ERJ
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online before print November 29, 2006, 10.1183/09031936.00032806
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Permissions
Right arrowRequest Permissions
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Naline, E.
Right arrow Articles by Molimard, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Naline, E.
Right arrow Articles by Molimard, M.
Eur Respir J 2007; 29:575-581
Copyright ©ERS Journals Ltd 2007

Effect of indacaterol, a novel long-acting ß2-agonist, on isolated human bronchi

E. Naline1, A. Trifilieff2, R. A. Fairhurst2, C. Advenier1 and M. Molimard3

1 Research Unit EA220, Faculty of Medicine, Versailles University, Hospital Foch, Suresnes, and 3 Dept of Pharmacology, University Victor Segalen Bordeaux 2, Bordeaux, France. 2 Novartis Institute for BioMedical Research, Horsham, UK.

CORRESPONDENCE: M. Molimard, Département de Pharmacologie, CHU de Bordeaux, Université Victor Segalen-INSERM U657, 33076 Bordeaux cedex, France. Fax: 33 557574671. E-mail: mathieu.molimard{at}pharmaco.u-bordeaux2.fr

Keywords: Airways smooth muscle, ß2-adrenoceptor agonists, formoterol, indacaterol, isolated human bronchus, salmeterol

Received: March 7, 2006
Accepted November 21, 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Indacaterol is a novel ß2-adrenoceptor agonist in development for the once-daily treatment of asthma and chronic obstructive pulmonary disease. The present study evaluated the relaxant effect of indacaterol on isolated human bronchi obtained from lungs of patients undergoing surgery for lung carcinoma.

Potency (-logEC50), maximal relaxant effect (Emax) and onset of action were determined at resting tone. Duration of action was determined against cholinergic neural contraction induced by electrical field stimulation (EFS).

At resting tone, -logEC50 and Emax values were 8.82±0.41 and 77±5% for indacaterol, 9.84±0.22 and 94±1% for formoterol, 8.36±0.16 and 74±4% for salmeterol, and 8.43±0.22 and 84±4% for salbutamol, respectively.

In contrast to salmeterol, indacaterol did not antagonise the isoprenaline response. Indacaterol's onset of action (7.8±0.7 min) was not significantly different from that of formoterol (5.8±0.7 min) or salbutamol (11.0±4.0 min), but it was significantly faster than that of salmeterol (19.4±4.3 min). EFS-induced contractions were inhibited with -logIC50 values of 6.96±0.13 (indacaterol), 8.96±0.18 (formoterol), 7.18±0.34 (salmeterol) and 6.39±0.26 (salbutamol). Duration of action was >12 h for indacaterol and salmeterol, and 35.3±8.8 and 14.6±3.7 min for formoterol and salbutamol, respectively.

In isolated human bronchi, indacaterol behaved as a long-acting ß2-adrenoceptor agonist with high intrinsic efficacy and fast onset of action.

The introduction of long-acting inhaled ß2-adrenoceptor agonists (LABAs; salmeterol and formoterol) represented an important advance in asthma therapy. Treatment with LABAs provides better control of symptoms and lung function than short-acting ß2-agonists (SABAs) 1, 2. In fact, when combined with moderate doses of inhaled glucocorticosteroids, these drugs have been shown to improve symptoms and lung function more effectively than doubling the dose of inhaled corticosteroids 3–5. They have also been shown to reduce the number of asthma exacerbations during a 12-month treatment period, although to a lesser extent than doubling the dose of inhaled corticosteroids 4. LABAs are also used in the treatment of stable chronic obstructive pulmonary disease (COPD), according to the Global Initiative for Chronic Obstructive Lung Disease guidelines recommendations 6, 7.

The clinical efficacy and duration of action of formoterol and salmeterol appear to be very similar 8, 9. There are, however, some differences between the two compounds in terms of onset of action 10, 11 and interaction with the ß2-receptor 10, 12, 13. The ß2-receptor interaction is characterised in terms of the following factors: the ability to bind to the receptor and induce an intracellular response; potency, which is related to the amount of drug required for a physiological response; and efficacy, which is related to the drug's ability to induce a maximum physiological effect 10, 12, 13.

