- Email: [email protected]
Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma
Vol. 97 (2003) 667^ 671
E¡ect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma A. HASANI*, N.TOMS, J.O’CONNOR, J. P. DILWORTH AND J. E. AGNEW Departments of Thoracic Medicine and Medical Physics, Royal Free and University College Medical School, London, NW3 2QG, UK Abstract Lung mucociliary clearance isimpaired in stable asthma.The long-acting b2-agonist salmeterol has been shown in vitro to cause a significant increase in ciliary beat frequency.It seemed possible therefore that salmeterol may also have a favourable effect on lung mucociliary transport in asthmatic patients. Fourteen patients with asthma participated in a doubleblind, placebo-controlled, crossover study to assess the effect of 2 weeks of treatment with salmeterol MDI (50 mg b.d.) onlung mucociliaryclearance.The11patients who completed the study (seven males, four females) had a mean 7 SE age of 5074 years, % predicted FEV1 of 7478 % and a tobacco consumption history of 1377 pack-years (seven non-smokers, four exsmokers). Lung mucociliary transport was measured by a radioaerosol technique. Pulmonary function indices (FEV1, FVC, and PEF) were significantly improved on salmeterol relative to placebo.The main radioaerosol finding was a significantincrease inthe penetration of radioaerosolinto the lung with 24-h radioaerosolrising from 4075% on placebo to 4974% (Po0.01) on salmeterol. Despite this increased penetration, a slight favourable change occurred in tracheobronchial aerosol clearance.This study demonstrates that 2 weeks salmeterol treatment influences deposition of particles within the lung by increasing airway patency and indicates a beneficial effect of MDI salmeterol on lung mucociliary clearance. r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1053/rmed.2003.1498, available online at http://www.sciencedirect.com
Keywords asthma; mucociliary clearance; radioaerosol; salmeterol.
INTRODUCTION Asthma is a disease characterised by reversible airway obstruction caused by mucosal oedema, bronchial smooth muscle contraction and hypersecretion of mucus (1). Death from ciliary insu⁄ciency and mucus plugging of small airways in asthmatic patients has been known for many years (2). Lung mucociliary clearance is impaired in patients with mild stable asthma (3) and during acute exacerbation of their disease (4). It has also been shown that lung mucociliary clearance in asthmatic patients is signi¢cantly impaired even during remission (5). Enhancement of a depressed lung mucociliary clearance can considered to be of bene¢t as reducing the residence time of bronchial secretions should lessen the risk of chest infections (6). A bronchodilator is extensively used by asthmatic patients for the relief of their bronchospasm. If such a drug is shown also to enhance clearance of secretions then this would be considered as an additional bene¢cial Received10 June 2002, accepted in revised form 4 November 2002 Correspondence should be addressed to. Dr. A. Hasani, Department of Medical physics, Royal free Hospital, London NW3 2QG. Fax: 02074331621. E-mail: [email protected]
e¡ect of the drug. Salbutamol has been shown to enhance lung mucociliary clearance when given topically from a metered dose inhaler albeit at 2.5 times the normal recommended dose (7). Such enhancement of mucus transport can be due to a direct stimulatory action on ciliary beat frequency. Salbutamol has been shown in vitro to have such stimulatory e¡ect (8). This may in vivo contribute to reducing small airways obstruction and mucus plugging. Salmeterol xinafoate is a long-acting b2 adrenoceptor agonist (9). The bronchodilator e¡ect of single doses of salmeterol, when compared with cumulative doses of salbutamol, in patients with asthma was 8 ^10 times more potent (10). For systemic e¡ects, salmeterol was 7^17 times more potent than salbutamol (11). The relative e¡ects of salmeterol and salbutamol, in a time- and dose-dependent manner, on ciliary beat frequency have been compared in vitro (12). Salmeterol was shown to be maximally active at a very low concentration of 10 6 M and caused a signi¢cantly rapid and prolonged increase in ciliary beat frequency. In contrast salbutamol was optimally active at a concentration of 10 4 M and caused a transient but signi¢cant increase in ciliary beat frequency.
