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.     

Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis

PURPOSES: To evaluate quantitative air trapping measurements in children with mild cystic fibrosis (CF) lung disease during a 1-year, double-blind, placebo-controlled, recombinant human deoxyribonuclease (rhDNase) [dornase alfa] intervention trial and compare results from quantitative air trapping with those from spirometry or visually scored high-resolution CT (HRCT) scans of the chest. MATERIALS AND METHODS: Twenty-five children with CF randomized to either daily rhDNase or placebo aerosol were evaluated at baseline, and at 3 months and 12 months by spirometer-triggered HRCT and spirometry. Outcome variables were percentage of predicted FVC, FEV1, and forced expiratory flow, midexpiratory phase (FEF(25-75%)); total and subcomponent visual HRCT scores; and quantitative air trapping measurements derived from chest HRCT images. RESULTS: At baseline, there were no statistical differences between groups in any of the variables used as an outcome. After 3 months of treatment, both groups had improvements in percentage of predicted FEV1 and FEF(25-75%), and total HRCT visual scores. In contrast, the rhDNase group had a 13% decrease in quantitative air trapping from baseline (severe air trapping [A3]), compared to an increase of 48% in the placebo group (p = 0.023). After 12 months, both groups had declines in percentage of predicted FVC and FEV1, but the rhDNase group retained improvements in percentage of predicted FEF(25-75%) and quantitative air trapping. The mucus plugging and total HRCT visual scores were also improved in the rhDNase group after 12 months of treatment, with and without significant differences between groups (p = 0.026 and p = 0.676). Quantitative air trapping (A3) remained improved in the rhDNase group (- 15.4%) and worsened in the placebo group (+61.3%) with nearly significant differences noted between groups (p = 0.053) after 12 months of treatment. CONCLUSIONS: Quantitative air trapping is a more consistent sensitive outcome measure than either spirometry or total HRCT scores, and can discriminate differences in treatment effects in children with minimal CF lung disease.     

The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.

It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways. Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF). This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF). Mucus clearance was measured using a radioaerosol/gamma camera technique. Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min. Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls. However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%). There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%). Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%). Values of FEV1 returned to baseline by the end of the study. Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients. Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol.     

Fexofenadine decreases sensitivity to and montelukast improves recovery from inhaled mannitol

We studied, separately, the effects of the histamine antagonist, fexofenadine hydrochloride, and the leukotriene antagonist, montelukast sodium, and their placebos on airway sensitivity to and recovery from inhaled mannitol in subjects with asthma. Two 180-mg doses of fexofenadine were taken over 14 h, and three 10-mg doses of montelukast over 36 h, with the last dose 5 h before challenge. Fexofenadine reduced sensitivity to mannitol and the PD(15) was (mean [95% confidence interval] 138 [95, 201]) mg versus placebo (51 [25, 106] mg) (p < 0.001). The final percent reduction in FEV(1) with fexofenadine was 20.8 +/- 5.4% and not different from placebo (20.1 +/- 5.3%) (p = 0.7); however, recovery was slower with fexofenadine compared with placebo (p < 0.001). By contrast, montelukast had no effect on sensitivity to mannitol and the PD(15) was 71 [36, 144] mg versus placebo (87 [51, 148] mg (p = 0.35). The total dose of mannitol delivered and the final percent reduction in FEV(1) with montelukast were 171 +/- 142 mg and 21 +/- 4% and for placebo were 182 +/- 144 mg and 20 +/- 5% (p = 0.35, p = 0.59, respectively). However, recovery of FEV(1) to baseline was faster with montelukast, with the area under the percent reduction FEV(1)-versus-time curve reduced (220 +/- 121% change.min) compared with placebo (513 +/- 182% change.min) (p < 0.001). We conclude that whereas histamine is important for the initial airway response, leukotrienes are important in sustaining the airway response to inhaled mannitol.     

Montelukast attenuates the airway response to hypertonic saline in moderate-to-severe COPD.