Indacaterol is a novel inhaled ß2-adrenoceptor agonist under clinical development for the treatment of asthma and COPD. In pre-clinical studies in guinea pigs, indacaterol demonstrated a longer duration of action and faster onset than salmeterol 14. Clinical studies have indicated that indacaterol might be used as a once-daily compound 15, which would be of great interest regarding patient convenience and compliance with treatment.

The present study aimed to evaluate the relaxant effect (potency and maximal efficacy) and the onset and duration of action of indacaterol in comparison with marketed compounds (formoterol, salbutamol and salmeterol) on isolated human bronchial rings. The interaction of indacaterol, formoterol and salmeterol with isoprenaline-induced bronchial relaxation was also studied. Since isoprenaline is a SABA, this permitted the assessment of the potential antagonism of these compounds with the use of SABA rescue medicine.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Human bronchial tissue sampling
Lung tissue was obtained from 34 patients (26 males and eight females, mean age 61.5±1.7 yrs) who were undergoing surgery for lung carcinoma. None of the patients had a history of asthma. The use of human lung tissue for in vitro experiments was approved by the local ethics committee. After the resection of one or more lung lobes, a piece of macroscopically normal tissue at a distance of ≥20 mm from the malignancy was supplied by the hospital pathologist and submerged in a physiological salt solution (PSS; Kreb's solution, composition in mM: NaCl 118, KCl 4.7, CaCl2 2.5, MgSO4 0.6, KH2PO4 1.1, NaHCO3 25.0, glucose 11.7) at 4°C. After removal of adhering lung parenchyma and connective tissue, eight to 24 rings from each bronchus were prepared (4–5 mm lengthx2–4 mm diameter) as previously described elsewhere 16. The preparations were stored overnight at 4°C in PSS equilibrated with 5% CO2 in O2 and the experiments were performed the next day. Previous experience in the laboratory and other published data have demonstrated that overnight storage of tissue does not alter its reactivity 10, 16, 17.

Experimental procedures
Tissue preparation
The total number of rings used in the present study was 411. Bronchial rings were suspended in parallel on tissue hooks in 10-mL organ baths containing PSS, gassed with 5% CO2 in O2 at 37°C (pH 7.4). Each preparation was connected to a force displacement transducer (UF1 Pioden strain gauges; EMKA Technologies, Mitry Mory, France) and isometric tension changes were recorded (I.O.X. recorder system; EMKA Technologies). The preparations were suspended under an initial load of 3 g and equilibrated for 60–90 min with changes in bath PSS every 15–20 min before any pharmacological intervention occurred. At the end of the equilibration period, the resting load was stable at 2–4 g. In all experiments, human bronchi were first contracted maximally with acetylcholine (3 mM). The tissues were then washed and equilibrated for 60 min before beginning the experimental procedure. Under these conditions, responses were optimal and reproducible according to data from the present authors’ laboratory and other studies 10, 16–18.

Potency and efficacy
A total of 110 rings obtained from 10 patients were used for the following experiments and only one concentration–response curve for one compound was recorded in each ring. Within a given set of experiments, the response for each patient was tested in duplicate. Concentration–response curves for indacaterol, formoterol, salmeterol and salbutamol were produced by cumulative addition of the compounds at intervals of 5–30 min to obtain a relaxation plateau on bronchi at resting tone and on bronchi pre-contracted with histamine (10 µM, representing 30% of 3 mM acetylcholine) or carbachol (1 µM, representing 40% of 3 mM acetylcholine). At the end of the experiment, theophylline 3 mM was added to the bath to determine the maximal relaxation.

Antagonism of isoprenaline-induced relaxation
A total of 93 rings obtained from seven patients were used for the following experiments and only one concentration–response curve for isoprenaline was recorded in each ring. Within a given set of experiments, the response for each patient was tested in duplicate. Following the resting period, bronchial rings were contracted with 1 µM carbachol. After the contraction plateau was reached, bronchial rings were incubated for 30 min with PSS (control) or with equi-effective concentrations of formoterol (10–9 M and 3x10–9 M) or indacaterol (10–7 M and 3x10–7 M), which induced ~20 and 35% inhibition of the carbachol-induced contraction. As a result of its partial agonistic activity, salmeterol (10–7 M and 3x10–7 M) did not induce >20% inhibition of the carbachol-induced contraction. Thereafter, concentration–response curves to isoprenaline in the presence of ß2-adrenoceptor agonist drugs or PSS were recorded by applying increasing concentrations of isoprenaline (10–8–10–5 M) at 8–15-min intervals. At the end of the experiment, theophylline (3 mM) was added to the bath to determine maximal relaxation.

