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Published ahead of print on March 17, 2004, doi:10.1164/rccm.200311-1544OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 1131-1134, (2004)
© 2004 American Thoracic Society

Original Article

Effect of Montelukast and Fluticasone Propionate on Airway Mucosal Blood Flow in Asthma

Eliana S. Mendes, Michael A. Campos, Andres Hurtado and Adam Wanner

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Miami School of Medicine, Miami, Florida

Correspondence and requests for reprints should be addressed to Adam Wanner, M.D., Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine, P.O. Box 016960 (R-47), Miami, FL 33101. E-mail: awanner{at}miami.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Asthma is associated with an increase in airway blood flow (aw), presumably as a manifestation of airway inflammation. We therefore determined the effect of the antiinflammatory agents montelukast (ML) and fluticasone propionate (FP) on aw in 12 patients with mild intermittent asthma. Using a double-blind approach, aw along with FEV1 and max50 were determined before and after a 2-week treatment period with either ML (10 mg/day), FP (440 µg/day), or 10 mg of ML plus 440 µg of FP daily, separated by 2-week washout periods. Mean (± SEM) aw ranged from 68 ± 4.2 to 71.8 ± 5.9 µl · minute–1 · ml–1 anatomic dead space before the treatment periods. ML, FP, and ML plus FP decreased mean aw by 21.5, 20.8, and 26.9%, respectively (p < 0.05 for all). No significant difference was observed among the three regimens. FEV1 and max50 were not changed by any of the treatments. We conclude that at the dosages used, ML and FP are equipotent in reducing aw in patients with mild asthma, and that the magnitude of the response is not greater if the two drugs are combined. The results also suggest that the vascular effects of these agents can be assessed independent of their effects on airway function.

Key Words: airway inflammation • asthma • bronchial circulation • glucocorticosteroids • leukotriene modifiers

Inhaled glucocorticosteroids (ICS) and orally administered leukotriene modifiers are the preferred antiinflammatory agents in the treatment of asthma (1). ICS exert their effect by interfering with a variety of inflammatory pathways (2). Cysteinyl leukotrienes contribute to the clinical manifestations of asthma by participating in the inflammatory process (3, 4); because the synthesis and release of cysteinyl leukotrienes in the airways of individuals with asthma are not blocked by ICS, leukotriene modifiers are thought to have an independent antiinflammatory effect (5, 6).

Several methods have been used to assess the presence and intensity of airway inflammation in asthma and to compare the effect of antiinflammatory agents. Those methods include airway responsiveness to methacholine, analysis of exhaled nitric oxide, analysis of exhaled air condensate, analysis of cellular and soluble markers of inflammation in expectorated sputum or bronchoalveolar lavage fluid (5, 7–14), and bronchial biopsy (15–19). The results of those assessments have been inconsistent, including in studies in which ICS and leukotriene modifiers were compared (7–10).

Because tissue inflammation is associated with new vessel formation and local vasodilation, which in turn leads to vascular hyperperfusion (20, 21), we reasoned that the measurement of airway blood flow (aw) could be used as an index of the severity of airway inflammation and of the antiinflammatory effectiveness of ICS and leukotriene modifiers.

In the present study, we therefore determined the effects of the ICS fluticasone propionate (FP) and the leukotriene modifier montelukast (ML) as single agents and in combination on aw in patients with asthma. The rationale for evaluating the combined therapy was given by the previously reported observations that, although the addition of ML to an ICS provides improved disease control in patients with chronic asthma (8, 22), other outcomes such as airway function and markers of airway inflammation may not benefit from combination therapy (12).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Test Subjects
Twelve nonsmokers with mild intermittent asthma as defined by the Global Initiative for Asthma participated in the study (1). The subjects were between 18 and 65 years of age. At study entry, all subjects were clinically stable; had an FEV1 exceeding 70% of the predicted value; had not used inhaled or systemic glucocorticoids, ML, methylxanthines, or other controller medication for at least 2 weeks; and had only occasional daytime symptoms and no nocturnal awakenings. Subjects taking cardiovascular medications were excluded. Women of childbearing potential were excluded unless they used appropriate forms of birth control as discussed with the physician responsible for the study. All subjects denied having experienced an acute respiratory infection for more than 1 month before the study and no subject developed an acute respiratory infection during the study.

The University of Miami Institutional Review Board approved the study protocol. All subjects provided written informed consent and received financial remuneration for their participation.

Spirometry
The FEV1, FVC, FEV1/FVC, and maximum expiratory flow at 50% of FVC (max50) were determined with a Spirovit SP10 spirometer (Welch-Allyn, Skaneateles Falls, NY). The tracing with the highest FVC of three maneuvers was analyzed. Predicted normal values were taken from Crapo and coworkers (23). The values were expressed as absolute values and as percentages of predicted values.

