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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Short-acting 
2-agonists provide greater protection to bronchoconstriction induced by adenosine-5'-monophosphate (AMP) than does methacholine. Because AMP produces bronchoconstriction through release of mediators from mast cells, and methacholine directly constricts airway smooth muscle, this
suggests that 2-agonists stabilize mast cells in vivo. This in vivo property has not been demonstrated
with long-acting 2-agonists. We undertook two double-blind, randomized, crossover, placebo-controlled studies to investigate the effects of salmeterol and albuterol on airway responsiveness (AR) to
AMP and histamine in patients with mild asthma. In the first study, 19 patients attended on four occasions to inhale salmeterol 50 µg or placebo 2 h before challenge with AMP or histamine. In the second study 16 patients (13 of whom had participated in the first study) were studied in a similar fashion but inhaled albuterol 400 µg or placebo 30 min prior to challenge. Salmeterol reduced AR to AMP
and histamine by 3.4 ± 0.3 and 3.9 ± 0.3 doubling doses, respectively (NS). In contrast, albuterol
demonstrated a greater protective effect on AMP than on histamine, reducing AR by 5.1 ± 0.3 and
3.8 ± 0.2 doubling doses, respectively (p < 0.005). Thus, in contrast to albuterol, salmeterol did not
demonstrate mast-cell stabilizing properties in vivo at a time corresponding to maximal bronchodilatation. These findings might be explained by the unique pharmacologic profile of salmeterol in combination with the differential 2-adrenoceptor pharmacology of bronchial mast cells and bronchial
smooth muscle.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Inhaled 2-agonists are the most effective bronchodilators available for the relief of asthma symptoms (1). In addition to their
bronchodilator properties 2-agonists also protect against a
variety of direct and indirect bronchoconstrictor stimuli (2). We and others have demonstrated previously that short-acting
2-agonists provide greater protection to the indirect stimulus
adenosine-5'-monophosphate (AMP) than to the direct smooth
muscle stimuli methacholine and histamine in patients with mild
asthma (5, 6), although this has not been confirmed in a recent
study (7). Because AMP stimulates the release of histamine
and other preformed spasmogenic mediators from mast cells (8,
9), this property of short-acting 2-agonists has been attributed to mast cell stabilization. Furthermore, in one study (5),
regular terbutaline produced greater tachyphylaxis to the protective effect of terbutaline to AMP than to methacholine, which suggested a preferential down-regulation of 2-receptors on mast cells rather than on smooth muscle. This property
is particularly relevant for the long-acting 2-agonists, which
are more potent, provide sustained bronchodilatation, and are
prescribed on a regular basis.
Salmeterol is a long-acting 2-agonist that maintains bronchodilatation for as long as 12 h (10). Although the mast-cell stabilizing properties of salmeterol have been demonstrated in vitro (11, 12), these have not been confirmed in vivo (13). In
patients with mild asthma, salmeterol provides equal protection to AMP and histamine 14 h after a single 50-µg inhalation
(13), suggesting that at this time point it acts through functional antagonism of airway smooth muscle rather than mast-cell stabilization. Although in this study the power to detect a
difference in bronchoprotection was low, it is possible that
mast-cell stabilization was not apparent 14 h after inhalation
and occurred at an earlier time point during the action of the
drug.
To investigate this further we undertook a similar study to determine the mast-cell stabilizing properties of salmeterol in patients with mild asthma 2 h after a single inhalation. In keeping with our observations of terbutaline (5), we hypothesized that salmeterol would provide greater protection to the mast-cell stimulus AMP than to the direct stimulus histamine. As a direct comparison we also studied a second group of patients who performed the same experimental protocol but inhaled albuterol 30 min prior to challenge with either AMP or histamine.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Twenty-three nonsmoking patients 21 to 39 yr of age (13 male, 10 female) (Table 1) took part in the study. All patients had mild asthma
with FEV1 greater than 70% of predicted, demonstrated a positive skin
test in response to common airborne allergens (Dermatophagoides
pteronyssinus, mixed grass pollen, or cat fur), and documented sensitivity to histamine or methacholine (geometric PC20 
1 mg/ml) and
AMP (geometric PC20 20 mg/ml) during the previous 6 mo. None
had an exacerbation of asthma or a respiratory tract infection during
the preceding 6 wk. Patients were steroid naïve and received no regular medications for their asthma apart from treating occasional symptoms with intermittent short-acting 2-agonists. Written informed consent was obtained from each patient, and the study was approved by
the Ethics Committee of the Royal Brompton Hospital.
