Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma

Lung mucociliary clearance is impaired in stable asthma. The long-acting beta2-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 double-blind, placebo-controlled, crossover study to assess the effect of 2 weeks of treatment with salmeterol MDI (50 microg b.d.) on lung mucociliary clearance. The 11 patients who completed the study (seven males, four females) had a mean +/- SE age of 50 +/- 4 years, % predicted FEV1 of 74 +/- 8% and a tobacco consumption history of 13 +/- 7 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 significant increase in the penetration of radioaerosol into the lung with 24-h radioaerosol rising from 40 +/- 5% on placebo to 49 +/- 4% (P < 0.01) 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.     

Effect of aerosolized uridine 5'-triphosphate on mucociliary clearance in mild chronic bronchitis.

Previous studies show that uridine 5'-triphosphate (UTP), a P2Y(2) receptor agonist, is effective at acutely enhancing mucociliary clearance in healthy, nonsmoking adults. UTP solution for inhalation is being developed by Inspire Pharmaceuticals under the compound number INS316. In a double-blind, randomized, crossover, placebo-controlled study we tested the single-dose effect of UTP in chronic smokers with mild chronic bronchitis (n = 15) by measuring the clearance of (99m)Tc-Fe(2)O(3) particles (4.0 microm mass median aerodynamic diameter [MMAD]) after inhalation of nebulized placebo (0.9% saline) and two doses of UTP (20 and 100 mg in the nebulizer). On each study day, gamma camera scanning was performed over a 2-h period. After an initial deposition scan, subjects inhaled placebo or UTP during the first 20 min of scanning. Analysis of whole lung clearance showed that the retention-time curves for each day were biphasic and that the earliest break point in the average curves occurred at 50 min. Mean particle clearance rate (Clr in %/min) through 50 min for placebo treatment was Clr = 0.65 +/- 0.27 whereas treatment with UTP showed Clr significantly increased to 0.95 +/- 0.48 and 0.93 +/- 0.44 for the 20-mg and 100-mg dose respectively, p < 0.005 for both as compared with placebo. These data show that mucociliary clearance associated with mild chronic bronchitis is acutely improved with minimal doses of aerosolized UTP, presumably because of its stimulation of ciliary beating and hydration of airway secretions.     

Influence of 0.2 mg ipratropium bromide on mucociliary clearance in patients with chronic bronchitis

14 patients with chronic bronchitis were subdivided into 2 groups of 7 patients. They were given at random 10 puffs of placebo or ipratropium bromide (0.2 mg). The mucociliary clearance rate was measured immediately after ipratropium inhalation (group 1) or 24 h after ipratropium inhalation (group 2). In group 1, the mucociliary clearance after ipratropium bromide was significantly better than after placebo (p less than 0.01). In group 2 there was no difference in the mucociliary clearance rates measured after ipratropium bromide or placebo, but the clearance rate still tended in favour of ipratropium bromide. We conclude that ipratropium bromide should be inhaled in high doses (0.2 mg) by hypersecretory patients with chronic bronchitis to improve mucociliary transport.     

Mucociliary clearance in patients with chronic bronchitis and bronchial carcinoma

We measured the mucociliary clearance rates and lung function data of 40 normal subjects, of 30 smokers with chronic bronchitis and of 64 patients with bronchial carcinoma. The mucociliary clearance rate of cancer patients was significantly lower than that of normal subjects and of patients with chronic bronchitis who smoked the same amount of cigarettes. The fast clearing phase of the central bronchial tree is more delayed than the peripheral mucociliary clearance rate in smokers with and without carcinoma. With our mucociliary clearance measurement we assessed the self-cleaning filter function of about the first 10 generations of the branching bronchial tree where also most bronchial carcinomas develop. The correlation between lung function data (MMEF) and smoking habits is much better (r = 0.73) than with the measured mucociliary clearance rates (r = 0.3), suggesting that inborn errors of mucociliary transport are nearly as important as external lung damage due to smoking and infection in the development of chronic bronchitis and bronchial carcinoma.     

Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis

The aim of the study was to measure the effect of a short course of recombinant human deoxyribonuclease I (rhDNase) on ciliary and cough clearance in a group of cystic fibrosis patients, using a radioaerosol and gamma camera technique. Patients were initially randomized to receive either rhDNase (2.5 mg qd) or placebo. Following the measurement of baseline clearance, patients were given a 7-day course of either rhDNase or placebo. The patient then returned on the seventh day for follow-up clearance measurements. This was followed by a 2-week washout period before the whole process was repeated with the alternative inhalation solution. On each of the study days, mucociliary clearance was initially measured for a period of 60 min (IC). This was followed by cough clearance (CC) measurements for 30 min, during which patients were requested to cough a total of 120 times. Post-cough clearance (PCC) was then measured for a further 60 min. Thirteen patients completed the study. Patients' age ranged between 18-38 years, and they had baseline values of FEV(1) of 27-103% of predicted values. Following completion of the course of rhDNase, there was a mean percent increase from baseline of 7.5% for FEV(1) and 5.4% for FVC% (P = 0. 03). There was a small, nonsignificant increase in IC (6.2 +/- 3.6%) on the rhDNase arm compared with the placebo arm (-2.3 +/- 2.9%), P = 0.1. No changes were seen in either CC (1.0 +/- 3.2% [rhDNase] vs. 1.9 +/- 2.4% [placebo], P = 0.9) or PCC (-0.7 +/- 1.5% [rhDNase] vs. 0.9 +/- 1.7% [placebo], P = 0.3). Patients who achieved a 10% or greater improvement in FEV(1) (n = 5) in response to rhDNase did not show any greater change in clearance than nonresponders. In conclusion, we were unable to demonstrate any improvements in either ciliary or cough clearance in response to a short course of rhDNase. The mechanism of action of this drug in vivo remains uncertain.     

Effect of oral N-acetylcysteine on mucus clearance

Oral N-acetylcysteine has been advocated as a mucolytic agent for use in chronic bronchitis. We have investigated the effects of regular use of this drug at a dose of 200 mg thrice daily for 4 weeks in nine patients with chronic bronchitis on lung function, lung mucociliary clearance and sputum viscosity in a controlled, double-blind, crossover study. No significant differences were found in lung function, mucociliary clearance curves or sputum viscosity following treatment with N-acetylcysteine compared to control or placebo measurements.     

Mucociliary clearance in patients with chronic asthma: effects of beta agonists

OBJECTIVE: Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long-term treatment with salmeterol in combination with inhaled corticosteroids (ICS). METHODOLOGY: MCC was measured at baseline and in response to 1 mg terbutaline (or placebo) on three visits over 80 min in 16 asthmatics (52+/-13 years of age). Subjects who had greater than 10% absolute increase in MCC above baseline and placebo, after terbutaline, were categorized in group A and subjects who had less than 10% in group B. RESULTs: In group A subjects (n=6), MCC increased from 23.7+/-4.0% at baseline to 43.7+/-4.9% with terbutaline (P<0.0001) and to 34.4+/-5.7% with placebo (P<0.01). In group B subjects (n=10), MCC remained similar: 11.3+/-3.2% at initial baseline, 12.0+/-3.2% with terbutaline and 7.3+/-3.0% with placebo (P>0.05). Group B subjects withdrew from all beta(2) agonists for a week and MCC was remeasured. After withdrawal, baseline MCC (7.0+/-1.8%) was similar to the initial baseline value (P>0.1) and MCC with terbutaline (15.8+/-4.9%) was greater than baseline (P<0.005) but remained abnormal in most subjects. Baseline percentage predicted FEV(1) and FEF(25--75%) were 77.3+/-7.2 and 41.7+/-5.6 in group A and 59.9+/-8.1 and 29.5+/-8.4 in group B subjects, respectively. CONCLUSION: MCC was impaired in most of these asthmatics with persistent airway obstruction and sputum production, despite regular treatment with ICS and salmeterol. In addition, there was little or no stimulation of MCC acutely after terbutaline in most of these asthmatics.     

Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium.

The efficacy and safety of salmeterol alone was compared with the combination of salmeterol plus ipratropium and with placebo during long-term treatment in patients with stable chronic obstructive pulmonary disease. In addition, the single-dose effect in response to the first dose of treatment was studied over 12 h. The patients (n=144; age 64+/-7 yrs, forced expiratory volume in one second (FEV1) 44+/-11% pred) participated in a three-centre double-blind double-placebo parallel group study and were randomized after a run-in period of 2 weeks to receive either salmeterol 50 microg b.i.d., salmeterol 5 microg b.i.d. plus ipratropium 40 microg q.i.d. or placebo for a period of 12 weeks. The single-dose study demonstrated that salmeterol produced a significant increase in FEV1 (peak of 7% pred) and specific airway conductance (sGaw) (maximum of 60% baseline) for > or =12 h. The combination of salmeterol plus ipratropium elicited a greater bronchodilator response (11% and 94% increases respectively) than salmeterol alone during the first 6 h after inhalation. During treatment there were significant improvements in daytime symptom scores and morning peak expiratory flow in both the salmeterol and the salmeterol plus ipratropium groups (p<0.001), with an associated decrease in the use of rescue salbutamol. Improvements in FEV1 and sGaw were greater in the salmeterol plus ipratropium group than in the patients receiving only salmeterol. Thirty-five patients had an exacerbation; 11 (23%) in the salmeterol group (versus placebo NS), six (13%) in the salmeterol plus ipratropium group (versus placebo p<0.01) and 18 (36%) in the placebo group. In conclusion, in patients with severe stable chronic obstructive pulmonary disease, long-term treatment with either salmeterol alone or salmeterol plus ipratropium is safe and effective. There was added benefit from the combination therapy in terms of improvement in airways obstruction, but not for improvement in symptom control or need for rescue salbutamol.     

Impaired mucus clearance in patients with chronic bronchial sepsis, sinusitis and dextrocardia

Published reports have indicated that patients with Kartagener's syndrome (dextrocardia, sinusitis and bronchiectasis) have no significant lung mucociliary clearance. With a radioaerosol technique we measured over a 6-hour observation period the tracheobronchial clearance of 8 patients with dextrocardia, chronic bronchial sepsis and chronic sinusitis (DC). The tracheobronchial clearance of these patients was significantly reduced (p less than 0.02) compared with that of 29 healthy subjects of similar age. However, even when allowance was made for productive coughing during the observation period, the reduced clearance was much better than anticipated from published reports in patients with Kartagener's syndrome, which confined their observations to a 2-hour period. The tracheobronchial clearance of the DC patients, adjusted for productive coughing, was as bad as that found in an older group of patients with chronic obstructive airways disease who refrained from expectorating during the equivalent test period. Our study implies one or more of the following possibilities: (a) a spectrum of mucociliary impairment in patients with DC; (b) an effective cough clearance deeper in the lung than hitherto believed, and (c) two-phase flow of mucus cephalad as an effective clearance mechanism in patients with DC.     

In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation

Systemic corticosteroids have been recommended as a therapeutic option in patients with moderate to severe COPD. In an early stage of the disease, i.e. chronic bronchitis with mild or no airflow obstruction, a trial with inhaled steroids could reveal potential benefits, particularly in terms of a modulation of airway inflammation. We therefore investigated the effect of inhaled fluticasone (1000 microg day(-1)) on markers of airway inflammation in 19 patients with chronic bronchitis (mean+/-SEM FEV1, 83.4+/-3.0% predicted; FEV1/VC, 67.5+/-2.4%) in a double-blind, cross-over, placebo-controlled manner. Visits were performed before and after two 4-week treatment periods. separated by a 4-week washout period. Lung function, the concentration of exhaled nitric oxide, differential cell counts in induced sputum and the number of cells positive for iNOS, as well as the levels of LDH, ECP, neutrophil elastase and IL-8 in sputum supernatants were determined. Although the total cell number decreased significantly after fluticasone (geometric mean 12.3 vs. 7.7 x 10(6)/ml; P<0.05) it was not significantly different from the change observed after placebo (14.2 vs. 10.6 x 10(6)/ml; n.s.). None of the other parameters showed statistically significant changes after fluticasone or placebo and the results did not depend on the presence of airway hyperresponsiveness. We conclude that in patients with chronic bronchitis short-term treatment with inhaled corticosterids did not improve lung function or inflammatory parameters to an extent which was statistically significant as compared to spontaneous variability.     

Mucociliary transport and cough in humans

The mucus lining of the respiratory tract originates from products of secretory cells interspersed among mucosal cells or within submucosal glands and protects the underlying mucosa from dehydration. Current understanding is that the lining is a two-fluid model in which the upper layer is a viscoelastic gel (mucus, cross-linked glycoproteins) that overlies a sol layer (serous). Thus mucus propelled by ciliary beating, flows above the sol layer and contains sloughed cells and xenobiotic materials that come into contact with it. Sensory stimuli enhance mucus secretion and cause bronchoconstriction; responses that are usually coupled to cough and two-phase gas-liquid clearance of mucus. Airway clearance can be measured by scintigraphy using insoluble radio-labeled markers deposited by aerosol delivery onto the mucus layer. In a healthy airway, lung inflation/deflation reflexes and perhaps shearing forces at the airway surface during high rates of airflow, stimulate mucociliary clearance. During the early stages of smoke-related airway pathology and mucus hypersecretion, mucus layer transport is delayed, and abnormal clearance predominates in the smaller peripheral airways. If high velocity of expiratory airflow is preserved then even with chronic exposure to respiratory irritants and cigarette smoke, mucus clearance remains effective due to cough and two-phase, gas-liquid interactions. However, in patients with advanced airway obstruction and incapable of generating forceful expiratory flows, cough and shearing are ineffective and mucociliary clearance is disparate with markedly slowed mucus layer transport within central airways. Mucolytic therapy for patients with advanced airway obstruction improves ventilation and reduces the frequency of exacerbation.     

Effect of aerosolized uridine-5'-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormal ciliary structure and function and impaired mucociliary clearance. Because patients with PCD use cough clearance as an airway defense mechanism, we tested the hypothesis that aerosolized uridine-5'-triphosphate (UTP) would improve clearance during cough by its actions to stimulate Cl- secretion and mucin release by goblet cells. We measured clearance during cough in 12 patients with PCD (ages 14 to 71 yr, FEV1 43% to 89% predicted) in a double blind, randomized, crossover study after aerosolization of a single dose of UTP (5 mg/ml, 3.5 ml) or vehicle (0.12% saline, 3.5 ml). Clearance during cough (whole lung) was quantified during and after a series of controlled coughs by measuring the clearance of [99mTc]Fe2O3 particles via gamma camera scanning over 120 min. Safety parameters were recorded during and after drug delivery. Aerosolized UTP improved whole-lung clearance during cough as compared with vehicle (from 0 to 60 min: 0.40 +/- 0.07%/min [UTP] versus 0.26 +/- 0. 04%/min [vehicle] [mean +/- SEM], p = 0.01), and from 0 to 120 min: 0.38 +/- 0.05%/min [UTP] versus 0.25 +/- 0.04%/ min [vehicle], p = 0. 02). Aerosolized UTP is safe, with no serious adverse effects. Whole-lung clearance during cough in patients with defective ciliary function is enhanced after inhalation of UTP.     