Onset of action
A total of 32 rings obtained from four patients were used for the following experiments and only one compound and one concentration were studied in each ring. Within a given set of experiments, the response for each patient was tested in duplicate. The onset of action was measured on resting tone and was calculated as the time (min) to induce 50% of the maximal relaxation observed for the compound 10, 17. Equi-effective drug concentrations (salbutamol, salmeterol and indacaterol 3x10–8 M and formoterol 10–9 M) corresponding to 80% of the maximal relaxation observed for each compound, were used.

Electrical field stimulation
Experiments were performed as previously described elsewhere 19. A total of 176 rings obtained from 13 patients were used for the following experiments and only one compound and one concentration were studied in each ring. Each organ bath was fitted with two platinum plate electrodes (1 cm2) placed alongside the tissue (10 mm apart) for transmural electrical field stimulation (EFS; biphasic pulse width 1 ms, constant current of 320 mA for 10 s at 5 Hz). A first control response was established for all bronchi preparations by adding 3 mM acetylcholine to obtain a plateau of maximal contraction. After washing, bronchi were allowed to equilibrate for 60 min with a change of the PSS every 15 min. For the subsequent duration of the experiment, 1 µM montelukast and 1 µM indomethacin were present in the buffer to avoid the influence on the neuronal responses of indirect effects of leukotrienes and prostaglandins, respectively.

After tension had returned to the baseline tone, the preparation was stimulated every 10 min at 5 Hz, pulse width 1 ms and 320 mA current for 10 s using a stimulator (EMKA Technologies) where the voltage output was adjusted to give a constant current and biphasic rectangular pulse of alternating polarity. These contractions represent 20–50% of the maximal contraction induced by 3 mM acetylcholine. Compounds or vehicle were then added to the bath for 1 h and washed out before the beginning of a second train of stimulations every 20 min for 12 h (fig. 1Go).


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 1— Schematic representation of the protocol to measure duration of action of ß2-agonists on electrical field stimulation-induced contraction. ACh: acetylcholine; MK476: montelukast.

 
To determine the respective potency in preventing EFS-induced contraction (-logIC50), the following drugs were tested at different concentrations: indacaterol (10–8–10–5 M), formoterol (3x10–10–10–6 M), salbutamol (10–6–10–4 M) and salmeterol (10–9–10–5 M). For the measurement of the duration of action, drug concentrations that induced 50% of maximal inhibition of EFS-induced contraction were used, i.e. salbutamol 10–6 M, formoterol 10–9 M and salmeterol and indacaterol 10–7 M.

Expression and analysis of data
The maximal relaxant effect (Emax) of each ß2-adrenoceptor agonist was expressed as a percentage of the relaxation induced by 3 mM theophylline. Potency was determined by the value of concentration producing 50% of the maximal effect of a given compound (EC50). The onset of action was calculated as the time (min) from compound administration to the attainment of half its maximal relaxation.

The concentration of each ß2-adrenoceptor agonist that induced a diminution of EFS response equal to 50% of the first control response (IC50) was determined. The duration of action was then calculated as the time taken for response to 50% recovery from maximum inhibition.

A statistical significance of p<0.05 was assessed using ANOVA and a t-test for paired or unpaired data. Data are presented as mean±SEM.

Drugs
Indacaterol maleate and formoterol fumarate were synthesised by the Dept of Chemistry (Novartis Horsham Research Centre, Horsham, UK). Salmeterol xinafoate was either synthesised or isolated from clinical dosage forms by the Dept of Chemistry (Novartis Horsham Research Centre) or purchased from Tocris Cookson Ltd (Bristol, UK). Acetylcholine HCl, indomethacin, carbachol (carbamylcholine chloride), salbutamol hemisulphate, theophylline and histamine were purchased from Sigma (Saint Quentin Fallavier, France), montelukast (MK476) from Merck (Paris, France) and isoprenaline HCl from Laboratoires Winthrop (Paris, France). Salmeterol and formoterol were dissolved in distilled water in the presence of HCl and DMSO (3%). Indacaterol was dissolved in distilled water in the presence of acetic acid (2%) and ethanol (20%). Indomethacin and MK476 were dissolved in pure ethanol and then diluted in PSS. Stock solutions (1 mM) were kept at -20°C until use.