668
The purpose of the present study was to investigate the e¡ect of salmeterol xinafoate administered from a MDI, on lung mucociliary clearance in patients with mild-to moderate stable asthma.
METHODS Patients Fourteen volunteer patients (nine men, ¢ve women) with asthma from our outpatient clinics were studied. The diagnosis of asthma was based on clinical criteria (13). Each patient entered into the study after showing an increase in his/her forced expiratory volume in 1s (FEV1) of 15% or more following inhalation of 200 mg of salbutamol. Patients on oral b2 -agonist drugs and corticosteroid therapy were not entered into the study. All patients had been free of symptoms of respiratory tract infection for at least 4 weeks before study commencement.Three (two men) were withdrawn, two had angina (during the salmeterol period), and the third because he was unable to manage without ‘salmeterol’ or additional bronchodilator therapy during the placebo period. The patients who completed the study had a mean7SE age and height of 5074 years and 1.6970.01m, respectively. Seven patients were lifelong non-smokers and the remaining four patients were ex-smokers with a mean7SE tobacco consumption of 1377 pack years.The mean7SE of their percentage predicted FEV1, FVC, and PEF were 7478%, 9475%, and 9777%, respectively. All 11 patients were receiving treatment with inhaled b2 agonists, nine were also taking inhaled corticosteroid drugs. Three of the patients were also receiving treatment with long-acting bronchodilator, which was discontinued at the start of the study.
STUDY DESIGN The study was designed in a controlled, double-blind, and crossover (within patients) manner. Patients were allocated randomly to receive either salmeterol xinafoate (2 pu¡s b.d.; 25 mg per pu¡) or placebo from metered dose inhalers. Randomisation was arranged so that half the patients should receive salmeterol ¢rst.The patients were instructed to use the trial inhaler for 2 weeks and at the end of this period their mucociliary clearance and lung function were assessed. The treatments were then crossed over and after a further period of 2 weeks a second assessment was carried out. The two assessments were identical in all respects. This study was not designed to assess the bronchodilator e¡ect of salmeterol.The patients were therefore allowed to take their regular (maintenance) treatment of inhaled b2 -agonists and corticosteroids drugs throughout the study recording on diary cards the number of pu¡s taken daily of their usual b2 -agonist inhaler. Inhaled
RESPIRATORY MEDICINE b2 -agonist drugs were withheld for the 6 h preceding each assessment day and for the 6 h -period during which lung mucociliary clearance measurement was made to avoid any in£uence on mucociliary function. The study was approved by the ethics committee of the Royal Free Hospital and informed, written consent was obtained from each patient prior to commencement of study.
MUCOCILIARYCLEARANCE Lung mucociliary clearance was measured using an objective non-invasive radioaerosol technique. Polystyrene particles (5 mm in diameter), ¢rmly labelled with the radionuclide technetium (99mTc), were inhaled by the volunteer patients under strictly controlled conditions (14). Inspiratory £ow rate of the radioaerosol particles was measured by a pneumotachygraph. The initial radioaerosol lung deposition was measured and its subsequent clearance was monitored by two suitably collimated scintillation counters (15). A count was made immediately following the radioaerosol inhalation to ascertain the initial whole lung burden. Thereafter, counts were made at half-hourly intervals for 6 h and a ¢nal count was made at 24 h post-inhalation.The amount of radioaerosol remaining in the lung at 24 hours was used to estimate alveolar deposition (AD), (16) which is the radioaerosol particles deposited in the non-ciliated airways and was therefore unavailable for mucociliary clearance. Subtracting the AD from the whole lung clearance curve yielded a tracheobronchial clearance curve (17). Tracheobronchial clearance was assessed by measuring the area under the curve for the 6 -h observation period (AUC0 - 6). The initial topographical distribution of the radioaerosol within the lungs was assessed by a large ¢eld of view gamma camera.The radioaerosol distribution was quantitatively expressed in terms of a penetration index (PI) (18). Throughout the 6 -h observation period all coughs were recorded and any sputum produced was collected and its radioactive content expressed as a percentage of the initial tracheobronchial deposition. This percentage was added back to the clearance curves to account for the e¡ect of productive coughing thus yielding a mucociliary clearance curve. (19)
PULMONARY FUNCTION The pulmonary function of each patient was assessed before the inhalation of the radioaerosol on each study day. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory £ow (PEF) were measured using a Vitalograph spirometer. The highest value for each pulmonary function index
EFFECTOF SALMETEROLON MUCOCILIARYCLEARANCE
was recorded out of three technically acceptable measurements.