Airway carcinoembryonic antigen concentrations in patients with central lung cancer or chronic bronchitis

To determine the clinical utility of airway carcinoembryonic antigen (CEA) concentrations to distinguish malignant from inflammatory airway disease in patients undergoing bronchoscopy, we determined CEA concentrations by enzyme immunoassay in bronchial washings recovered in 48 subjects, including 20 patients with central lung cancer, 18 patients with chronic bronchitis, and ten nonsmoking patients with a diagnosis of pneumonia or peripheral granuloma. Concentrations of CEA in bronchial washings were standardized by using the total protein concentration in recovered fluid (CEA/TP). Concentrations of CEA were significantly increased in bronchial washings recovered from both patients with chronic bronchitis and lung cancer compared with patients with pneumonia or granuloma (252 +/- 47 ng/mg and 199 +/- 64 ng/ml vs 62 +/- 11 ng/mg, SEM, p less than 0.005). Airway CEA concentrations in patients with chronic bronchitis were somewhat increased compared with concentrations recovered from a cancer-involved airway (252 +/- 47 ng/ml vs 199 +/- 64 ng/mg, SEM, p less than 0.05). Measurement of airway CEA concentrations is not useful in distinguishing malignant from inflammatory airway disease as airway concentrations of CEA may be markedly increased in patients with both conditions.     

Chronic bronchitis: the role of viruses

Mucus is produced by the epithelial cells in the glands, gland ducts, and the cells lining the airway lumen in the lower airways.The chronic cough and sputum production that defines chronic bronchitis is associated with an inflammatory reaction involving this mucus-secreting apparatus. Respiratory viral infections target the epithelial cells of the lung producing desquamation, microvascular dilatation, edema, and an inflammatory cell infiltrate. These changes predispose the lower airways to bacterial infection by interfering with mucociliary clearance and reducing bacterial killing by macrophages. The exact role of those infections in the pathogenesis of chronic bronchitis has not been clearly determined but they probably play a critical role in inducing bacterial colonization and initiating acute exacerbations of COPD. This article reviews the classification of the viral agents responsible for respiratory tract infection and the nature of the changes they produce in the normal airways and in the airways of patients with chronic bronchitis during acute infections.     

Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease: A crossover, placebo-controlled comparison of onset and duration of action.

BACKGROUND: In contrast to the well-known activity profile in asthma, the precise efficacy and optimum dose schedules of long-acting beta(2)-agonists in chronic obstructive pulmonary disease (COPD) are not clear. OBJECTIVE: In this study, we aimed to compare the onset and the duration of action of a single inhalation of formoterol and salmeterol in COPD patients having partially reversible airway obstruction. METHODS: In a double-blind, randomized, crossover and placebo-controlled study design, the respiratory functions of 22 patients (mean age 57.3+/-5.4 years) having mild to severe COPD (5 mild, 8 moderate and 9 severe) and partially reversible airway obstruction [mean baseline reversibility of forced expiratory volume in 1 s (FEV(1)) 19.3+/-3.1%] were evaluated after inhalation of 12 microg formoterol and 50 microg salmeterol. RESULTS: Regarding the onset of bronchodilator action, the mean absolute increase of 0.20 liters in FEV(1) 10 min after inhalation of formoterol was significantly higher than baseline and that of placebo (0.04 liters), whereas that of salmeterol (0.11 liters) did not reach statistical significance. At 20 min, both formoterol (0.25 liters) and salmeterol (0.20 liters) produced a significant increase in FEV(1) compared with baseline and with that of placebo (0.04 liters). The peak bronchodilator effects occurring at 60 and 120 min following formoterol (0.39 liters) and salmeterol (0.40 liters) inhalation, respectively, were significantly higher than the corresponding levels of placebo (0.02 and -0.12 liters, respectively). Concerning the duration of action, the 12-hour values of both formoterol (0.25 liters) and salmeterol (0.22 liters) were significantly higher than that of placebo (-0.12 liters). The area under the curve values of FEV(1) of formoterol (3.5+/-1.3 l.h) and salmeterol (3.2+/-1.2 l x h) averaged over 12 h were comparable and higher than placebo values (1.2+/-0.5 l x h). After formoterol inhalation 2 patients experienced tremor and 1 had palpitation; 1 tremor and 1 headache attack were noted after salmeterol. For the pharmacologically predictable side effects, there was no difference between the drugs. CONCLUSIONS: In conclusion, this study revealed that a single dose of 12 microg formoterol and 50 microg salmeterol provided comparable bronchodilation within 12 h and had tolerable side effects in patients with mild to severe COPD having partially reversible airway obstruction.     