   RESULTS
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Potency and efficacy
On basal tone preparations, all compounds relaxed the bronchi with the following order of potency: formoterol > indacaterol > salbutamol ≥ salmeterol. The order of maximal efficacy was: formoterol > salbutamol > indacaterol ≥ salmeterol (table 1Go, fig. 2aGo).


View this table:
[in this window]
[in a new window]

  		Table 1— Potency(-logEC50) and intrinsic efficacy (Emax) of ß2-adrenoceptor agonists on isolated human bronchi at resting tone or after pre-contraction with 10 µM histamine or 1 µM carbachol

 

Figure 2
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 2— Effect of ß2-agonists on the isolated human bronchus a) at resting tone and on bronchi pre-contracted with b) 10 µM histamine (30% acetylcholine (ACh) maximum (max)) or c) with 1 µM carbachol (40% ACh max). Data are shown as % of theophylline-induced relaxation and are expressed as mean + SEM from three to seven patients (table 1Go). {blacksquare}: Indacaterol; {triangleup}: formoterol; •: salmeterol; {diamond}: salbutamol.

 
When compared with the effect on basal tone, the potency and efficacy of all compounds were not statistically different when histamine was used as a contractile agent (table 1Go, fig. 2bGo). Conversely, carbachol pre-contraction decreased the potency of indacaterol (p<0.01), formoterol (p<0.01) and salbutamol (p<0.01). However, a decrease in the maximal relaxant effect was only observed for formoterol (p<0.01), salmeterol (p<0.001) and salbutamol (p<0.01; table 1Go, fig. 2cGo).

Antagonism of isoprenaline-induced relaxation
On preparations pre-contracted with 1 µM carbachol and at concentrations inducing ~20 and 35% inhibition, formoterol and indacaterol did not affect the potency of isoprenaline-induced bronchi relaxation. In contrast, in the presence of salmeterol, at a concentration inhibiting the contraction by ~20%, a statistically significant decrease in isoprenaline potency was observed (table 2Go, fig. 3Go).


View this table:
[in this window]
[in a new window]

  		Table 2— Isoprenaline potency(-logEC50) in the absence or presence of ß2-adrenoceptor agonists on the isolated human bronchus

 

Figure 3
View larger version (8K):
[in this window]
[in a new window]

  		Fig. 3— Effect of ß2-agonists on the isoprenaline-induced relaxation of the isolated human bronchus. Data are shown as % of theophylline-induced relaxation and expressed as mean+SEM from five to six patients (table 2Go). {diamondsuit}: Physiological salt solution; {square}: indacaterol 10–7 M; •: indacaterol 3x10–7 M; {blacksquare}: formoterol 10–9 M; {circ}: formoterol 3x10–9 M; {blacktriangleup}: salmeterol 10–7 M; {triangledown}: salmeterol 3x10–7 M.

 
Onset of action on human bronchi at resting tone
Using concentrations that induced ~80% of the maximal relaxation at resting tone, the onset of action of indacaterol (3x10–8 M; 7.8±0.7 min, n = 4) was not significantly different from that of formoterol (10–9 M; 5.8±0.7 min, n = 4) and salbutamol (3x10–8 M; 11.0±4.0 min, n = 4) but was significantly faster than that of salmeterol (3x10–8 M; 19.4±4.3 min, n = 4; p<0.05).