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Patients were studied in two groups: Nineteen patients took part in the salmeterol study and sixteen patients took part in the albuterol study (Table 2). Thirteen patients took part in both studies.
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Study Protocol
Each study had a randomized, double-blind, placebo-controlled, crossover design and consisted of four visits. Patients refrained from using rescue medication and caffeinated beverages for at least 12 h prior to each visit, and they attended the laboratory at the same time in the morning. Salmeterol 50 µg, albuterol 400 µg, and matched placebo were administered as a dry powder through a Diskhaler.
Salmeterol Study
After baseline lung function measurements, which were performed by an independent observer who took no further part in the study, patients inhaled salmeterol 50 µg or placebo 2 h before challenge with either AMP or histamine. The sequence of challenges was randomized in balanced order such that one challenge agent was administered on the first two visits and the other on the second two visits. A minimum washout period of 72 h separated each visit.
Albuterol Study
This was undertaken in exactly the same manner as the salmeterol study, except patients inhaled albuterol 400 µg or placebo 30 min before challenge. A minimum washout period of 48 h separated each visit and 72 h each study for those patients participating in both.
Histamine and AMP Challenges
Fresh solutions of histamine and AMP (Sigma, Poole, UK) were made up in 0.9% saline in a range of concentrations from 0.0625 to 32 mg/ml for histamine and from 0.39 to 800 mg/ml for AMP. Each solution was administered from a nebulizer attached to a breath-activated dosimeter (Mefar, Brescia, Italy). The nebulizer delivers particles with an aerodynamic mass median diameter of 3.5 to 4.0 µm at an output of 9 µl per breath.
Pulmonary function was assessed by measurement of FEV1 with a dry wedge spirometer (Vitalograph, Buckingham, UK). A standard challenge protocol was used for all provocation tests. Three measurements of FEV1 were taken at 1-min intervals, the best of which was taken as the baseline. The patients then inhaled a series of five breaths of saline as control, followed by a series of five breaths of doubling concentrations of histamine or AMP at 3-min intervals (i.e., during each sequential inhalation, the concentration of histamine or AMP administered was doubled). FEV1 was measured 90 and 150 s after each inhalation, and the highest value was recorded for analysis. The challenges were terminated when a 20% decrease in FEV1 from the postsaline value was recorded. A log dose-response curve was constructed for each agonist, and the concentration producing a 20% fall in FEV1 (PC20) was calculated by linear interpolation. For those patients who did not demonstrate a 20% decrease in FEV1 after inhalation of the last concentration of either solution, the log PC20 was taken as the highest concentration (1.51 for histamine, 2.90 for AMP) and included in the analysis as censored data.
Analysis of Data
All results were expressed as mean ± standard error of the mean (SEM) unless otherwise stated. PC20 values were log-transformed for analysis, and the geometric means were calculated. The protective effect of salmeterol and albuterol on responses to provocation of each challenge was calculated by comparing the difference in PC20 after inhaling the respective active treatment and placebo in each subject. This effect was expressed in terms of doubling doses using the formula:
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Dose-response curves were constructed for each spasmogen after treatment in both study groups. The FEV1 values obtained after inhaling the final four concentrations of spasmogen during each challenge were calculated as a percentage of the postsaline value and compared by multifactorial analysis of variance (ANOVA). Serial measurements within groups (baseline FEV1, change from baseline FEV1 after treatment) were analyzed by repeated-measures ANOVA, followed by pairwise comparisons using the Bonferroni t test (14). Paired data within groups (log PC20 values, doubling dose changes in log PC20) and unpaired data between groups (screening data, doubling dose changes in log PC20) were compared using the appropriate two-tailed t test. Statistical significance was taken as p < 0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline screening parameters did not differ significantly between the salmeterol study group and the albuterol study group (Tables 1 and 2), and baseline FEV1 on the four study visits did not significantly differ. Five patients did not achieve a 20% fall in FEV1 after inhalation of the last concentration of spasmogen: three to AMP after albuterol, and two to histamine after salmeterol (Table 3).