This study assessed the effect of the leukotriene receptor antagonist montelukast on hypertonic saline-induced airway obstruction. A total of 29 patients with chronic obstructive pulmonary disease (forced expiratory volume in one second (FEV1), 42+/-4% predicted) received either 10 mg montelukast and 3 h later placebo via metered-dose inhaler (MDI) (M), or placebo and 3 h later 200 microg salbutamol (S), or two doses of placebo (P), in a randomised order. Patients inhaled salbutamol 1 h after MDI and the challenge was performed 15 min later (3% saline, 5 min). Data are given as per cent changes versus baseline. Compared to P, S caused significant bronchodilation in FEV1 (7.3%) and forced inspiratory volume in one second (FIV1) (4.5%), and M in FIV1 (1.5%). The saline-induced fall in FEV1 was lower after M (-5.8%), compared with S (-10.3%) and P (-13.1%). FEV1 (11.3%) and FIV1 (7.6%) was improved over baseline after recovery by M but not P and S. Recovery times regarding FEV1 (8.5 min) and FIV1 (15.2 min) were shortest after M, respective values for S being 16.8 and 20.4 min, and for P 15.9 and 21.2 min. Effects were strongest in patients with low baseline FEV1 and/or inhaled corticosteroids. Data from this study indicate beneficial effects of montelukast on hypertonic saline-induced airway responses in patients with chronic obstructive pulmonary disease, particularly those with severe disease. The major effect was an accelerated recovery leading to values above baseline.     

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.     

Endogenous opioids modulate the increase in ventilatory output and dyspnea during severe acute bronchoconstriction

The aim of this study was to evaluate whether endogenous opioids are involved in the regulation of breathing pattern and respiratory drive during bronchoconstriction induced by methacholine (MCh). We studied six male asymptomatic asthmatics 18 to 35 yr of age. In a preliminary study we determined the concentration of MCh causing a 60% fall in FEV1 (PC60 FEV1). On two subsequent days, we measured breathing pattern, dyspnea sensation (Borg scale), mouth occlusion pressure (P0.1), and FEV1 before and 10 min after an intravenous injection of either naloxone (0.1 mg/kg) or saline according to a randomized double-blind crossover design. A MCh concentration equal to the PC60 FEV1 was then inhaled, and measurements were repeated 5 min later. Neither placebo nor naloxone affected baseline breathing pattern, P0.1, and FEV1. Naloxone pretreatment did not influence airway response to MCh; the mean percent fall in FEV1 was 65.9 +/- 1.3 and 64.7 +/- 1.2% (mean +/- 1 SE) on the placebo day and the naloxone day, respectively. After MCh inhalation no significant changes in VE, VT, and breathing frequency occurred when patients received placebo. However, P0.1 increased from 1.48 +/- 0.17 to 3.43 +/- 0.70 cm H2O (p less than 0.05), and VT/TI fell from 0.66 +/- 0.08 to 0.52 +/- 0.04 L/s (p less than 0.05). Naloxone pretreatment resulted in an increase in breathing frequency (from 18.2 +/- 1.7 to 22.8 +/- 2.6 breaths/min; p less than 0.05) and VT/TI (from 0.58 +/- 0.06 to 0.74 +/- 0.05 L/s; p less than 0.05) after MCh.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of computerized tomography and chest x-rays in evaluating efficacy of aerosolized recombinant human DNase in cystic fibrosis patients younger than age 5 years: a preliminary study

The aim of this study was to evaluate the ability of high-resolution computerized tomography (HRCT) of the chest and chest x-rays (CXR) to determine efficacy of inhaled recombinant human DNase (rhDNase) in cystic fibrosis (CF) patients younger than 5 years of age. A randomized, double-blind, placebo-controlled pilot study of 12 patients with CF younger than 5 years of age, attending the University of Michigan Cystic Fibrosis Center (Ann Arbor, MI) was conducted. The changes in the HRCT and CXR score from baseline to day 100 of therapy were assessed using a previously validated scoring system. The mean changes of HRCT scores between the rhDNase and placebo groups were found to be significant at the 95% level, with mean change +/- SE mean of - 1.00 +/- 0.53 and 0.58 +/- 0.24 for rhDNase and placebo groups, respectively (P = 0.02). The difference in CXR score was not significant between the two groups. An analysis was performed to relate HRCT subscores to CXR score; only thickening of the intra-interlobular septae was significantly correlated with the total CXR score (r = - 0.7, P < 0.01). There was improvement in the parents' assessments of the patients' well-being, with improvement in physical activity, decreased cough, sleep quality, and appetite in those subjects receiving rhDNase. We conclude that the administration of rhDNase was associated with improvement in the HRCT scan in CF patients younger than 5 years of age. Findings indicate that HRCT of the chest is useful and sensitive in studying responses to therapy in patients with CF lung disease. To our knowledge, this is the first report of the use of HRCT to assess the effectiveness of a therapeutic modality in so young a CF patient population.     