Protection against cholinergic neural bronchoconstriction
EFS-induced contractions were inhibited in a concentration-dependent manner by all compounds with the following order of potency: formoterol > salmeterol > indacaterol > salbutamol (fig. 4Go, table 3Go). The duration of protection against cholinergic neural bronchoconstriction determined at doses corresponding to their respective IC50 values was >12 h for indacaterol and salmeterol, 35 min for formoterol and 15 min for salbutamol (table 3Go). At high doses, indacaterol, formoterol and salbutamol induced close to full inhibition of the EFS-induced contraction. At the highest dose tested (10–5 M), the effect of indacaterol lasted ≤12 h, whereas formoterol (10–6 M) and salbutamol (10–4 M) showed a 20% reduction of the inhibition of the cholinergic response at 5 and 1.5 h, respectively. Salmeterol (10–5 M) induced a maximal inhibition of the cholinergic response of 80%, followed by a 20% reduction of the inhibition of the cholinergic response at 4 h.


Figure 4
View larger version (32K):
[in this window]
[in a new window]

  		Fig. 4— Effect of a) indacaterol (n = 5; {blacksquare}: stimulation control; {square}: 10–8 M &cirf;: 3x10–8 M; &cir;: 10–7 M; {diamondsuit}: 3x10–7 M; {diamond}: 10–6 M; {blacktriangleup}: 3x10–6 M; {triangleup}: 10–5 M); b) formoterol (n = 7; {blacksquare}: stimulation control; {square}: 3x10–10 M; •: 10–9 M; {circ}: 3x10–9 M; {diamondsuit}: 10–8 M; {diamond}: 3x10–8 M; {blacktriangleup}: 10–7 M; {triangleup}: 3x10–7 M; {blacktriangledown}: 10–6 M); c) salbutamol (n = 3; {blacksquare}: stimulation control; {square}: 10–6 M; •: 10–5 M; {circ}: 10–4 M) and d) salmeterol (n = 6; {blacksquare}: stimulation control; {square}: 10–9 M; •: 3x10–9 M; {circ}: 10–8 M; {diamondsuit}: 3x10–8 M; {diamond}: 10–7 M; {blacktriangleup}: 3x10–7 M; {triangleup}: 10–6 M; {blacktriangledown}: 3x10–6 M; {triangledown}: 10–5 M) on electrical field stimulation (EFS)-induced contraction of isolated human bronchi. Data are shown as % of initial EFS contraction and expressed as mean + SEM.

 

View this table:
[in this window]
[in a new window]

  		Table 3— Potency(-logIC50) and duration of action determined after electrical field stimulation

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
The present study describes for the first time the pharmacological profile of indacaterol on isolated human bronchi. In the current system, indacaterol behaved as a nearly full ß2-adrenoceptor agonist that had no antagonistic effect on isoprenaline-induced relaxation. In addition, indacaterol had an onset of action similar to that of salbutamol and a duration of action of >12 h.

Under the present experimental conditions, indacaterol at resting tone or in the bronchi contracted with histamine was about 10 times less potent than formoterol but about three times more potent than salbutamol and salmeterol. When the bronchi were pre-contracted with carbachol, the compounds' potencies were moderately (1 log unit for formoterol) or strongly reduced (1.98 log units for salbutamol and 2.61 log units for indacaterol). Salmeterol's potency was not affected when compared with the resting tone condition. This decrease in potency observed in carbachol-treated bronchi could be related to the fact that carbachol induced a greater contraction when compared with histamine (40 versus 30% of the maximal effect seen with acetylcholine, respectively). However, it is difficult to believe that such a minimal difference in the strength of the contraction could explain such a dramatic effect on the potency of the compounds studied. A more likely explanation resides in a functional antagonism between the ß2-adrenoceptor and the muscarinic receptor, probably due to ß2-adrenoceptor or Gs protein phosphorylation by protein kinase C 20, 21 or to the inhibition of adenylate cyclase by the muscarinic M2 receptor-mediated Gi protein 22.

In terms of efficacy, which is related to the ability of the drugs to activate the ß2-adrenoceptor, all four drugs seem to be full agonists on preparations at resting tone. In the presence of histamine, none of the compounds had a statistically significant reduction in maximal effect. However, in the presence of carbachol, the efficacy of salbutamol and salmeterol was moderately to considerably reduced, whereas formoterol and indacaterol were marginally or not affected. This suggests that formoterol and indacaterol are nearly full agonists, whereas salbutamol and salmeterol are partial agonists, as previously demonstrated elsewhere 10, 23, 24. These differences in the intrinsic efficacy of the four drugs were confirmed by the inhibition by salmeterol in the present and other studies 10, 12, 23, and by salbutamol 10, 12, but not by formoterol and indacaterol, of the relaxation induced by isoprenaline. These results are in agreement with receptor theories suggesting that a partial agonist has to occupy more receptors than a full agonist and thereby creates a situation in which functional receptor number becomes limiting in terms of obtaining a maximal response. As a consequence, a partial agonist behaves as an antagonist in the presence of an agonist with higher efficacy acting on the same receptor.