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Salmeterol Study
Two hours after inhalation, salmeterol increased FEV1 by 11 ± 2.6% prior to histamine challenge (p < 0.01 versus placebo, 2.2 ± 1.1%) and 13.8 ± 2.7% prior to AMP challenge (p < 0.001 versus placebo, 2.1 ± 1.7%) (Table 4). The log PC20 for
histamine after placebo was 
0.40 ± 0.09 (geometric mean,
0.40 mg/ml), increasing to 0.79 ± 0.10 (geometric mean, 6.19 mg/ml) after salmeterol (p < 0.0001) (Table 3). The log PC20
for AMP after placebo was 0.73 ± 0.10 (geometric mean, 5.4 mg/ml), increasing to 1.75 ± 0.16 (geometric mean, 55.7 mg/ml)
after salmeterol (p < 0.0001) (Table 3). The protective effect
of salmeterol, 3.9 ± 0.3 and 3.4 ± 0.3 doubling doses for histamine and AMP, respectively, did not differ significantly (Figure 1).
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p < 0.001 versus salmeterol/AMP change in PC20.
The dose-response curves to histamine and AMP were similar in shape after placebo and were not significantly altered by salmeterol (Table 5 and Figure 2).
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Albuterol Study
Thirty minutes after inhalation, albuterol increased FEV1 by
11.0 ± 2.6% prior to histamine challenge (p < 0.005 versus
placebo, 1.6 ± 1.2%) and 16.4 ± 2.3% prior to AMP challenge
(p < 0.0001 versus placebo, 0.3 ± 1.5%) (Table 4). The log PC20
for histamine after placebo was 0.24 ± 0.10 geometric mean,
0.58 mg/ml), increasing to 0.91 ± 0.11 (geometric mean, 8.21 mg/ml) after albuterol (p < 0.0001) (Table 3). The log PC20 for
AMP after placebo was 0.69 ± 0.13 (geometric mean, 4.90 mg/ml), increasing to 2.22 ± 0.17 (geometric mean, 164.60 mg/ml) after albuterol (p < 0.0001) (Table 3). Thus the protective effect of albuterol was 3.8 ± 0.2 and 5.1 ± 0.3 doubling
doses for histamine and AMP, respectively (Figure 1). This
protection against AMP was significantly greater than the corresponding protection against histamine (p < 0.005). Furthermore in comparing the two study groups, although the protection afforded by albuterol and salmeterol against histamine
did not differ, the protective effect of albuterol against AMP
was significantly greater than that of salmeterol (5.1 ± 0.3 versus 3.4 ± 0.3 doubling doses, respectively, p < 0.001).
The dose-response curves to histamine and AMP were similar in shape after placebo and were not significantly altered by albuterol (Table 5 and Figure 2).