Effect of four-week treatment with oxitropium bromide on lung mucociliary clearance in patients with chronic bronchitis or asthma

The effect of oxitropium bromide on lung mucociliary clearance, pulmonary function and viscoelastic properties of sputum was investigated in 10 asthmatics and 10 chronic bronchitics. A controlled, double-blind, crossover study was performed. Following a baseline (B) measurement the patients were, in a random order, allocated placebo (P) or oxitropium bromide (O; 0.1 mg/puff), administered from metered dose inhalers, which they used for 4 weeks at a dose of 2 puffs t.d.s. This test medication was used in conjunction with their normal medication. At the end of the treatment period the patients were assessed, the treatments were then crossed over and a final assessment made 4 weeks later. The administration of oxitropium bromide resulted in (1) small but statistically significant increases in pulmonary function (less than 10% vs. placebo); (2) increased penetrance of radioaerosol into the lungs (mean +/- SEM alveolar deposition: 35 +/- 3, 26 +/- 3 and 24 +/- 3% for the O, P and B runs respectively; p less than 0.025); (3) no significant change in particle clearance rate from the lungs despite their deeper penetration (mean +/- SEM area under the tracheobronchial clearance curves between 0 and 6 h: 317 +/- 26, 324 +/- 25 and 287 +/- 25%.h for the O, P and B runs respectively; p greater than 0.1); (4) no alteration in sputum production, and (5) no significant changes in apparent viscosity (mean +/- SEM: 640 +/- 162, 446 +/- 79 and 557 +/- 115 mPa.s for the O, P and B runs, respectively; p greater than 0.1) and elasticity (mean +/- SEM: 3,682 +/- 1,383, 1,779 +/- 353 and 2,061 +/- 366 mPa for the O, P and B runs, respectively; p greater than 0.1) of sputum. When the two groups, i.e. the chronic bronchitics and asthmatics, were studied separately, no significant differences in any parameter measured (other than radioaerosol penetrance which was significantly enhanced on oxitropium bromide in chronic bronchitics) were noted between the three assessments.     

Definition and assessment of asthma

Bronchial obstruction, its reversibility, airway hyperreactivity and inflammation are key variables of asthma. In clinical practice they can be assessed with repeated noninvasive lung function measurements (spirometry and mucociliary clearance). The asthmatic inflammation in contrast to chronic bronchitis is characterized by increased IgE and eosinophils depending on the disease state (seasonal, perennial, chronic symptomatic or asymptomatic asthma). Based on the above-mentioned clinically applicable measurements, a classification of asthma, chronic (obstructive) bronchitis, and emphysema is proposed because the three groups of diseases have different etiology and need different prophylactic and symptomatic treatment.     