Airway Blood Flow
A previously validated soluble inert gas uptake method was used to measure aw (24, 25). The subjects first inhaled room air to total lung capacity position. After exhaling 500 ml, they rapidly inhaled the same volume of a gas mixture from a Teflon bag, consisting of 10% dimethyl ether (DME), 5% helium, and balance oxygen. After a predetermined breath-hold time, the subjects then exhaled into a spirometer through a critical flow orifice to standardize expiratory flow. During exhalation, instantaneous concentrations of DME, nitrogen, and helium were measured at the airway opening with a mass spectrometer (Perkin-Elmer, Pomona, CA, USA) along with the expired gas volume. The maneuver was performed with two breath-hold times each of 5, 10, 15, and 20 seconds in random order.

The helium-corrected decrease in DME concentration over time was obtained by least-squares fit, using the two measurements per gas for each of the four breath-hold times. This was done in the expired volume fraction corresponding to the anatomic dead space minus the most proximal 50 ml, which was designated DS. Anatomic dead space (VD) was determined from the expired nitrogen concentration curve as described by Fowler and coworkers (26). From the helium-corrected DME slope multiplied by the DS (DME), the mean DME concentration in the DS (FDME), and the solubility coefficient for DME in blood and tissue ({alpha}),aw was calculated using Fick's principle (aw = DME/{alpha} · FDME). aw was normalized for VD and expressed as microliters per minute per milliliter. Five to 8 minutes were required for one aw determination. At the time of each aw measurement, systemic blood pressure and pulse were also determined.

Protocol
The subjects were instructed to abstain from ingesting alcoholic beverages the night before the study and coffee or caffeinated drinks before the study. For each subject, the experiment was started at the same time on the various study days. The first measurement of aw and spirometry were performed at least 12 hours after the last inhalation of on-demand ß-agonist aerosol or protocol antiinflammatory medication to avoid the acute effects of ß-adrenergic agonists and ICS on aw (21, 25, 27).

A double-blind study protocol was used. Each subject had four 2-week treatment periods separated by three 2-week washout periods (total study duration, 14 weeks). The four treatment periods were FP via metered dose inhaler (220 µg twice daily via spacer) plus a 10-mg ML tablet once a day, FP via metered dose inhaler plus placebo tablet, placebo via metered dose inhaler plus ML tablet, and placebo via metered dose inhaler plus placebo tablet. Treatments were administered in random order. The subjects as well as the investigators were blinded to the treatment assignments. Measurements of aw and spirometry were performed before each of the seven periods (four treatment and three washout) and at the end of the seventh period.

Statistical Analysis
Data were analyzed using JMP for Macintosh, version 4.0 (SAS Institute, Cary, NC). Multifactorial analysis of variance was used to determine overall differences among treatments followed by a paired t test to identify specific pair differences. Significance was accepted when the p value was less than 0.05. Values are presented as means ± SEM.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic and baseline physiologic data on the study population are shown in Table 1 . Baseline mean aw, FEV1, max50, and VD values were not different before each of the four treatment periods (Table 2 and Figure 1) . As compared with the respective baseline values, FP decreased mean aw by 20.8% (p < 0.05), whereas ML decreased aw by 21.5% (p < 0.05). The combination of FP plus ML decreased mean aw by 26.9% from baseline (p < 0.05) (Figure 2) . Although the change tended to be greater after FP plus ML, there were no significant differences among the mean changes in aw after the three treatment regimens. Mean FEV1 and max50 tended to increase after the three active treatment periods, but this did not reach statistical significance (Table 2).


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  		TABLE 1. Demographics and baseline physiological data

 

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  		TABLE 2. Effect of fluticasone propionate and montelukast on airway blood flow, fev1, maximum expiratory flow at 50% of fvc, and anatomic dead space

 


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  		Figure 1. aw before (solid columns) and after (gray columns) the 4 treatment periods in 12 subjects with asthma. FP = fluticasone; ML = montelukast. Data represent means ± SEM. *p < 0.05 versus pretreatment value.

 


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  		Figure 2. Change in aw after the four treatment periods in 12 subjects with asthma. Data are expressed as {Delta}aw (percent change from pretreatment baseline). Data represent means ± SEM. *p < 0.05 versus placebo.

 
There was no correlation between changes in aw and FEV1 or max50.

Mean VD, systolic and diastolic blood pressure, and pulse rate remained stable before and after all treatments (Table 2). At some point during the study 3 of the 12 subjects complained of headaches or sleepiness, but after unblinding the treatment assignments no association with any specific therapy or placebo administration could be found.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study showed that a 2-week treatment with either FP or ML at clinically recommended doses causes a decrease in aw and that the decrease in aw is similar for both agents. The combination of the two agents tended to have a greater effect on aw; however, this did not reach statistical significance. The effect of the agents on aw was time limited, as aw returned to baseline levels 2 weeks after discontinuing the treatments. On the basis of pharmacologic considerations, it is likely that the responses to FP and ML reflected class effects rather than molecule-specific actions. It would have been preferable to enroll patients with mild persistent or moderate asthma in the study, as they are likely candidates for antiinflammatory controller therapy. However, to avoid a potentially confounding effect of fluctuating airway caliber on aw and because of the need to study glucocorticosteroid-naive subjects, we selected subjects with mild-intermittent asthma.