Patients Who Participated in Both Studies
In the 13 patients who participated in both studies the log PC20
for histamine after placebo in the salmeterol study was 0.33 ± 0.12 (geometric mean, 0.45 mg/ml), increasing to 0.89 ± 0.11 (geometric mean, 7.76 mg/ml) after salmeterol, a protective effect of 4.1 ± 0.3 doubling doses (p < 0.0001). The log PC20 for
AMP after placebo was 0.77 ± 0.12 (geometric mean, 5.90 mg/ml), increasing to 1.82 ± 0.19 (geometric mean, 66.80 mg/ml)
after salmeterol, a protective effect of 3.5 ± 0.4 doubling doses
(p < 0.0001). In the albuterol study, the log PC20 for histamine
after placebo was 0.27 ± 0.10 (geometric mean, 0.54 mg/ml),
increasing to 0.85 ± 0.12 (geometric mean, 7.09 mg/ml) after
albuterol, a protective effect of 3.7 ± 0.2 doubling doses (p < 0.0001). The log PC20 for AMP after placebo was 0.64 ± 0.16 (geometric mean, 4.39 mg/ml), increasing to 2.10 ± 0.20 (geometric mean, 124.6 mg/ml) after albuterol, a protective effect of 4.8 ± 0.4 doubling doses (p < 0.0001). This protection
of albuterol against AMP was significantly greater than the corresponding protection against histamine (p < 0.05), and the
protective effect of albuterol against AMP was significantly
greater than that of salmeterol (p < 0.05).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The results of this study have demonstrated that a single inhaled dose of salmeterol reduced airway responsiveness to histamine and AMP to the same extent (by 3.9 and 3.4 doubling doses, respectively) 2 h after administration. In contrast, 30 min after inhalation, a single dose of albuterol reduced airway responsiveness to histamine by 3.8 doubling doses, but it caused a significantly greater reduction in airway responsiveness to AMP (by 5.1 doubling doses). It is theoretically possible that these differences may have resulted from bias introduced through different patient characteristics between the two groups. We attempted to control for this by recruiting patients with similar entry characteristics, and indeed the results of the 13 patients who participated in both studies were similar to those of the overall study.
Thus this effect of albuterol confirms our previous findings with terbutaline (5) and suggests that the greater protection afforded by albuterol to AMP reflects mast-cell stabilization. For salmeterol, however, which did not provide greater protection to AMP 2 h after inhalation, this suggests that at this time point salmeterol does not have mast-cell stabilizing properties. Taken in combination with the lack of salmeterol to provide greater protection to AMP over histamine 14 h after a single inhalation (13), it is likely this compound does not have important mast-cell stabilizing properties throughout its course of action in vivo.
We chose to perform bronchial challenges 2 h after salmeterol inhalation for two reasons. First, salmeterol produces
maximal bronchodilatation between 2 and 4 h after inhalation
(10). As terbutaline, and as we have now shown albuterol, exert
mast-cell stabilizing properties in vivo at a time corresponding
to maximal bronchodilatation, we felt that if salmeterol were
also to exhibit mast-cell stabilizing properties, in keeping with
short-acting 2-agonists, this would be apparent at maximal
bronchodilatation. Although we do not know whether maximal bronchodilatation was achieved by albuterol and salmeterol in our study, significant and comparable increases in
FEV1 were achieved prior to challenge. Secondly, Soler and
colleagues (13) suggested that the lack of any mast-cell stabilizing properties of salmeterol 14 h after inhalation may have
reflected mast-cell 2-adrenoceptor down-regulation, which
had occurred within hours of salmeterol inhalation. As salmeterol provides continual mast-cell 2-adrenoceptor stimulation
for at least 20 hours (11), it is possible that receptor down-regulation or desensitization could occur within this time period.
We felt that if rapid 2-adrenoceptor down-regulation was to
occur because of continual receptor stimulation it would be
unlikely to occur within 2 h.
We included in the analysis censored data on the five patients in whom we were unable to measure a PC20 after active treatment because of profound bronchoprotection (three with AMP after albuterol and two with histamine after salmeterol). The effect of this was to underestimate the bronchoprotective effects of albuterol on AMP, and salmeterol on histamine, which would otherwise only have enhanced the significance of our results. Although there was a clear statistical difference between both drugs in terms of doubling dose protection against AMP, it is likely that censored data accounted for the smaller difference observed between the mean PC20 to AMP after salmeterol and albuterol (p = 0.05).
