Inhaled beta-agonists improve lung function but not maximal exercise capacity in cystic fibrosis. Effect of albuterol on maximal exercise capacity in cystic fibrosis. Bronchodilatory effects of salbutamol, ipratropium bromide, and their combination: double-blind, placebo-controlled crossover study in cystic fibrosis. Tiotropium Respimat in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials. Effectiveness and tolerability of high-dose salmeterol in cystic fibrosis. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. Effects of standard and high doses of salmeterol on lung function of hospitalized patients with cystic fibrosis. Effects of salmeterol on arterial oxyhemoglobin saturations in patients with cystic fibrosis. Testing Two Different Doses of Tiotropium Respimat® in Cystic Fibrosis: Phase 2 Randomized Trial Results A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis.
BACKGROUND To investigate the effects of inhaled beta-agonists on sub-maximal and maximal exercise capacity , breathing pattern , dyspnoea , leg-discomfort and spirometry in patients with cystic fibrosis ( CF ) . OBJECTIVES Eight patients performed two maximal incremental cycle-ergometry tests on separate days with inhaled placebo or salbutamol ( 600 microg ) administered before each test in a r and omized , double-blind , placebo-controlled crossover trial . Primary outcomes were exercise duration ( Exdur ) in seconds ( s ) and maximal oxygen uptake ( VO2max ) in litres/minute ( L/min ) . Forced expiratory volume in 1 s ( FEV1 ) was measured immediately pre-inhaler , post-inhaler and post-exercise . Dyspnoea and leg-discomfort were assessed post-exercise . RESULTS Within-day FEV1 comparisons demonstrated that the placebo test day FEV1 improved significantly post-exercise ( 0.11 L , p<0.05 ) and the salbutamol test day FEV1 improved significantly post-inhaler ( 0.22 L , p<0.001 ) and post-exercise ( 0.07 L , p<0.01 ) . Between-day FEV1 comparisons demonstrated significant improvements in post-inhaler ( 0.17 L , p<0.05 ) and post-exercise ( 0.13 L , p<0.05 ) FEV1 following salbutamol . Sub-maximal and maximal exercise showed no significant difference as shown by Exdur ( 547+/-154 s vs. 529+/-127 s ) and VO2max ( 1.9+/-0.5 L/min vs. 1.9+/-0.6 L/min ) . No significant change in breathing pattern , dyspnoea or leg-discomfort was detected . The study had a power of 92 % to detect a 10 % improvement in Exdur . CONCLUSIONS In adults with CF , salbutamol improves post-exercise FEV1 and is safe when administered immediately before exercise but does not improve exercise capacity , exercise-induced dyspnoea or leg-discomfort BACKGROUND Inhaled , short-acting beta-adrenergic agonists ( SAbetaAs ) are widely prescribed in cystic fibrosis ( CF ) subjects , despite a lack of convincing data for efficacy and the potential for these agents to result in airway instability . We tested the hypothesis that inhaled albuterol would improve maximal exercise performance in CF subjects with airflow obstruction , as a result of acute bronchodilation . METHODS R and omized , double-blind , placebo-controlled crossover study of the effect of inhaled albuterol on maximal exercise performance in 20 stable adult CF patients ( mean + /- SD age , 23.3 + /- 6.1 years ; FEV(1 ) , 57.65 + /- 17.13 % of predicted ) . RESULTS Ventilatory limitation to exercise was demonstrated in 16 subjects ( 80 % ) . Significant bronchodilation occurred with exercise alone ( end-exercise FEV(1 ) , 2.24 + /- 0.8 L ; vs preexercise FEV(1 ) , 2.09 + /- 0.77 L ; p < 0.0001 ) , but albuterol result ed in significantly greater exercise-induced bronchodilation than placebo ( change in FEV(1 ) , 0.3 + /- 0.15 L vs 0.15 + /- 0.11 L ; 95 % confidence interval [ CI ] , + 0.07 to + 0.23 ; p < 0.001 ) . However , there was no difference in maximal workload achieved  ( albuterol , 158 + /- 46 W ; vs placebo , 158 + /- 45 W ; 95 % CI , - 4.41 to + 4.71 ; p = 0.95 ) , nor any other measure of exercise performance including maximal oxygen uptake . CONCLUSIONS Despite causing significant acute bronchodilation , inhaled albuterol did not improve maximal exercise performance in ventilatory-limited CF adults , adding to the body of literature that fails to show any clinical benefit of SAbetaAs in CF subjects . The current results provide further evidence to question the widespread use of these agents , although the potential for adrenergic beta-agonists to instead improve submaximal exercise performance merits further investigation The efficacy of inhaled sympathomimetic and anticholinergic agents on airway obstruction in cystic fibrosis ( CF ) has been proven in several studies . However , studies comparing combined therapy with monotherapy led to divergent results , probably due to different study design s , different dosages , and the small numbers of patients investigated . Therefore , we wanted to answer the question which inhalation has the best short term effect : a sympathomimetic or an anticholinergic agent , or the combination of both . We investigated 17 patients with CF on 4 successive days in the morning , using pulmonary function testing before and 30 min after inhalation . Each patient received aerosolized salbutamol ( SB , maximum dose ( max . ) 2.5 mg ) , ipratropium bromide ( IB , max . 