The FP-induced decrease in aw in the present study is consistent with the results of a previous study in which we showed that a 2-week course of FP (440 µg daily) caused a decrease in aw in glucocorticosteroid-naive subjects with asthma, with a return of aw to the pretreatment level 2 weeks after cessation of fluticasone treatment (21). That observation and the fact that all pretreatment aw values were similar in the present study strongly argue against a carryover vascular effect of the drugs due to an insufficient washout period. The magnitudes of the responses were similar in the two investigations. To our knowledge, airway vascular effects of leukotriene modifiers have not been previously examined in humans.

Our previous studies showed that aw was 30–40% higher in patients with mild asthma than in healthy control subjects; the absolute values in the patients with asthma were similar to those in the present investigation. The posttreatment aw was still above the previously reported range for healthy subjects (21, 25). Possibly, a longer treatment period and/or higher drug dose would have had a greater effect on aw.

It cannot be determined from our findings whether the FP- and ML-induced changes in aw reflected a general effect on airway inflammation or a selective effect on the vascular component of the inflammatory process. In the former case, the drugs would reduce the intensity of inflammation and secondarily the effects of inflammatory vasoactive factors on the airway circulation. In the latter case, the airway vasculature would be the primary target of the drugs, and they would not affect other aspects of tissue inflammation. We believe that the changes in aw in our study were the expression of the drugs' general antiinflammatory actions in the airway for several reasons. First, two antiinflammatory agents with different modes of action had similar effects on aw, suggesting that aw is a nonspecific index of inflammation. Second, a previous morphologic investigation of the effect of ICS on airway remodeling in asthma showed a correlation between the ICS-induced decrease in eosinophilia and reversal of hypervascularity in the airway wall (20). Third, although ICS can cause transient vasoconstriction in the airway directly though a nongenomic mechanism, this vascular response peaks at 30–60 minutes and wanes by 90 minutes after drug inhalation (25, 27–29). Because we measured aw at least 12 hours after the last FP dose, acute ICS-induced vasoconstriction could not have been present in the present study. Finally, experiments in pigs have shown that cysteinyl leukotrienes constrict bronchial arteries, and that this vasoconstriction is blocked by a cysteinyl leukotriene receptor antagonist (30). If ML had a direct effect on the airway circulation in our study, an increase in aw would have been expected after its administration. Yet, we found an opposite effect, suggesting that the drug interfered with inflammatory pathways and did not directly reduce airway vascular tone.

The FP- and ML-induced decreases in aw could have resulted from a reversal of inflammatory vasodilation or inflammatory angiogenesis, or both. Histamine, prostaglandins E1 and E2, platelet-activating factor, and bradykinin, mediators involved in the pathogenesis of asthma, are vasodilators (13, 31). Their effects on aw could be reduced as FP and ML reduce the intensity of the inflammatory process in the airway tissue. Asthma is also associated with vascular remodeling in the airway wall with an increased number and volume of small blood vessels (32); the drugs could have decreased aw by reversing this process. This has indeed been reported with the administration of high-dose ICS for 6 weeks in patients with asthma (20). Low-dose ICS may not be effective (16, 33). The fact that FP and ML had a significant effect on aw within 2 weeks and that the effect waned 2 weeks after cessation of therapy seems to be more consistent with reversal of inflammatory vasodilation than inflammatory new vessel formation. However, structure–function studies would be required to support this notion.

Previous investigations have suggested that airway function is not a good parameter on which to evaluate the antiinflammatory actions of pharmacologic agents in asthma (5). The results of our study are in keeping with that position. Neither FP nor ML, nor the combination of the two drugs, had a significant effect on FEV1 or max50, although there was a tendency toward improved airway function after drug treatment. Treatment for longer periods of time may well have disclosed improvements in airway function as reflected by FEV1 and airway responsiveness, with additive effect of combined therapy (18, 22). With the short treatment protocol used in the present investigation we were able to demonstrate that the antiinflammatory actions of ICS and leukotriene modifiers can be dissociated from their effects on airway function. This may not have been possible after a longer treatment period.

In conclusion, our study demonstrated that (1) a 2-week course of FP, ML, or FP plus ML decreases aw in patients with mild asthma; (2) the magnitude of the response is not significantly greater with the combination of the two drugs; and (3) the effect of all three regimens is no longer present after a 2-week washout period. We suggest that aw is an index of airway inflammation in asthma.


   FOOTNOTES
 
Supported by an academic research grant from Merck and Company.

Conflict of Interest Statement: E.S.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.W. has received an academic research grant from GSK in 2003.

Received in original form November 12, 2003; accepted in final form March 13, 2004


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 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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