Salmeterol improves fluid clearance from alveolar-capillary membrane in COPD patients: a pilot study

The cardiovascular component associated with chronic obstructive pulmonary disease (COPD) plays a major role in disease prognosis, accounting for 25% of the deaths. Experimental and initial clinical data suggest that beta-adrenergic agonists accelerate fluid clearance from the alveolar airspace, with potentially positive effects on cardiogenic and noncardiogenic pulmonary oedema. This pilot study investigated the acute effects of the long-acting beta-2 agonist, salmeterol, on alveolar fluid clearance after rapid saline intravenous infusion by evaluating diffusive and mechanical lung properties. Ten COPD and 10 healthy subjects were treated with salmeterol or placebo 4 h before the patient’s mechanical and diffusive lung properties were measured during four non consecutive days, just before and after a rapid saline infusion, or during a similar period without an infusion.ResultsIn both COPD and healthy subjects, rapid saline infusion with placebo or salmeterol premedication lead to a significant decrease in diffusion capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1). Nonetheless, salmeterol pretreatment lead to a significantly reduced gas exchange impairment caused by saline infusion (?64% of DLCO reduction compared with placebo), whereas it did not affect changes in FEV1. In the control setting with no infusion, we found no significant change in either DLCO or mechanical properties of the lung.ConclusionsSalmeterol appears to provide a protective effect, not related to bronchodilation, against an acute alveolar fluid clearance challenge secondary to lung fluid overload in COPD patients.     

Mucociliary clearance in COPD can be increased by both a D2/beta2 and a standard beta2 agonists

In addition to breathlessness and cough, excessive mucus production is one of the main symptoms of chronic obstructive pulmonary disease (COPD). Excess mucus coupled with deteriorating mucociliary clearance is associated with a decline in lung function and an increased risk of death from pulmonary infection. The effect of Viozan (Sibenadet HCl, AR-C68397AA), a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, on mucociliary clearance was investigated together with that of a beta2-adrenoceptor agonist, salbutamol. Using a double blind, parallel group study design, 15 patients with COPD, all habitual smokers, were randomised to receive nebulised sidenadet (3mg tid; n = 7) or salbutamol (5mg tid; n = 8) for 10 days. Lung mucociliary clearance rates were measured, by a standard radioaerosol technique, before and after the treatment period, as were 24-h sputum volumes. Both sibenadet and salbutamol therapies resulted in significant (P<0.02) enhancement of lung mucociliary clearance. The 24-h sputum volume was significantly reduced following sibenadet therapy (P<0.03) whereas salbutamol therapy had no effect. Our results, in addition to illustrating the effects of a standard beta2 agonist on mucociliary clearance, strongly suggest the potential dual benefit of dual-agonist compounds in lessening sputum production whilst simultaneously enhancing mucociliary clearance. For reasons unconnected with the present study, development work on this specific formulation is no Longer proceeding.     

Chronic inhalation of nebulized levalbuterol does not increase mucociliary clearance in healthy subjects

Acute inhalations of beta 2-adrenergic receptor agonists increase mucociliary clearance (MCC). Less is known about the effect of long-term inhalations of these agents on MCC, or cough clearance (CC). We hypothesized that chronic inhalations of nebulized levalbuterol, the R-isomer of albuterol, would enhance MCC and/or CC in healthy subjects, compared to albuterol or placebo. This was a randomized, double-blind, placebo-controlled trial in ten healthy, adult subjects who inhaled nebulized levalbuterol (1.25mg), albuterol (2.5mg), or placebo for 7 days, three times daily. MCC and CC were measured 6-7h after the last dose of drug on the 7th day of treatment. These were quantified from gamma camera images of the lungs following inhalation of an aerosol containing the isotope (99m)technetium. Levalbuterol did not improve MCC or CC. MCC averaged (+/-SD) 12.3+/-8.3%, 9.2+/-4.7% and 10.0+/-9.6% with placebo, albuterol and levalbuterol, respectively. CC averaged 3.9+/-6.8%, 4.9+/-4.3% and 3.8+/-6.4% with placebo, albuterol and levalbuterol, respectively. These results indicate that chronic inhalations of nebulized levalbuterol for 1 week do not increase MCC or CC in healthy subjects, compared to albuterol or placebo.