Tolerance to bronchodilating effects of salmeterol in COPD

Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications. Initially, tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties. However, generally such observations have been reported in asthma. A 6-month randomized, double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD. Spirometry was measured over 12h at baseline and at days 15, 57, 116 and 169. Changes over time from baseline were compared relative to changes observed with placebo. A total of 623 patients participated (tiotropium = 209, salmeterol = 213, placebo = 201). The groups were similar in age (mean = 65 years), gender (75% men), and baseline FEV1 (mean = 1.08 +/- 0.37l [40 +/- 12% predicted]). Relative to placebo, both active drugs improved morning pre-drug, peak and average FEV1 and FVC throughout the trial. However, from day 1 to 169, salmeterol was associated with a higher decline in average FEV1 and FVC (0-12h) (difference from placebo: -36 and -115 ml, P < 0.05), which was most prominent over the 8-12 h period (difference from placebo: -45 and -138 ml, P < 0.01). Significant declines in peak FVC relative to placebo (-83 ml, P < 0.05) but not FEV1 (-12ml) were observed with salmeterol. Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial. In conclusion, tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics.     

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.     

Inhaled hyaluronic acid against exercise-induced bronchoconstriction in asthma

Hyaluronic acid (HA) is a polysaccharide that is present in human tissues and body fluids. HA has various functions, including a barrier effect, water homeostasis, stabilizing the extracellular matrix, increased mucociliary clearance and elastin injury prevention. It may therefore exert prophylactic activity in the treatment of asthma. We tested the hypothesis that HA inhalation will prevent exercise-induced bronchoconstriction (EIB) in a randomised double-blinded placebo-controlled crossover study. Sixteen asthmatic patients with EIB were included in the study (mean (SD)) (age 24.5 (7.3) yr, FEV1 88.6 (11.3) %predicted, PC20 methacholine (g-mean (SD in DD)) 0.4 (1.5) mg/ml). On two separate visits an exercise challenge was performed 15 min post-inhalation of either HA (3 ml 0.1% in PBS) or placebo (3 ml PBS). The maximum fall in FEV1 and the AUC 30 min post-exercise were used as outcomes. After inhalation of both HA and placebo, baseline FEV1 decreased significantly (HA 4.1 (3.1)%, placebo 2.9 (4.1)%, P<0.017). The maximum fall in FEV1 following exercise challenge was not significantly different between HA versus placebo (median HA 22.50%, placebo 27.20%, P=0.379), as was the AUC (median HA 379.3 min*%fall, placebo 498.9 min*%fall, P=0.501). We conclude that at the current dose, inhaled HA does not significantly protect against EIB. This suggests that HA is not effective as a prophylaxis for EIB in patients with asthma.     

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.     

Inhaled isotonic alkaline versus saline solution and radioaerosol clearance in chronic cough.

The aim of the present study was to test the influence of inhaled isotonic Ems salt (brine from the spa of Bad Ems, Germany) compared to isotonic saline on radioaerosol clearance (RC) in patients with chronic cough. Ems salt is an alkaline solution (pH 8.0-9.0) containing largely bicarbonate ions rather than the chloride ions present in isotonic saline (pH 6.4). RC was assessed with a radioaerosol technique using technetium-99m albumin in supine patients. After a 30-min baseline measurement of RC according to a single blind and randomized design, patients inhaled Ems salt (n=22, 20-77 yrs) or isotonic saline (n=21, 34-72 yrs) via a jet nebulizer (Pari Boy) for 10 min and were scanned for an additional 30 min. There was no difference between the two groups before intervention in terms of deposition pattern, lung function and baseline RC rate. After inhalation of Ems salt, the RC rate (1/tau) improved significantly from 0.15+/-0.14 (mean+/-SD) to 0.53+/-0.70 L.h(-1) (p<0.005); no change was found after isotonic saline (0.13+/-0.13 to 0.08+/-0.09 L.h(-1), NS). Voluntary coughs performed after 60 min had no effect on the RC rate. However, in the Ems salt group, significantly more patients reported an inhalation induced cough. Compared to the Ems salt patients, who did not cough during and after inhalation, the RC rate in the cough group was enhanced significantly (0.10+/-0.12 versus 0.73+/-0.83, p=0.017), this effect being seen more frequently in females (p=0.003). It is concluded that Ems salt improves radioaerosol clearance significantly in patients with chronic cough. The underlying mechanism, regarding whether induced cough, increased water content in the mucus or enhanced ciliary beat frequency is the leading cause of Ems salt action, remains unclear.     

Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report.

Macrolide antibiotics have immunomodulatory effects that may be beneficial to patients with chronic inflammatory pulmonary conditions. The aim of this study was to evaluate the effects of azithromycin on lung function, bronchial hyperresponsiveness (BHR), and airway inflammation in asthmatic children. Sixteen asthmatic children were treated with either azithromycin or placebo for 8 weeks. Lung function, BHR expressed as the dose-response slope (DRS) of forced expiratory volume in 1 second (FEV1) fall after hypertonic saline inhalation (DRS), and induced sputum were evaluated at baseline and after treatment. No significant change was observed in lung function before and after treatment. DRS (percent fall of FEV1/mL) decreased from (X +/- SD) 2.75 +/- 2.12 to 1.42 +/- 1.54 (p = 0.02) in azithromycin-treated children but not in the placebo group, which was 1.48 +/- 1.75 at baseline and 1.01 +/- 1.38 at the end of the study period. Neutrophil leukocytes decreased significantly in the azithromycin-treated group from 10 +/- 5.3% to 2.2 +/- 2.4% (p < 0.01) but not in the placebo group, with 7.2 +/- 4.2% at baseline and 3.3 +/- 3.6% at the end of the study. A short course of azithromycin is associated with amelioration of BHR and reduction in airway neutrophil infiltration in some children with asthma.     

Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD.

AIMS: Evaluation of tiotropium efficacy in patients with mild chronic obstructive pulmonary disease (COPD) defined by the 2003 Swedish Society of Respiratory Medicine guidelines (post-bronchodilator FEV1/FVC <70%; FEV1 >60% predicted). METHODS: In this 12-week, randomised, double-blind, placebo-controlled study of tiotropium 18 mcg once daily versus placebo, respiratory function was assessed on Days 1, 15 and 85 (baseline: pre-dose Day 1). RESULTS: Mean+/-SD baseline FEV1 (% predicted) was 73.4+/-12.5 (tiotropium, n=107; placebo, n=117). Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose (AUC0-2 h) FEV1 versus placebo, by 166+/-26 mL (mean+/-SE) at study end (p<0.0001). With tiotropium, there were significant increases in the change in AUC0-2 h FVC versus baseline, and trough FEV1 and FVC, versus placebo, on all test days (p<0.01). Adverse event rates were similar. CONCLUSION: Compared with placebo, tiotropium improved lung function in patients with mild COPD.     

Effect of salmeterol on mucociliary and cough clearance in chronic bronchitis

The effect of long acting beta(2)-adrenergic bronchodilators on impaired mucociliary clearance in chronic bronchitis is unknown. Using a radiolabeled aerosol (technetium-99m-labeled sulfur colloid) and gamma camera analysis, we measured the acute effect of salmeterol vs. placebo on mucociliary and cough clearance in mild-moderate chronic bronchitics (n = 14) over a 2h period. During the 1-1(1/2) h period of observation patients performed 60 controlled coughs on each study day. Average whole lung clearance through 1 and 2h after administration of salmeterol (42 microg) or placebo via metered dose inhaler (double-blinded, crossover design study) showed no significant difference between treatments. Similarly, for the specific period when cough was added to mucociliary clearance, there was no difference on whole lung clearance between treatments. However, when clearance from the peripheral region of the lung was assessed over the entire 2h period of observation, salmeterol provided a 30% enhancement of airway clearance compared to placebo, average peripheral 2h clearance (%) = 22 +/- 9 vs. 17 +/- 10 for salmeterol vs. placebo (P = 0.05 by paired analysis). Thus, in addition to its bronchodilating effects, salmeterol acutely enhances peripheral airway clearance of secretions in mild-moderate chronic bronchitis.     

RhDNase before airway clearance therapy improves airway patency in children with CF

INTRODUCTION: Little is known about the optimal timing of rhDNase nebulization in relation to airway clearance therapy (ACT). OBJECTIVE: To compare the effects of rhDNase before ACT versus rhDNase after ACT in children with CF. METHODS: Design: randomized, double blind, double dummy, cross over study. Inclusion criteria: CF, stable clinical condition, rhDNase maintenance therapy. Children in Group I inhaled rhDNase 30 minutes before ACT, and placebo directly after ACT in week 1-3. The protocol was reversed during week 4-6. Group II performed the reversed sequence. Patients continued their daily routine ACT. Primary endpoint: MEF(25) %pred. Pulmonary functions tests were performed on days 0, 14, 21, 35 and 42. In weeks 3 and 6 children scored cough and sputum production on daily diary cards. RESULTS: 24 patients completed the study. Mean age = 12 years (range 7-19). Mean MEF(25) %pred was 5.8% higher after 3 weeks of rhDNase before ACT, compared to rhDNase after ACT (58.3% vs 52.5%, p=0.01). There were no significant differences for any of the other variables. CONCLUSION: Inhalation of rhDNase before ACT improves peripheral airway patency in children with cystic fibrosis. Since all children were already on maintenance rhDNase therapy before the study, this effect is additional to any existing effect of regular rhDNase.     