STATISTICAL ANALYSIS As the data were not normally distributed the non-parametric Wilcoxon test for paired di¡erences was used. The level of signi¢cance was taken as Po0.05.
669
TABLE 2. Mean7SE radioaerosol inspiratory £ow rate, alveolar deposition (AD), and penetration index (PI) for the 11 patients following treatment with salmeterol and placebo. Placebo Flow rate (l/min) AD (%) P7
1772 4075 0.5770.04
Salmeterol 1672 4974 0.7470.02
P NS o0.01 o0.01
RESULTS Six patients received salmeterol treatment ¢rst while the other ¢ve patients received placebo. The mean7SE of the percentage predicted pulmonary function indices for the patients following treatment with salmeterol and placebo are given inTable 1. FEV1, FVC, and PEF were statistically signi¢cantly improved following salmeterol compared to placebo. Table 2 gives the mean7SE radioaerosol inspiratory £ow rate, alveolar deposition and penetration indices for the two treatments. The radioaerosol was inspired at a similar £ow rate during the two treatment days, whereas alveolar deposition and penetration indices
TABLE 1. Mean7SE pulmonary function indices for the 11patients following treatment with salmeterol and placebo.
% Pred.FEV1 % Pred.FVC % Pred.PEF
Placebo
Salmeterol
P
7378 9575 9477
7678 10075 10077
0.02 0.03 0.04
were signi¢cantly increased following treatment with salmeterol relative to placebo. The mean tracheobronchial clearance curves for the salmeterol and placebo treatments were shown in the ¢gure. The tracheobronchial clearance after salmeterol treatment was on average, but not statistically so, faster when compared to placebo. The mean7SE areas under the tracheobronchial clearance curves (AUC0 - 6) were 333724% h after treatment with salmeterol, and 347730% h on placebo. Four patients had no coughs. However, the number of coughs and sputum weight produced during the 6 -h observation by the other seven patients was similar between salmeterol and placebo treatment. The mean7SE number of coughs was 1574 and 1076; sputum weight was 2.170.8 and 2.671.2 g following treatment with salmeterol and placebo, respectively.
DISCUSSION The long acting b2 adrenergic drug salmeterol xinafoate has been known for some years to have excellent bronchodilating properties and a demonstrable
FIG. 1. Mean tracheobronchial clearance curves for11volunteer patients after placebo (~) and salmeterol (*) treatment.