Interpretation of the results of our study are dependent upon
a similar dose-response relationship between the two spasmogens, such that a unit shift in the dose-response curve to
one stimulus is equivalent to the same unit shift to another
stimulus. We compared the shape of the dose-response curves
of each spasmogen and found there to be no difference after
active and placebo treatment. Thus both salmeterol and albuterol shifted the dose-response curves to AMP and histamine in a parallel manner to placebo, which confirms a greater
unit shift in response to AMP than histamine. As the end
point of our study was the PC20 variable, we did not measure the slope of the dose-response curve as there were insufficient data points to calculate the true slope of the curve prior to the
maximal response plateau. Although we did not observe any steepening of the dose-response curve to either spasmogen in
response to salmeterol or albuterol over the concentrations required to produce a 20% fall in FEV1, it is possible this could
have become apparent with greater degrees of bronchoconstriction, a phenomenon observed with direct spasmogens after single dose and regular treatment with short and long-acting 2-agonists (15, 16). It is not known whether this occurs
with indirect spasmogens such as AMP.
Given the in vitro evidence of the mast-cell stabilizing properties of both salmeterol (11, 12) and albuterol (17), the differential effect of these agents to protect against direct and indirect challenges was unexpected. If salmeterol had mast-cell stabilizing properties in vivo we would have anticipated greater protection to the indirect stimulus AMP than the direct stimulus histamine. We cannot explain these findings by differences in lung deposition of each drug as the same inhaler device was used in both studies. Furthermore our observations do not reflect differences in the dosage of albuterol and salmeterol as both drugs increased FEV1 to the same extent prior to challenge and had a similar protective effect against histamine (3.9 to 3.8 doubling doses for salmeterol and albuterol, respectively). However, as these patients were only mildly asthmatic with near normal lung function, it is possible that equipotency in terms of bronchodilatation may not be appropriate as these doses might be close to the plateau of maximal improvement in FEV1. Furthermore, it could be argued that both salmeterol 50 µg and albuterol 400 µg are not equivalent in their bronchoprotective effect against histamine and that the observed equivalence in our study reflects supramaximal bronchoprotection by both agonists against this spasmogen. Data available on the dose-response relationship between these agonists and their bronchoprotective effect against histamine suggest that although albuterol 400 µg may be near the plateau of this dose-response curve (18), higher doses of salmeterol are able to exert additional bronchoprotection (19, 20). Thus, it is likely that salmeterol 50 µg and albuterol 400 µg do exert equivalent bronchoprotection against histamine, and therefore the observed differences in airway responsiveness to AMP after each agonist reflect true differences in pharmacologic activity rather than any difference in dose effect between the two drugs.
Salmeterol's apparent lack of in vivo mast-cell stabilizing
properties might be explained by its unique pharmacologic
profile, in combination with the differential 2-adrenoceptor
pharmacology of bronchial mast cells and bronchial smooth
muscle. Structurally, salmeterol contains a long lipophilic side
chain, which may bind within the ligand binding cleft of the 2-adrenoceptor (21). This high affinity binding may anchor the
molecule within the binding cleft, allowing persistent 2-adrenoceptor stimulation, and account for the prolonged duration of
action of salmeterol. With persistent stimulation, it is possible
that 2-adrenoceptor desensitization could occur after a single
dose of salmeterol. Indeed, desensitization of 2-agonist inhibition of histamine release from human lung mast cells in vitro
occurs within 4 h of continuous isoproterenol stimulation (22).
Furthermore, functional desensitization of 2-adrenoceptors
on peripheral blood lymphocytes has been demonstrated to
occur within 3 h in vivo (23) and 1 h in vitro (24).
It is apparent, therefore, that 2-adrenoceptor desensitization can develop rapidly with persistent stimulation. However, this does not appear to be the case for all 2-agonist effects since desensitization occurs more readily for systemic responses than bronchodilatation (25), suggesting that 2-adrenoceptor pharmacology in different tissues are differentially regulated after persistent 2-agonist stimulation (23). Furthermore, tissue differences in 2-adrenoceptor pharmacology may also explain the observation that the onset of action of salmeterol to
inhibit histamine release from human lung mast cells is rapid
(< 1 min) whereas its onset of action on airways smooth muscle is relatively slow (> 30 min) (11).
Thus, tissue difference in 2-adrenoceptor pharmacology
and the persistent receptor stimulation of salmeterol may explain the observations of our study. We propose that after inhalation salmeterol binds and induces rapid 2-adrenoceptor
stimulation on bronchial mast cells. Within 2 h it is possible that
some degree of receptor desensitization has occurred, thus reducing its mast-cell stabilizing properties. As the onset of action of salmeterol on smooth muscle 2-adrenoceptors is slower
(11), significant desensitization has not occurred within 2 h of
inhalation. Furthermore, this phenomenon is not apparent 30 min after albuterol inhalation as this time period is not long
enough for receptor desensitization to occur on either smooth
muscle or mast cells. One might predict that with continued
exposure to salmeterol greater 2-adrenoceptor desensitization
might occur. It is interesting, therefore, to observe that in the
study by Soler and colleagues (13), although not statistically
significant, bronchoprotection afforded by salmeterol 14 h after inhalation was greater to histamine than to AMP, which may indicate further receptor desensitization at this time
point.
In addition to histamine release, AMP also induces the release of other spasmogenic mediators from mast cells. Leukotrienes may be important in this respect (9), and it is possible
that albuterol may inhibit the release of leukotrienes to a
greater extent than salmeterol. This is unlikely, as although
2-agonists inhibit leukotriene production in vitro (11, 17, 26),
both albuterol and salmeterol have been shown not to attenuate the rise in urinary LTD4 excretion after allergen challenge,
a potent mast-cell stimulus, in asthmatic patients at equivalent
doses used in this study (27).
It has been suggested that the reason tachyphylaxis to bronchoprotection develops more readily than tachyphylaxis to bronchoconstriction in asthmatic patients after regular salmeterol
treatment (28, 29) may reflect down-regulation of 2-adrenoceptors on mast cells and other inflammatory cells (29). It has
further been suggested that this may also reflect differences in
2-adrenoceptor pharmacology between the bronchodilating
activity and smooth muscle functional antagonism of salmeterol (28). Despite these suggestions, the mechanisms by which
2-agonists produce bronchoprotection remain poorly understood. The results of this study support these comments and
suggest that salmeterol preferentially and rapidly desensitizes
2-adrenoceptors on mast cells and other nonbronchial smooth
muscle receptors lessening the bronchoprotective properties with repeated use. Furthermore, our hypothesis would suggest
this phenomenon occurs even after a single dose of salmeterol,
and it is interesting, therefore, to note that in asthmatic patients the loss of bronchoprotection by salmeterol to methacholine occurs after two doses (30).
It is possible that the partial agonist nature of salmeterol is
also relevant. In guinea-pig eosinophils the full agonist, formoterol, inhibits the release of mediators, whereas salmeterol is ineffective and even blocks the action of formoterol (31). This may reflect a low receptor reserve in eosinophils. It will, therefore, be important to investigate the bronchoprotective
properties of other long-acting 2-agonists, and in particular
formoterol, which in addition to its full agonist properties does
not anchor to the ligand binding cleft of the 2-adrenoceptor
(32).
The bronchoprotective properties of salmeterol at earlier
time points, and albuterol at later time points after inhalation should also be investigated. This will provide insight into the potential for rapid 2-adrenoceptor desensitization induced by these agents. The clinical importance of this and the findings of our study remain to be determined, but it has been suggested that salmeterol may have anti-inflammatory properties
(33) and that this in part is due to mast-cell stabilization (11).
Our data suggest that this is unlikely to be a clinically important property of salmeterol.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Professor P. J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.
(Received in original form March 12, 1997 and in revised form July 17, 1997).
Acknowledgments: Supported by a grant from the Imperial College School of Medicine.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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