In isolated human bronchi, indacaterol has a fast onset of action, similar to that of salbutamol and formoterol. Although this could seem to be of secondary importance for maintenance therapy, such a profile could still be of interest. Indeed, a rapid improvement in breathlessness could increase a patient's confidence in treatment and, subsequently, increase treatment compliance. Furthermore, a fast onset of action could permit the use of indacaterol as rescue medicine.

The duration of action was evaluated as the protection against cholinergic neural bronchoconstriction induced by EFS and was shown to be markedly higher for indacaterol and salmeterol when compared with formoterol and salbutamol. Although in the present system the duration of action for salmeterol is in line with its known clinical profile, the duration of action of formoterol does not reflect the clinical situation. This discrepancy has been previously reported in human bronchus 25, 26 and a number of theories have been put forward to explain this inconsistency. The most rational explanation for the observed duration of action of formoterol in males almost certainly lies within the high local concentrations achieved after inhalation and the interaction with the membrane lipid bilayer as a key component 27. The present model of EFS-induced contraction does not allow a study for >12 h. Indeed, even under control conditions, a 30–50% loss in bronchial cholinergic response was observed after 12 h of EFS. As a result, the duration of action of indacaterol could not be differentiated from that of salmeterol. However, at the highest concentration tested, indacaterol induced ~100% relaxation, with this level being maintained for ≤12 h, whereas salmeterol induced a maximal relaxation of 80% and demonstrated a loss of ~20% of this maximal effect after 4 h of stimulation. This suggests that a longer duration of action can be achieved for indacaterol when compared with salmeterol. Indeed, in clinical studies, indacaterol has demonstrated a profile compatible with once-daily dosing 15.

In conclusion, in the isolated human bronchus indacaterol efficiently prevents the occurrence of bronchial contraction, has a fast onset of action and possesses a very long duration of action. Furthermore, in contrast to salmeterol, indacaterol does not antagonise the effect of rescue medication. All these characteristics, which are promising regarding the use of indacaterol as a very long-acting ß2-adrenoceptor agonist, are now being tested in clinical studies 15.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors would like to thank G. Hébert for his help in manuscript preparation.