High-dose lidocaine reduces airway mucus transport velocity in intubated anesthetized dogs

BACKGROUND: Assessment of mucociliary clearance with displacement of charcoal markers in the central airways needs a bronchoscopic procedure and thus local anesthesia of the upper airways. However, the effects of lidocaine administration on mucus transport in airways are inconclusive. Therefore, detailed information is needed to establish the effects of high- and low-dose lidocaine administration. OBJECTIVES: To study the dose-dependent effect of instillation of lidocaine on mucus transport velocity (MTV) in intubated, anaesthetized dogs. METHODS: Displacement of a charcoal spot in time was studied with a bronchoscope in 10 anaesthetized dogs before and after administration of respectively 5 and 10 ml of either 2% lidocaine (n=5) or NaCl 0.9% (n=5). In addition, mucus viscoelastic properties were determined. RESULTS: No significant differences in MTV were observed after administration of 5 ml of NaCl (8.2+/-3.2 mm/min) or 2% lidocaine (6.7+/-3.8 mm/min) compared to baseline values. By contrast, MTV was reduced after administration of 10 ml of 2% lidocaine (1.9+/-1.0 mm/min; P<0.05 vs. baseline and 5 ml of 2% lidocaine vs. controls, P=0.0035), but not after 10 ml of NaCl (6.2+/-2.1 mm/min). A trend towards an increased mucociliary clearability index was observed for the lidocaine-treated group as compared to the control group (P=0.07). The cough clearability index was not different between groups (P=0.89). CONCLUSIONS: High-dose lidocaine reduces MTV. Therefore, only low-dose lidocaine administration should be applied in the bronchoscopic procedure for assessment of MTV.     

Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma.

The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4 can cause airway smooth muscle contraction and have been implicated in the pathophysiology of asthma. MK-571 is a selective, potent LTD4 receptor antagonist that could attenuate airway obstruction in asthma by inhibiting the actions of sulfidopeptides at the LTD4 receptor site. The objectives of this study were to investigate the potential for MK-571 to cause bronchodilation in asthma patients with existing airway obstruction and to evaluate its effect on the bronchodilation response to an inhaled beta 2-agonist (albuterol). Twelve male patients (ages 19 to 42 yr) with asthma (baseline FEV1 50 to 80% predicted) participated in this placebo-controlled, randomized, two-period, cross-over study. On separate treatment days, each patient received either MK-571 or placebo intravenously for 6 h; inhaled albuterol was administered at the fifth and sixth hour of MK-571/placebo treatment to achieve maximal bronchodilation on that study day. Spirometry (forced expiratory volume in 1 s, FEV1) was monitored at intervals throughout each study period. MK-571 caused clinically significant bronchodilation; the increase in FEV1 above baseline, 20 min after the start of the MK-571 infusion, was 22 +/- 3.9% compared with 1.3 +/- 2.3% for placebo (mean +/- SE, p < 0.01). This degree of bronchodilation was maintained throughout the MK-571 infusion. In addition, bronchodilation from inhaled albuterol appeared additive with MK-571. Finally, baseline airway obstruction correlated with the degree of bronchodilation achieved with MK-571 (r = -0.73; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

A pilot study of ranolazine in patients with intermittent claudication.

AIM: This pilot study provides preliminary information regarding safety and changes in exercise performance during treatment with ranolazine extended-release in patients with reproducible claudication during exercise treadmill testing (ETT). METHODS: We enrolled 45 patients with documented peripheral arterial disease, reproducible claudication on ETT, and ankle-brachial indices <0.85 at rest that decreased by at least 0.15% or 20% immediately postexercise. Randomized patients received double-blind treatment with either ranolazine 1 000 mg b.i.d. (n=22) or placebo (n=23) for 4 weeks. RESULTS: Compared with baseline, peak walking time (PWT) increased (mean+/-SEM) by 53+/-34 s with ranolazine (P=0.13) and by 41+/-33 s with placebo (P=0.22). Pain-free walking time during ETT increased by 62+/-18 s with ranolazine (P=0.002) and 36+/-18 s with placebo (P=0.045). Supplemental analyses, excluding patients with baseline exercise duration (16 min and (12 min, showed additional improvement with ranolazine on PWT. CONCLUSIONS: Ranolazine was well tolerated and these data provide a rationale for proceeding with a definitive trial.