0.5 mg ) , the combination of both , or placebo ( normal saline ) in a r and omized , double-blind crossover design . The mean forced expiratory volume in the first second improved significantly ( adjusted P-value < 0.017 ) after each treatment compared to placebo . Analysis of variance showed that SB and combination therapy with SB and IB were superior to IB alone , without significant difference between SB and combination therapy . Response of a patient to combined therapy was usually associated with response to SB . Long-term efficacy and side effects of treatment with bronchodilators still remain to be investigated after this short term study . We conclude that in CF patients bronchodilator therapy with sympathomimetic agents is usually sufficient . Only in cases with proven additional benefit from inhalation by anticholinergics should combination therapy be recommended BACKGROUND Tiotropium Respimat improved lung function in a phase 2 trial in patients with cystic fibrosis ( CF ) . We investigated its efficacy and safety in a phase 3 trial , including a pre-specified pooled analysis of the phase 2 and 3 trials . METHODS 12-week , r and omized , double-blind , placebo-controlled trial of tiotropium Respimat 5 μg once daily in patients with CF ( N=463 ) . RESULTS Co- primary efficacy endpoints showed no statistical difference between tiotropium and placebo : percent-predicted forced expiratory volume in 1s ( FEV1 ) area under the curve from 0 - 4h ( AUC0 - 4h ) ( 95 % CI ) : 1.64 % ( 0.27,3.55 ; p=0.092 ) ; percent-predicted trough FEV1 ( 95 % CI ) 1.40 % ( 0.50,3.30 ; p=0.15 ) . Adverse events were similar between groups . Pooled phase 2/3 trial results showed a treatment difference in favor of tiotropium : percent-predicted FEV1 AUC0 - 4h ( 95 % CI ) : 2.62 % ( 1.34,3.90 ) . CONCLUSION Tiotropium was well tolerated in patients with CF ; lung function improvements compared with placebo were not statistically significant in the phase 3 trial . CLINICAL TRIALS These studies are registered with clinical trial identifier numbers NCT00737100 and NCT01179347 NCT00737100 NCT01179347 . These studies are also registered with the EudraCT number : 2008 - 001156 - 43 and 2010 - 019802 - 17 The efficacy and tolerability of high-dose salmeterol ( 100 mcg , BID ) and albuterol ( 2.5 mg , BID ) were compared with those of albuterol ( 2.5 mg , BID ) in out patients with cystic fibrosis in a r and omized , double-blind , double-dummy , placebo-controlled , crossover study with both short- ( 4 weeks of each ) and long-term ( 24 weeks of each ) treatment periods . The primary outcome measure was the difference in mean change in forced expired volume in 1 sec ( FEV(1 ) ) from baseline to the end of each treatment , and secondary measures included changes in forced vital capacity ( FVC ) , forced expiratory flow between 25 - 75 % of FVC ( FEF(25 - 75 ) ) , patient-rated weekly symptom scores , number of extra ( rescue ) albuterol treatments , and number of antibiotic treatments . Tolerability was evaluated by changes in vital signs and adverse events .  Thirty-six out of 44 patients enrolled finished the short-term treatment period , and 19 out of 23 who continued the study also finished the long-term treatment period . There was no significant difference in the mean % change in FEV(1 ) from baseline to completion of 4 weeks with each drug in the short-term treatment period ( 0.1 % vs. 0.06 % , albuterol vs. salmeterol ; respectively ) . In the long-term treatment period , there was a significant decrease from baseline in FEV(1 ) with albuterol vs. salmeterol , as measured after both 12 and 24 weeks of each treatment ( -6.2 % vs. 1.8 % , P = 0.013 after 12 weeks , and -6.5 % vs. 1.7 % , P = 0.002 , after 24 weeks , respectively ) . In both treatment periods , salmeterol was well-tolerated . While there were more rescue treatments per patient per week with albuterol than with salmeterol treatment in both the short- and long-term periods ( 0.67 vs. 0.40 and 1.76 vs. 0.74 , respectively ) , rescue treatments were needed significantly more often for only the long-term period with albuterol compared to salmeterol ( P = 0.022 ) . Also , there were more antibiotic interventions with albuterol than with salmeterol treatment in both the short- and long-term periods ( 25 vs. 10 and 56 vs. 42 , respectively ) ; however , antibiotics were needed significantly more often for only the short-term period ( P = 0.011 ) . In addition , there was a significantly higher symptom score with albuterol