   REFERENCES
TOP
 ABSTRACT
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

  1. Kips JC, Pauwels RA. Long-acting inhaled ß2-agonist therapy in asthma. Am J Respir Crit Care Med 2001;164:923–932.[Free Full Text]
  2. Sears MR, Lötvall J. Past, present and future--ß2-adrenoceptor agonists in asthma management. Respir Med 2005;99:152–170.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  3. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994;344:219–224.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  4. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337:1405–1411.[Abstract/Free Full Text]
  5. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481–1488.[Abstract]
  6. Cazzola M, Dahl R. Inhaled combination therapy with long-acting ß2-agonists and corticosteroids in stable COPD. Chest 2004;126:220–237.
  7. Pauwels RA, Buist AS, Ma P, Jenkins CR, Hurd SS. GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care 2001;46:798–825.[Medline] [Order article via Infotrieve]
  8. Rabe KF, Jorres R, Nowak D, Behr N, Magnussen H. Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma. Am Rev Respir Dis 1993;147:1436–1441.[Web of Science][Medline] [Order article via Infotrieve]
  9. van Noord JA, Smeets JJ, Raaijmakers JA, Bommer AM, Maesen FP. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Eur Respir J 1996;9:1684–1688.[Abstract]
  10. Naline E, Zhang Y, Qian Y, et al. Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus. Eur Respir J 1994;7:914–920.[Abstract]
  11. Wegener T, Hedenstrom H, Melander B. Rapid onset of action of inhaled formoterol in asthmatic patients. Chest 1992;102:535–538.
  12. Molimard M, Naline E, Zhang Y, Le Gros V, Begaud B, Advenier C. Long- and short-acting ß2-adrenoceptor agonists: interactions in human contracted bronchi. Eur Respir J 1998;11:583–588.[Abstract]
  13. Hanania NA, Sharafkhaneh A, Barber R, Dickey BF. ß-agonist intrinsic efficacy: measurement and clinical significance. Am J Respir Crit Care Med 2002;165:1353–1358.[Free Full Text]
  14. Battram C, Charlton SJ, Cuenoud B, et al. In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel inhaled ß2-adrenoceptor agonist with a 24-h duration of action. J Pharmacol Exp Ther 2006;317:762–770.[Abstract/Free Full Text]
  15. Beier J, Chanez P, Martinot JB, et al.: Safety, tolerability and efficacy of indacaterol, a novel once-daily ß2-agonist, in patients with COPD: a 28-day randomised, placebo controlled clinical trial. Pulm Pharmacol Ther 2006; [Epub ahead of print PMID: 17088091]
  16. Sarria B, Naline E, Cortijo J, et al. Functional, biochemical and morphological studies on human bronchi after cryopreservation. Br J Pharmacol 1995;116:2569–2574.[Web of Science]
  17. Naline E, Qian Y, Advenier C, Raeburn D, Karlsson JA. Effects of RP 73401, a novel, potent and selective phosphodiesterase type 4 inhibitor, on contractility of human, isolated bronchial muscle. Br J Pharmacol 1996;118:1939–1944.[Web of Science]
  18. Watson N, Magnussen H, Rabe KF. The relevance of resting tension to responsiveness and inherent tone of human bronchial smooth muscle. Br J Pharmacol 1998;123:694–700.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  19. Takahashi T, Belvisi MG, Patel H, et al. Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways. Am J Respir Crit Care Med 1994;150:1640–1645.[Abstract]
  20. Van Amsterdam RG, Meurs H, Ten Berge RE, Veninga NC, Brouwer F, Zaagsma J. Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by ß-adrenoceptor agonists. Am Rev Respir Dis 1990;142:1124–1128.[Web of Science][Medline] [Order article via Infotrieve]
  21. Barnes PJ. ß-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995;152:838–860.[Web of Science][Medline] [Order article via Infotrieve]
  22. Sarria B, Naline E, Zhang Y, et al. Muscarinic M2 receptors in acetylcholine-isoproterenol functional antagonism in human isolated bronchus. Am J Physiol Lung Cell Mol Physiol 2002;283:L1125–L1132.[Abstract/Free Full Text]
  23. Linden A, Bergendal A, Ullman A, Skoogh BE, Lofdahl CG. Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: differences in maximum relaxant effect and potency but not in functional antagonism. Thorax 1993;48:547–553.[Abstract/Free Full Text]
  24. Rabe KF, Giembycz MA, Dent G, Perkins RS, Evans P, Barnes PJ. Salmeterol is a competitive antagonist at ß-adrenoceptors mediating inhibition of respiratory burst in guinea-pig eosinophils. Eur J Pharmacol 1993;231:305–308.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  25. Anderson GP, Linden A, Rabe KF. Why are long-acting ß-adrenoceptor agonists long-acting? Eur Respir J 1994;7:569–578.[Abstract]
  26. Nials AT, Coleman RA, Johnson M, Magnussen H, Rabe KF, Vardey CJ. Effects of ß-adrenoceptor agonists in human bronchial smooth muscle. Br J Pharmacol 1993;110:1112–1116.[Web of Science][Medline] [Order article via Infotrieve]
  27. Nials AT, Ball DI, Butchers PR, et al. Formoterol on airway smooth muscle and human lung mast cells: a comparison with salbutamol and salmeterol. Eur J Pharmacol 1994;251:127–135.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
R. G. Sturton, A. Trifilieff, A. G. Nicholson, and P. J. Barnes
Pharmacological Characterization of Indacaterol, a Novel Once Daily Inhaled 2 Adrenoceptor Agonist, on Small Airways in Human and Rat Precision-Cut Lung Slices
J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 270 - 275.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Permissions
Right arrowRequest Permissions
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Naline, E.
Right arrow Articles by Molimard, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Naline, E.
Right arrow Articles by Molimard, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS