or 500 µg and formoterol 4.5 µg with budesonide 80 and 160 µg (expressed as delivered dose). Clinical studies with these combination products confirm that they are as effective as the monocomponents administered via separate inhalers (31). At the same time, these studies again illustrate the clinical superiority of the combined treatment modality to monotherapy with LABA or ICS (34), even if the latter are given at higher doses (37). A major advantage of the single inhaler combination product is that it guarantees the prescribing physician that LABA will not be used in monotherapy. In addition, it can be hoped that by reducing the number of inhalations required, they will also improve patient compliance.

	CLINICAL POSITIONING IN CHILDREN

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

As in adults, single doses of LABA in children have a long lasting bronchodilating and bronchoprotective effect (40, 41). It is also clear that maintenance use of LABA in monotherapy should be avoided, as this is clearly less beneficial than low doses of BDP (200 µg/d), resulting in an increased exacerbation rate (9). Conversely, adding LABA to ICS reduces asthma symptoms and improves lung function (42, 43). It has been claimed that the added benefit is less clear than in adults (44). However, most of the studies performed in children included a relatively small number of subjects over limited treatment periods, thus hampering a proper comparison with the larger scale studies conducted in adults. Differences in patient characteristics at study entry also need to be taken into account.

Meijer and coworkers reported that over 16 wk of treatment, adding salmeterol offered a 5% improvement in FEV₁ when compared with placebo. Whereas in the study by Woolcock and coworkers, subjects were symptomatic with a baseline FEV₁ at entry into the study of 72%, the 40 children in this study were well controlled, with a baseline FEV₁ of 93%, limiting the potential benefit of adding a bronchodilator (45). Verberne and coworkers compared the effect of adding salmeterol versus doubling the dosis of ICS in 177 children. Treatment consisted of BDP 400 µg/d with or without salmeterol or BDP 800 µg/d. Baseline FEV₁ at entry was 86%. Over the 1-yr treatment period no consistent differences between the three groups were observed. Adding salmeterol to 400 µg BDP improved morning peak flow by 42 L/min, which is similar to the effect obtained in the study by Woolcock and coworkers. In contrast to the study in adults, however, the increase in peak flow in the patients treated with BDP alone was far more pronounced, amounting to 27 L/min in the BDP 400 µg/d and 41 L/min in the BDP 800 µg/d group (46). These substantial steroid-mediated effects could therefore at least in part explain the apparent limited effectiveness of adding LABA. Throughout the various studies, treatment with salmeterol was well tolerated. No differences in the exacerbation rates were observed. Overall, based on the currently available data, it would therefore seem that as in adults, LABA are of value in children from the age of 5 whose asthma is insufficiently controlled despite a low to moderate dose of steroids.

	ADDITIVE EFFECT OF LABA AND ICS

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

The mechanisms underlying the apparent additive effect of LABA and ICS on asthma control remain to be fully clarified. A first possible explanation is the obvious difference in pharmacologic profile between both compounds. ICS are clearly anti-inflammatory (47), whereas the smooth muscle relaxing effect of LABA results in prolonged bronchodilation and bronchoprotection (41, 50). It can be assumed that the combination of both pharmacologic activities is clinically particularly beneficial. However, it is uncertain whether this can fully explain the difference with the limited benefit of adding short-acting inhaled ₂-agonists, as dosing with these compounds four times a day would also seem to offer reasonable bronchoprotection throughout the day (58). In vitro and in vivo animal data demonstrate the anti-inflammatory potential of LABA, either through ₂AR stimulation, or by a membrane-stabilizing effect (Table 1).

An additional explanation for this beneficial effect therefore is that in the presence of ICS, LABA might somehow influence the inflammatory process underlying human asthma. Although still debated (59), there are limited data to support this hypothesis. First, LABA seem to have an effect on plasma exudation. Salmeterol has been shown to inhibit vascular permeability induced by nasal allergen challenge, whereas formoterol was reported to have a profound inhibitory effect on histamine-induced plasma exudation in the lower airways (60, 61). The effect of LABA on the cellular component of the inflammation is more debatable. That the different studies currently performed differ in the marker of inflammation examined only adds to the confusion. Salmeterol inhibits the rise in serum eosinophil cationic protein (ECP) induced by allergen exposure. This has been shown not only under laboratory conditions at allergen dose used to elicit a dual asthmatic response, but also under natural conditions during the pollen season (62, 63). On the other hand, others have shown that salmeterol does not influence the rise in urinary leukotriene E₄ (LTE₄) excretion, 24 h after allergen challenge (64). Similarly, formoterol and salmeterol do not have a consistent effect on the antigen-induced increase in sputum eosinophil count (65). In addition, salmeterol does not alter the cellular composition of bronchoalveolar lavage fluid (BALF) when given either to steroid-treated asthmatics or to steroid-naive patients with nocturnal asthma (68, 69).

Recent biopsy studies offer a more direct evaluation of the effect of LABA on the mucosal inflammation in the central airways. Monotherapy with formoterol during 8 wk significantly reduced mucosal eosinophil counts but only in a subgroup of patients with a pronounced degree of inflammation at the start of the study (defined as  10 eosinophils/mm² biopsy tissue) (70). Salmeterol, when given in monotherapy during 6 wk, had no discernable effect (71). When added during 12 wk on top of daily maintenance treatment with 100 to 500 µg ICS, salmeterol reduced significantly the number of EG1-positive but not EG2-positive eosinophils (72). Although theoretically LABA could also influence components of airway remodeling (73, 74), none of these relatively short-term biopsy studies reported any effect on the degree of subepithelial fibrosis (71).

These same effects have not been observed with short-acting inhaled ₂-agonists. In vitro studies indicate that formoterol, but not salbutamol inhibits chemotaxis of human eosinophils (75). Similarly, salmeterol but not salbutamol influences platelet-activating factor (PAF)-induced neutrophil and eosinophil accumulation in an in vivo guinea pig model (76). Moreover, in humans, monotherapy with short-acting inhaled ₂-agonists instead of reducing, significantly increases eosinophil numbers in biopsies and induced sputum (77, 78).

A final possible explanation for the apparent additive effect of LABA and ICS that needs mentioning is that apart from their own independent anti-inflammatory effects, both compounds enhance each other's anti-inflammatory potential. Several in vitro studies support this concept (79). Salmeterol 10⁷ M significantly enhances the inhibitory effect of FP 10⁹ M on the release of cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-1 (IL-1) from human blood mononuclear cells (79). In another study, fibroblasts were stimulated to express the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This was partly inhibited by low concentrations of budesonide and formoterol, with a significant additional effect when both compounds were combined (81). Preliminary data from a recent biopsy study illustrate the validity of this concept even at routinely used therapeutic doses in asthma. A significantly larger decrease in mast cells and IL-4⁺ cells was noted in subjects treated for 6 wk with the combination of FP 200 µg + salmeterol 50 µg twice daily, when compared with treatment with FP 500 µg twice daily (84).

Overall, these various studies illustrate that LABA when given alone have very limited, if any, anti-inflammatory effect in asthma. To what extent this is different when combined with ICS remains to be fully established.

	MOLECULAR INTERACTIONS BETWEEN LABA AND ICS

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

The molecular basis underlying the putative additive effects of LABA and ICS are currently intensively investigated. Increasing evidence illustrates a profound influence of ICS on ₂AR and vice versa. As a detailed description of these interactions goes beyond the scope of the current review, we will only briefly highlight the general principles that are currently considered to be involved.

The human ₂AR is a G-protein coupled receptor. Agonist binding to the receptor activates adenyl cyclase via the stimulating Gs-protein, and results in an elevation of intracellular cyclic AMP (cAMP) levels. At the same time, compensatory mechanisms develop, leading to desensitization of the receptor (85, 86). A first step involves receptor phosphorylation by kinases such as protein kinase A, protein kinase C, and the G protein-coupled receptor kinase (GRK-2). This causes binding of ₂ arrestin on the ₂AR, thus sterically uncoupling G_s and reducing cAMP production. The desensitized receptor- arrestin complex internalizes through clathrin-coated pits and is either degraded or dephosphorylated and recycled to the cell surface (87).

It has been proposed that proinflammatory cytokines such as IL-1 can further enhance the ₂AR desensitization by increasing GRK-2 phosphorylation through a cyclooxygenase-2-dependent mechanism that releases prostaglandin E₂ (PGE₂) and thus further enhances cAMP production. Although salutary on its own, this PGE₂-induced cAMP production causes heterologous desensitization of the ₂AR (88). Steroids can interfere with this desensitization cascade at various levels (93, 94). This includes prevention of heterologous desensitization by inhibiting PGE₂ production, enhancement of G_s protein expression, and an increased rate of ₂AR transcription (88, 95, 96). That this occurs not only in vitro, but also in humans at normally advocated doses, was confirmed in a study showing that intranasal BDP 100 µg twice daily for 3 d, increases ₂AR receptor expression in nasal scrapings (97). These effects of steroids on ₂AR function illustrate why, especially in inflamed milieu, concomitant treatment with ICS may be required to preserve ₂-agonist activity, thus explaining why monotherapy with LABA is far less effective than when added to ICS (15). Unless oral or high doses of inhaled steroids are given (98, 99), ICS cannot fully prevent ₂AR desensitization caused by chronic treatment with LABA. This has been shown predominantly for the loss of bronchoprotective activity of LABA (100), which does occur even in subjects treated with a moderate dose of ICS (103). However, some degree of bronchoprotection is maintained and the clinical relevance of this observation has been questioned (105, 106, 109, 110).

The second aspect of the molecular interaction between LABA and ICS is the potential effect of LABA on steroid function. Glucocorticosteroids bind to cytosolic glucocorticoid receptors (GR) normally present under inactive form in the cytoplasm, bound to heat shock proteins (hsp). Upon binding, hsp dissociate and the complex migrates to the nucleus where it can exert its effect via transactivation and transrepression of gene transcription (111). The rate-limiting step in gene transcription which integrates signals induced through a range of transcription factors is CAMP response element binding protein (CREB) binding protein (CBP) or the related p300 protein (112). Binding of GR dimers to CBP activates the associated histone acetyl transferase (HAT), uncoiling DNA from around nucleosomes, thus making it accessible to RNA polymerase and initiating gene transcription. In addition, steroids can inhibit gene transcription via deacetylation but especially via binding to other stimulating transcription factors such as activator protein-1 (AP-1) and nuclear factor kappa B (NF-B) that are induced by a number of cytokines and proinflammatory mediators. By preventing binding of these transcription factors, steroids thus inhibit activation of cytokine-induced gene transcription. ₂-agonists can interfere in various ways with this sequence of events. ₂AR stimulation can induce protein kinase A (PKA)-mediated phosphorylation of CREB, which can inhibit CBP activation by glucocorticoid receptors (113). It was initially feared that this was the dominant effect of ₂-agonists on steroid function, thus reducing the efficacy of steroids. However, alternative interactions have also been identified. ₂AR-induced PKA activation can switch coupling of the ₂AR from the Gs to the Gi protein, thereby activating mitogen-activated protein kinases (MAPK) (114). This can induce instead of inhibit CBP activation (112). In addition, it has recently been reported that ₂-agonists can induce ligand- independent nuclear translocation and activation of glucocorticoid receptors (115). Therefore, instead of sequestrating CBP through CREB phosphorylation, ₂-agonists can also enhance the effect of steroids. The overall effect depends among other features on the cell type or the concomitant presence of other stimuli leading to activation of specific transcription factors. However, this clearly illustrates the possibility of a positive interaction between steroids and LABA, thus explaining the apparent additive clinical effect. Theoretically, by facilitating steroid-induced gene transactivation, LABA might also enhance steroid-induced side effects. Currently available data do not indicate that concomitant use of LABA increases the effect of ICS on serum or urinary cortisol levels (32, 34).

	DIFFERENCES BETWEEN FORMOTEROL AND SALMETEROL

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

In addition to their difference in molecular structure, formoterol and salmeterol also have distinct pharmacologic features. As is reflected in the routinely advocated doses for human use, formoterol has a higher potency than salmeterol (116). Comparative studies in healthy volunteers indicate that formoterol and salmeterol dose-dependently cause side effects with a potency ratio of approximately 5:1 (117, 118). This is similar to their difference in bronchodilator potency in asthmatics (119). In vitro studies, both on animal and human bronchial tissue preparations, indicate that formoterol also has a higher efficacy than salmeterol at relaxing smooth muscle (116, 120). Under these experimental conditions, formoterol behaves as a nearly full agonist, in contrast to salmeterol which acts as a partial agonist, antagonizing the relaxation induced by ₂-agonists of greater efficacy (116, 120, 121, 124). To what extent these pharmacologic differences are clinically relevant is unclear. To date, no significant clinical differences have been observed between the two molecules, except for the faster onset of action of the bronchodilator effect of formoterol. These similarities in clinical efficacy would suggest that either the in vitro models are not relevant to the clinical efficacy or that the appropriate clinical studies have not yet been conducted to identify possible, clinically relevant, differences.

Among the issues that remain to be further resolved is the question as to whether the interactions between LABA and ICS are class-specific, or whether they differ between both LABA. Theoretically, differences in efficacy will primarily be discernable in cell types that have a low receptor density or less efficient signal transduction coupling. In contrast to smooth muscle cells that have a high receptor density (30,000 to 40,000 per cell), inflammatory cells carry far less ₂AR (700 to 750 per lymphocyte) (3). Hence, the higher efficacy of formoterol versus salmeterol might mainly be discernable in their nonbronchodilator effects (125). Conversely, compounds with a higher efficacy could cause more side effects and induce more profound receptor desensitization, resulting in increased tolerance development (130, 131). Only a limited amount of direct comparative data addressing these issues has currently been published (Table 2).

The clinical relevance of these findings, however, remains unclear. A few case reports have been published showing a significantly stronger bronchodilating effect with formoterol than with salmeterol in severe persistent asthmatics with a baseline FEV₁ of less than 50% (132, 133). However, in a larger comparative study, including 24 subjects with severe persistent asthma, no difference was observed in the bronchodilating effect of both compounds (134). In addition, chronic treatment with salmeterol does not hamper the bronchodilating potential of salbutamol in an emergency care setting, indicating that in humans, salmeterol does not significantly antagonize the effect of another ₂-agonist on smooth muscle tone (135). Potential differences in bronchoprotective effect are equally unclear. At routinely advocated doses, single inhalation of both compounds has been shown to have not only the same bronchodilating but also bronchoprotective effect (53). Both compounds also develop a similar degree of tolerance as to their bronchoprotective effect (136). Only at higher doses of LABA has a difference been observed. It has recently been shown in an experimental setting that in mild asthma inhalation of formoterol 12, 60, or 120 µg dose dependently protects against methacholine-induced bronchoconstriction, whereas the degree of protection obtained with salmeterol reaches a plateau, 500 µg not being more effective than 250 µg. The higher efficacy of formoterol was also reflected in more pronounced systemic effects (119).

What also needs to be considered is to what extent differences in efficacy are reflected in the effect on asthma exacerbation rates. Exacerbations represent episodes of increased airway narrowing (137). The underlying pathogenetic mechanisms remain to be fully established, and it is unclear whether LABA in combination with ICS affect this phenomenon merely through smooth muscle cell relaxation. Adding formoterol has consistently been shown to significantly reduce the rate of exacerbations requiring treatment with oral steroids. In patients with moderately severe asthma, formoterol reduced the exacerbation rate over 1 yr by approximately 25%, when added to either 200 or 800 µg of budesonide per day (27). Preliminary data indicate an at least as pronounced effect in patients with milder disease, when added to 200 or 400 µg of budesonide (138). This has been less apparent in studies with salmeterol, albeit that in a meta-analysis it was shown that salmeterol offers a 2.4% larger reduction in severe exacerbations than a 2- to 2.5-fold increase in the maintenance dose of ICS (28). Differences in study design, patient population, and definition of exacerbations do not allow for a straightforward comparison between these various studies. Only a direct comparative study of sufficient size and long enough duration can further clarify this issue. To date, comparison of treatment with either compound has been very limited. An open study in 496 patients with mild to moderate asthma evaluated the effect of adding salmeterol or formoterol to a low dose of inhaled steroids. Formoterol had a larger effect on symptoms and peak flow over the first 4 wk of treatment, but no significant difference was observed between both compounds over the entire 8-wk treatment period. Similarly, the number of episodes of worsening of asthma was not different between both groups (139).

A related issue that needs to be further addressed as to its clinical relevance is the ₂AR polymorphism and the possible consequences on differences in the response to both LABA (140). Genetic polymorphism in the ₂AR has been clearly identified (141). The two most common variants are substitutions of glycine for arginine at position 16 (Gly 16) and glutamic acid for glutamine at position 27 (Glu 27). In vitro, the homozygous Gly 16 genotype has been reported to increase the susceptibility to ₂AR desensitization, whereas Glu 27 confers relative protection (142). It has been proposed that homozygous Gly 16 genotype also develops more tolerance toward the bronchodilating effect of formoterol (143). Subsequent studies have not confirmed that receptor polymorphism might affect tolerance development to the bronchodilating or bronchoprotective effect of both LABA (144, 145). On a more clinical level, an association has been suggested between severity of asthma and Gly 16 polymorphism (142, 146). However, no correlation has been found between ₂AR polymorphism and the development of exacerbations in patients chronically treated with salmeterol (147).

The only pharmacologic difference that has currently been established to be clinically relevant is the onset of action of both compounds. Formoterol has a faster onset of action than salmeterol. Single-dose studies in asthmatics illustrate that, in contrast to salmeterol, formoterol acts as quickly as salbutamol, both with regard to bronchodilation and reversal of bronchoconstriction (55, 148). Safety studies indicate that for a same degree of bronchodilation, formoterol does not induce more systemic effects than equipotent doses of terbutaline or albuterol (149, 150). The duration of systemic effects is also similar for formoterol and albuterol (150). As a consequence, the pharmacologic profile of formoterol might allow for its use not only as maintenance treatment, but also as rescue medication on an "as needed" basis. This concept is currently being explored in clinical trials. Tattersfield and coworkers compared terbutaline 0.5 mg with formoterol 4.5 µg as rescue medication in 362 moderately severe asthmatics who, despite being treated with a mean dose of 870 µg of inhaled steroids, were insufficiently controlled, as they required daily between 3 and 8 rescue inhalations of a short-acting ₂-agonist during the run-in phase. Over the 3 mo of the study, the use of formoterol as needed resulted in a significant improvement in morning peak expiratory flow rate symptom score, and time to first exacerbation, despite a reduction in the number of rescue inhalations (151).

Preliminary results from a similar trial in patients on maintenance treatment with steroids at a mean daily dose of 1,030 µg and formoterol 9 µg twice daily, indicate that formoterol 4.5 µg is as safe and effective as 0.5 mg terbutaline when used as needed for symptom relief (152). Also, when combined with systemic methylprednisolone 40 mg, repetitive inhalations of formoterol to a total daily dose of 90 µg proved as effective as terbutaline 10 mg in the treatment of acute asthma attacks in an emergency care setting (153). In this study, formoterol induced less systemic effects than terbutaline. As further data emerge, it will become clearer to what extent these observations have implications for differences in the positioning of both LABA in daily asthma management.

	CONCLUSION

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

Over the past years, long-acting inhaled ₂-agonists have gained acceptance as the preferred form of "add-on" treatment in persistent asthma. Combining LABA with inhaled glucocorticosteroids is a therapeutic option that at present should be considered for any patient with persistent asthma, who is insufficiently controlled with ICS at a daily dose of 400 µg or more. In the majority of these patients, adding LABA further improves symptoms and lung function, without evidence for a decrease in asthma control. The mechanisms underlying this apparent additive interaction between both compounds need to be further elucidated. There is increasing evidence that LABA, in addition to relaxing airway smooth muscle cells, might also have some anti-inflammatory effect in humans, probably mainly by potentiating the effect of ICS. Expressing their full therapeutic benefit requires the concomitant presence of ICS, as this counteracts at least in part ₂-adrenergic receptor desensitization. To what extent the higher efficacy of formoterol compared with salmeterol is clinically relevant also needs to be further addressed.

	Footnotes

Correspondence and requests for reprints should be addressed to Johan Kips, M.D., Ph.D., Department of Respiratory Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail : johan.kips{at}rug.ac.be

(Received in original form October 20, 2000 and in revised form June 14, 2001).

	References

TOP CONTENTS PHARMACOLOGY OF LONG-ACTING... CLINICAL POSITIONING IN ADULTS CLINICAL POSITIONING IN... ADDITIVE EFFECT OF LABA... MOLECULAR INTERACTIONS BETWEEN... DIFFERENCES BETWEEN FORMOTEROL... CONCLUSION REFERENCES

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