vs. salmeterol treatment during the second half of the long-term period ( 1.24 vs. 0.89 , P = 0.001).In conclusion , long-term high-dose salmeterol was equally safe and was associated with better pulmonary function , fewer interventions , and fewer respiratory symptoms compared to st and ard therapy with albuterol in a population of out patients with mild to moderate CF We evaluated patients with cystic fibrosis ( CF ) and moderate obstructive lung disease in pulmonary exacerbation in a double-blind placebo-controlled trial to determine the contribution of antibiotic-mediated reduction in sputum bacterial density to clinical improvement . For the first 4 days of study , all patients received bronchodilating aerosols and chest physiotherapy but no antibiotics . During this time , the patients showed significant improvement in mean FVC , FEV1 , and maximal midexpiratory flow rate ( FEF25 - 75 ) . In 12 of 13 trials , the patients showed no significant increases in the density of Pseudomonas aeruginosa during these first 4 days . In these 12 trials , the patients were stratified by their initial FVC and r and omized to receive either parenteral tobramycin and ticarcillin ( n = 7 ) or placebo ( n = 5 ) , in addition to continued aerosol and chest physiotherapy . In the remaining trial , the patient had a significant rise in the density of P. aeruginosa and was assigned to the antibiotic group . During the next 14 days of therapy , the antibiotic group showed significantly ( p less than 0.01 ) greater reductions in log10 colony-forming units ( cfu ) of P. aeruginosa per gram of sputum and greater increases in FVC , FEV1 , and FEF25 - 75 than did the placebo group . The degree of decrease in log10 cfu P. aeruginosa/g sputum correlated significantly ( p less than 0.001 ) with the degree of improvement in FVC , FEV1 , and FEF25 - 75 . ( ABSTRACT TRUNCATED AT 250 WORDS In a recent investigation we found that hospitalized patients with cystic fibrosis who received 0.5 cc of  0.5 % albuterol nebulizer solution TID significantly increased their pulmonary function across the day , but fell back to baseline overnight . To determine whether this fall could be prevented by the long-acting beta-2 agonist salmeterol at both st and ard ( 2 puffs : 42 mcg BID ) and high ( 4 puffs , 84 mcg BID ) doses , we evaluated the effects of salmeterol vs. albuterol ( 2 puffs , 180 mcg QID , and 4 puffs , 360 mcg BID ) in a placebo-controlled three-way r and om crossover , double-blind trial . Eighteen patients in the low-dose group and 10 of the same 18 patients in the high-dose group completed the 3 consecutive days of testing and received either salmeterol , albuterol , or placebo with each of four chest physiotherapy sessions given at 7 AM , 11 AM , 3 PM , and 7 PM . At st and ard doses ( 2 puffs ) , the mean percent changes in FEV1 pre- to post-7 AM therapy for salmeterol ( 5.5 % ) and albuterol ( 9.9 % ) were significantly greater than with placebo ( -1.2 % ) ( P < 0.05 and 0.01 , respectively ) . The mean percent changes in FEV1 from morning baseline with salmeterol were also significantly greater than placebo before 3 PM ( 12.1 % vs. 5.4 % , P < 0.01 ) , and neither albuterol nor salmeterol were significantly greater than placebo after 3 PM . At st and ard doses there was a significant carryover effect with salmeterol to the next morning for the FEV1 ( 7.3 % ) when compared to placebo ( 1.5 % ) and albuterol ( -0.7 % ) ( P < 0.05 and 0.05 , respectively ) . At high doses ( 4 puffs ) , the mean percent change in FEV1 with pre- to post-7 AM therapy increased to 22.7 % and remained significantly greater than with placebo until pretherapy at 7 PM . The carryover effect the next morning was 14.7 % . Salmeterol at 4 puffs compared favorably to albuterol nebulizer therapy given TID in both the incidence of responders for the FEV1 ( 70 % vs. 71 % ) and the mean changes after therapy at 7 AM ( 22.7 % vs. 14.9 % ) , and provided greater carryover effects to the next morning ( 14.7 % vs. -0.7 % ) , thus preventing the fall in pulmonary function back to baseline overnight . We recommend the use of high-dose salmeterol in hospitalized patients with FVC values of 40 % of predicted or greater , starting with 2 and increasing to 4 puffs BID as tolerated Sleep-related oxygen desaturation has been described in patients with cystic fibrosis ( CF ) . Thus we studied the effects of inhaled Salmeterol xinafoate , a long-acting beta-2 agonist , on transcutaneous oxyhemoglobin saturation in sleeping , stable CF patients . Patients with stable CF ( n = 23 ) were divided into responders and nonresponders to beta-2 agonists , based on an albuterol challenge during daytime testing , and then they received salmeterol before sleep , in a double-blind crossover design . Overnight oxyhemoglobin saturation measurements and spirometry on awakening were performed . Salmeterol administration before