670
therapeutic value in asthma (20,21). Although this study was not designed to test speci¢cally the bronchodilating properties of salmeterol, it nevertheless demonstrated that the addition of this drug resulted in statistically signi¢cant increases in indices of pulmonary function over placebo. Tracheobronchial clearance comprises mucociliary clearance and cough. Cough has been shown to be very important clearance mechanism in patients with chronic airways obstruction (22,23). Since in the 6 -h clearance periods the number of coughs and sputum production were small and similar after treatment with salmeterol and placebo, it can be reasonably surmised that any enhancement seen in tracheobronchial clearance would be attributable to an increase in mucociliary clearance following salmeterol treatment. Lung mucociliary clearance of deposited radioaerosol particles depends on the initial distribution of the radioaerosol within the lungs (24). If the median or average deposition depth with the tracheobronchial tree tends to move from bronchial to the bronchiolar airways, total clearance times from the conducting airways are expected considerable to increase (25). In this study a distal displacement of deposition sites within the lung certainly occurred as shown by signi¢cant changes in PI and AD. It is reasonable to infer that this will have included a distal shift within the tracheobronchial tree with, speci¢cally, some shift of deposition from bronchial to bronchiolar sites.This shift occurred despite the use of closely similar aerosol inhalation £ow rates in the two legs of the study and may reasonable to attributed to the increase in airway patency on salmeterol as demonstrated by the improvement seen in the pulmonary function data. Yet despite this likely shift of deposition sites within the conducting airways, tracheobronchial clearance was in fact slight faster on salmeterol than on placebo. Our data are thus consistent with salmeterol having a bene¢cial e¡ect in vivo on lung mucus clearance, paralleling its demonstrated e¡ect in vitro on the ciliary beat frequency of cultured cells (12). In summary, this study demonstrates that 2 weeks’ salmeterol treatment in£uences deposition of particles within the lung by increasing airway patency and indicates a bene¢cial e¡ect of MDI salmeterol on lung mucociliary clearance.
Acknowledgements We thank the volunteer patients for participating in the study and Allen&Hanburys for supplying the drugs.
REFERENCES 1. Lamb D, Corrin B. Asthma pathology. In: Brewis RAL, Corrin B, Geddes DM, Gibson GJ, editors. Respiratory medicine. London: Saunders WB, 1995. p. 1154–1160.
RESPIRATORY MEDICINE
2. Benatar SR. Fatal asthma. N Eng J Med 1986; 314: 423–428. 3. Bateman JRM, Pavia D, Sheahan NF, Agnew JE, Clarke SW. Impaired tracheobronchial clearance in patients with mild stable asthma. Thorax 1983; 38: 463–467. 4. Messina A, O’Riordan TG, Smaldone GC. Changes in mucociliary clearance during acute exacerbations of asthma. Am Rev Respir Dis 1991; 143: 993–997. 5. Pavia D, Bateman JRM, Sheahan NF, Agnew JE, Clarke SW. Tracheobronchial mucociliary clearance in asthma: impairment during remission. Thorax 1985; 40: 171–175. 6. Pavia D. Acute respiratory infections and mucociliary clearance. Eur J Respir Dis 1987; 71: 219–226. 7. Fazio F, Lafortuna C. Effect of inhaled salbutamol on mucociliary clearance in patients with chronic bronchitis. Chest 1981; 80: 827–830. 8. Yanaura S, Imamura N, Misama M. Effects of beta adrenoceptor stimulants on the canine tracheal ciliated cells. Japanese JPharmacol 1981; 31: 951–956. 9. Ullman A, Svedmyr N. Salmeterol, a new long acting inhaled beta 2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic. Thorax 1988; 43: 674–678. 10. Smyth ET, Pavord ID, Wong CS, Wisniewski AFZ, Williams J, Tattersfield AE. Interaction of dose equivalence of salbutamol and salmeterol in patients with asthma. BMJ 1993; 306: 543–545. 11. Bennett JA, Smyth ET, Pavord ID, Wilding PJ, Tattersfield AE. Systemic effects of salbutamol and salmeterol in patients with asthma. Thorax 1994; 49: 771–774. 12. Devalia JL, Sapsford RJ, Rusznak C, Toumbis MJ, Davies RJ. The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells in vitro. Pulmonary Pharmacol 1992; 5: 257–263. 13. National Asthma Education and Prevention Program. Expert panel report 2: Guidelines for the diagnosis and management of asthma. Publication No. 97-405. Bethesda, MD: National Institutes of Health, 1997. 14. Hasani A, Spiteri M, Pavia D, Agnew JE, Clarke SW. Tracheobronchial clearance in patients with pulmonary sarcoidosis. Chest 1992; 101: 1614–1618. 15. Hasani A, Spiteri MA, Pavia D, Lopez-Vidriero MT, Agnew JE, Clarke SW. Effect of temazepam on tracheobronchial mucus clearance. Thorax 1992; 47: 298–300. 16. Camner P, Philipson K. Human alveolar deposition of 4 mm Teflon particles. Arch Environ Health 1978; 36: 181–185. 17. Hasani A, Johnson M, Pavia D, Agnew JE, Clarke SW. Impairment of lung mucociliary clearance in pigeon fanciers. Chest 1992; 102: 887–891. 18. Agnew JE, Pavia D, Clarke SW. Airways penetration of inhaled radioaerosol: an index to small airways function? Eur J Respir Dis 1981; 62: 239–255. 19. Hasani A, Pavia D, Rotondetto S, Clarke SW, Spiteri MA, Agnew JE. Effect of oral antibiotics on lung mucociliary clearance during exacerbation of chronic obstructive pulmonary disease. Respir Med 1998; 92: 442–447. 20. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild to moderate asthma. N Eng J Med 1992; 327: 1420–1425. 21. Lundback B, Rawlinson DW, Palmer JB. Twelve month comparison of salmeterol and salbutamol as dry powder formulations in asthmatic patients. Thorax 1993; 48: 148–153. 22. Puchelle E, Zahm JM, Girard F, et al. Mucociliary transport in vivo and in vitro. Relations to sputum properties in chronic bronchitis. Eur J Respir Dis 1980; 61: 254–264. 23. Agnew JE, Bateman JRM, Sheahan NF, Lennard-Jones AM, Pavia D, Clarke SW. Effect of oral corticosteroids on mucus clearance by cough and mucociliary transport in stable asthma. Bull Europ Physiopath Resp 1983; 13: 37–41.
EFFECTOF SALMETEROLON MUCOCILIARYCLEARANCE
24. Agnew JE, Bateman JRM, Watts M, Paramananda V, Pavia D, Clarke SW. The importance of aerosol penetration for lung mucociliary clearance studies. Chest 1981; 80: 843–846.
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25. International Commission on Radiological Protection (ICRP). Human respiratory tract model for radiological protection. ICRP Publication 66 Ann ICRP 1994; 24: (1/4) 65–79.
E¡ect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma A. HASANI*, N.TOMS, J.O’CONNOR, J. P. DILWORTH AND J. E. AGNEW Departments of Thoracic Medicine and Medical Physics, Royal Free and University College Medical School, London, NW3 2QG, UK Abstract Lung mucociliary clearance isimpaired in stable asthma.The long-acting b2-agonist salmeterol has been shown in vitro to cause a significant increase in ciliary beat frequency.It seemed possible therefore that salmeterol may also have a favourable effect on lung mucociliary transport in asthmatic patients. Fourteen patients with asthma participated in a doubleblind, placebo-controlled, crossover study to assess the effect of 2 weeks of treatment with salmeterol MDI (50 mg b.d.) onlung mucociliaryclearance.The11patients who completed the study (seven males, four females) had a mean 7 SE age of 5074 years, % predicted FEV1 of 7478 % and a tobacco consumption history of 1377 pack-years (seven non-smokers, four exsmokers). Lung mucociliary transport was measured by a radioaerosol technique. Pulmonary function indices (FEV1, FVC, and PEF) were significantly improved on salmeterol relative to placebo.The main radioaerosol finding was a significantincrease inthe penetration of radioaerosolinto the lung with 24-h radioaerosolrising from 4075% on placebo to 4974% (Po0.01) on salmeterol. Despite this increased penetration, a slight favourable change occurred in tracheobronchial aerosol clearance.This study demonstrates that 2 weeks salmeterol treatment influences deposition of particles within the lung by increasing airway patency and indicates a beneficial effect of MDI salmeterol on lung mucociliary clearance. r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1053/rmed.2003.1498, available online at http://www.sciencedirect.com
Keywords asthma; mucociliary clearance; radioaerosol; salmeterol.