sleep result ed in statistically significant increases in mean arterial oxyhemoglobin saturation and in FEV(1 ) and FEF(25 - 75 ) on awakening compared to placebo values , but only in patients responding to daytime albuterol inhalation by showing improvement in lung function . We conclude that salmeterol inhalation at bedtime could prevent or reduce nocturnal hypoxemia in daytime albuterol-responsive CF patients , thus improving the long-term clinical outcome of CF lung disease Background Tiotropium is a once-daily , long-acting anticholinergic bronchodilator with the potential to alleviate airway obstruction in cystic fibrosis . Our objective was to evaluate the efficacy and safety of 2.5 and 5 µg once-daily tiotropium delivered via the Respimat Soft Mist Inhaler vs. placebo in people with cystic fibrosis . Methods This phase 2 , 12-week , r and omized , double-blind , placebo-controlled parallel-group study of tiotropium Respimat as add-on to usual cystic fibrosis maintenance therapy included people with cystic fibrosis with pre-bronchodilator forced expiratory volume in 1 second ( FEV1 ) ≥25 % predicted . Co- primary efficacy end points were change from baseline in percent-predicted FEV1 area under the curve from 0 to 4 hours ( FEV1 AUC0–4h ) , and trough FEV1 at the end of week 12 . Findings A total of 510 subjects with cystic fibrosis aged 5–69 years were r and omized . Both doses of tiotropium result ed in significant improvement compared with placebo in the co- primary efficacy end points at the end of week 12 ( change from baseline in percent-predicted FEV1 AUC0–4h : 2.5 µg : 2.94 % , 95 % confidence interval 1.19–4.70 , p = 0.001 ; 5 µg : 3.39 % , 95 % confidence interval 1.67–5.12 , p = 0.0001 ; in percent-predicted trough FEV1∶2.5 µg : 2.24 % , p = 0.2 ; 5 µg : 2.22 % , p = 0.02 ) . There was a greater benefit with tiotropium 5 vs. 2.5 µg . No treatment-related adverse events or unexpected safety findings were observed in patients taking tiotropium . Conclusions Tiotropium  significantly improved lung function in people with cystic fibrosis . The improvement was greater with the higher dose than the lower dose , with no difference in adverse events . Trial Registration Clinical Trials.gov NCT00737100 EudraCT 2008 - 001156 - 43 BACKGROUND Airway inflammation , mediated in part by LTB4 , contributes to lung destruction in patients with cystic fibrosis ( CF ) . LTB(4)-receptor inhibition may reduce airway inflammation . We report the results of a r and omized , double-blind , placebo-controlled study of the efficacy and safety of the leukotriene B(4 ) ( LTB(4))-receptor antagonist BIIL 284 BS in CF patients . METHODS CF patients aged ≥6 years with mild to moderate lung disease were r and omized to oral BIIL 284 BS or placebo once daily for 24 weeks . Co- primary endpoints were change in FEV(1 ) and incidence of pulmonary exacerbation . RESULTS After 420 ( 155 children , 265 adults ) of the planned 600 patients were r and omized , the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events ( SAEs ) in adults receiving BIIL 284 BS . Final analysis revealed SAEs in 36.1 % of adults receiving BIIL 284 BS vs. 21.2 % receiving placebo ( p = 0.007 ) , and in 29.6 % of children receiving BIIL 284 BS vs. 22.9 % receiving placebo ( p = 0.348 ) . In adults , the incidence of protocol -defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo ( 33.1 % vs. 18.2 % respectively ; p = 0.005 ) . In children , the incidence of protocol -defined pulmonary exacerbation was 19.8 % in the BIIL 284 BS arm , and 25.7 % in the placebo arm ( p = 0.38 ) . CONCLUSIONS While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown , the outcome of this trial provides a caution ary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections , as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events
BACKGROUND Cystic fibrosis is a life-limiting inherited condition which affects one in 2500 newborns in the UK and 70,000 children and adults worldwide .
The condition is multifaceted and affects many systems in the body .
The respiratory system is particularly affected due to a build up of thickened secretions and a predisposition to infection .
Inhaled bronchodilators are prescribed for 80 % of people with cystic fibrosis in order to widen the airways and alleviate symptoms .
Both short- and long-acting inhaled bronchodilators are used to improve respiratory symptoms .
Short-acting inhaled bronchodilators take effect in minutes and typically last for four to eight hours ( muscarinic antagonists ) .
Long-acting inhaled bronchodilators also take effect within minutes but typically last for around 12 hours and sometimes longer .
OBJECTIVES This review aims to evaluate long-acting inhaled bronchodilators in children and adults with cystic fibrosis in terms of clinical outcomes and safety .
If possible , we aim ed to assess the optimal drug and dosage regimen .