INTRODUCTION Asthma is a disease characterised by reversible airway obstruction caused by mucosal oedema, bronchial smooth muscle contraction and hypersecretion of mucus (1). Death from ciliary insu⁄ciency and mucus plugging of small airways in asthmatic patients has been known for many years (2). Lung mucociliary clearance is impaired in patients with mild stable asthma (3) and during acute exacerbation of their disease (4). It has also been shown that lung mucociliary clearance in asthmatic patients is signi¢cantly impaired even during remission (5). Enhancement of a depressed lung mucociliary clearance can considered to be of bene¢t as reducing the residence time of bronchial secretions should lessen the risk of chest infections (6). A bronchodilator is extensively used by asthmatic patients for the relief of their bronchospasm. If such a drug is shown also to enhance clearance of secretions then this would be considered as an additional bene¢cial Received10 June 2002, accepted in revised form 4 November 2002 Correspondence should be addressed to. Dr. A. Hasani, Department of Medical physics, Royal free Hospital, London NW3 2QG. Fax: 02074331621. E-mail: [email protected]
e¡ect of the drug. Salbutamol has been shown to enhance lung mucociliary clearance when given topically from a metered dose inhaler albeit at 2.5 times the normal recommended dose (7). Such enhancement of mucus transport can be due to a direct stimulatory action on ciliary beat frequency. Salbutamol has been shown in vitro to have such stimulatory e¡ect (8). This may in vivo contribute to reducing small airways obstruction and mucus plugging. Salmeterol xinafoate is a long-acting b2 adrenoceptor agonist (9). The bronchodilator e¡ect of single doses of salmeterol, when compared with cumulative doses of salbutamol, in patients with asthma was 8 ^10 times more potent (10). For systemic e¡ects, salmeterol was 7^17 times more potent than salbutamol (11). The relative e¡ects of salmeterol and salbutamol, in a time- and dose-dependent manner, on ciliary beat frequency have been compared in vitro (12). Salmeterol was shown to be maximally active at a very low concentration of 10 6 M and caused a signi¢cantly rapid and prolonged increase in ciliary beat frequency. In contrast salbutamol was optimally active at a concentration of 10 4 M and caused a transient but signi¢cant increase in ciliary beat frequency.
668
The purpose of the present study was to investigate the e¡ect of salmeterol xinafoate administered from a MDI, on lung mucociliary clearance in patients with mild-to moderate stable asthma.
METHODS Patients Fourteen volunteer patients (nine men, ¢ve women) with asthma from our outpatient clinics were studied. The diagnosis of asthma was based on clinical criteria (13). Each patient entered into the study after showing an increase in his/her forced expiratory volume in 1s (FEV1) of 15% or more following inhalation of 200 mg of salbutamol. Patients on oral b2 -agonist drugs and corticosteroid therapy were not entered into the study. All patients had been free of symptoms of respiratory tract infection for at least 4 weeks before study commencement.Three (two men) were withdrawn, two had angina (during the salmeterol period), and the third because he was unable to manage without ‘salmeterol’ or additional bronchodilator therapy during the placebo period. The patients who completed the study had a mean7SE age and height of 5074 years and 1.6970.01m, respectively. Seven patients were lifelong non-smokers and the remaining four patients were ex-smokers with a mean7SE tobacco consumption of 1377 pack years.The mean7SE of their percentage predicted FEV1, FVC, and PEF were 7478%, 9475%, and 9777%, respectively. All 11 patients were receiving treatment with inhaled b2 agonists, nine were also taking inhaled corticosteroid drugs. Three of the patients were also receiving treatment with long-acting bronchodilator, which was discontinued at the start of the study.
STUDY DESIGN The study was designed in a controlled, double-blind, and crossover (within patients) manner. Patients were allocated randomly to receive either salmeterol xinafoate (2 pu¡s b.d.; 25 mg per pu¡) or placebo from metered dose inhalers. Randomisation was arranged so that half the patients should receive salmeterol ¢rst.The patients were instructed to use the trial inhaler for 2 weeks and at the end of this period their mucociliary clearance and lung function were assessed. The treatments were then crossed over and after a further period of 2 weeks a second assessment was carried out. The two assessments were identical in all respects. This study was not designed to assess the bronchodilator e¡ect of salmeterol.The patients were therefore allowed to take their regular (maintenance) treatment of inhaled b2 -agonists and corticosteroids drugs throughout the study recording on diary cards the number of pu¡s taken daily of their usual b2 -agonist inhaler. Inhaled
RESPIRATORY MEDICINE b2 -agonist drugs were withheld for the 6 h preceding each assessment day and for the 6 h -period during which lung mucociliary clearance measurement was made to avoid any in£uence on mucociliary function. The study was approved by the ethics committee of the Royal Free Hospital and informed, written consent was obtained from each patient prior to commencement of study.
MUCOCILIARYCLEARANCE Lung mucociliary clearance was measured using an objective non-invasive radioaerosol technique. Polystyrene particles (5 mm in diameter), ¢rmly labelled with the radionuclide technetium (99mTc), were inhaled by the volunteer patients under strictly controlled conditions (14). Inspiratory £ow rate of the radioaerosol particles was measured by a pneumotachygraph. The initial radioaerosol lung deposition was measured and its subsequent clearance was monitored by two suitably collimated scintillation counters (15). A count was made immediately following the radioaerosol inhalation to ascertain the initial whole lung burden. Thereafter, counts were made at half-hourly intervals for 6 h and a ¢nal count was made at 24 h post-inhalation.The amount of radioaerosol remaining in the lung at 24 hours was used to estimate alveolar deposition (AD), (16) which is the radioaerosol particles deposited in the non-ciliated airways and was therefore unavailable for mucociliary clearance. Subtracting the AD from the whole lung clearance curve yielded a tracheobronchial clearance curve (17). Tracheobronchial clearance was assessed by measuring the area under the curve for the 6 -h observation period (AUC0 - 6). The initial topographical distribution of the radioaerosol within the lungs was assessed by a large ¢eld of view gamma camera.The radioaerosol distribution was quantitatively expressed in terms of a penetration index (PI) (18). Throughout the 6 -h observation period all coughs were recorded and any sputum produced was collected and its radioactive content expressed as a percentage of the initial tracheobronchial deposition. This percentage was added back to the clearance curves to account for the e¡ect of productive coughing thus yielding a mucociliary clearance curve. (19)
PULMONARY FUNCTION The pulmonary function of each patient was assessed before the inhalation of the radioaerosol on each study day. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory £ow (PEF) were measured using a Vitalograph spirometer. The highest value for each pulmonary function index
EFFECTOF SALMETEROLON MUCOCILIARYCLEARANCE
was recorded out of three technically acceptable measurements.
STATISTICAL ANALYSIS As the data were not normally distributed the non-parametric Wilcoxon test for paired di¡erences was used. The level of signi¢cance was taken as Po0.05.
669
TABLE 2. Mean7SE radioaerosol inspiratory £ow rate, alveolar deposition (AD), and penetration index (PI) for the 11 patients following treatment with salmeterol and placebo. Placebo Flow rate (l/min) AD (%) P7
1772 4075 0.5770.04
Salmeterol 1672 4974 0.7470.02
P NS o0.01 o0.01
RESULTS Six patients received salmeterol treatment ¢rst while the other ¢ve patients received placebo. The mean7SE of the percentage predicted pulmonary function indices for the patients following treatment with salmeterol and placebo are given inTable 1. FEV1, FVC, and PEF were statistically signi¢cantly improved following salmeterol compared to placebo. Table 2 gives the mean7SE radioaerosol inspiratory £ow rate, alveolar deposition and penetration indices for the two treatments. The radioaerosol was inspired at a similar £ow rate during the two treatment days, whereas alveolar deposition and penetration indices
TABLE 1. Mean7SE pulmonary function indices for the 11patients following treatment with salmeterol and placebo.
% Pred.FEV1 % Pred.FVC % Pred.PEF
Placebo
Salmeterol
P
7378 9575 9477
7678 10075 10077
0.02 0.03 0.04
were signi¢cantly increased following treatment with salmeterol relative to placebo. The mean tracheobronchial clearance curves for the salmeterol and placebo treatments were shown in the ¢gure. The tracheobronchial clearance after salmeterol treatment was on average, but not statistically so, faster when compared to placebo. The mean7SE areas under the tracheobronchial clearance curves (AUC0 - 6) were 333724% h after treatment with salmeterol, and 347730% h on placebo. Four patients had no coughs. However, the number of coughs and sputum weight produced during the 6 -h observation by the other seven patients was similar between salmeterol and placebo treatment. The mean7SE number of coughs was 1574 and 1076; sputum weight was 2.170.8 and 2.671.2 g following treatment with salmeterol and placebo, respectively.
DISCUSSION The long acting b2 adrenergic drug salmeterol xinafoate has been known for some years to have excellent bronchodilating properties and a demonstrable
FIG. 1. Mean tracheobronchial clearance curves for11volunteer patients after placebo (~) and salmeterol (*) treatment.
670
therapeutic value in asthma (20,21). Although this study was not designed to test speci¢cally the bronchodilating properties of salmeterol, it nevertheless demonstrated that the addition of this drug resulted in statistically signi¢cant increases in indices of pulmonary function over placebo. Tracheobronchial clearance comprises mucociliary clearance and cough. Cough has been shown to be very important clearance mechanism in patients with chronic airways obstruction (22,23). Since in the 6 -h clearance periods the number of coughs and sputum production were small and similar after treatment with salmeterol and placebo, it can be reasonably surmised that any enhancement seen in tracheobronchial clearance would be attributable to an increase in mucociliary clearance following salmeterol treatment. Lung mucociliary clearance of deposited radioaerosol particles depends on the initial distribution of the radioaerosol within the lungs (24). If the median or average deposition depth with the tracheobronchial tree tends to move from bronchial to the bronchiolar airways, total clearance times from the conducting airways are expected considerable to increase (25). In this study a distal displacement of deposition sites within the lung certainly occurred as shown by signi¢cant changes in PI and AD. It is reasonable to infer that this will have included a distal shift within the tracheobronchial tree with, speci¢cally, some shift of deposition from bronchial to bronchiolar sites.This shift occurred despite the use of closely similar aerosol inhalation £ow rates in the two legs of the study and may reasonable to attributed to the increase in airway patency on salmeterol as demonstrated by the improvement seen in the pulmonary function data. Yet despite this likely shift of deposition sites within the conducting airways, tracheobronchial clearance was in fact slight faster on salmeterol than on placebo. Our data are thus consistent with salmeterol having a bene¢cial e¡ect in vivo on lung mucus clearance, paralleling its demonstrated e¡ect in vitro on the ciliary beat frequency of cultured cells (12). In summary, this study demonstrates that 2 weeks’ salmeterol treatment in£uences deposition of particles within the lung by increasing airway patency and indicates a bene¢cial e¡ect of MDI salmeterol on lung mucociliary clearance.
Acknowledgements We thank the volunteer patients for participating in the study and Allen&Hanburys for supplying the drugs.
REFERENCES 1. Lamb D, Corrin B. Asthma pathology. In: Brewis RAL, Corrin B, Geddes DM, Gibson GJ, editors. Respiratory medicine. London: Saunders WB, 1995. p. 1154–1160.
RESPIRATORY MEDICINE
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