Significant Increase In FEV1 Research Articles

Long-acting beta2-agonists for chronic obstructive pulmonary disease patients with poorly reversible airflow limitation.

Chronic obstructive pulmonary disease (COPD) is characterised by partially reversible airflow limitation. Many patients have little reversibility to short acting bronchodilators, but long acting bronchodilators are frequently advocated. To determine the effectiveness of long acting beta-2 adrenoceptor agonists in COPD patients with low reversibility to short-acting bronchodilators. The Cochrane Airways Group register was searched. Bibliographies of identified randomised controlled trials (RCTs) were also searched. Authors of identified RCTs were contacted for other published and unpublished studies and unpublished studies were obtained from pharmaceutical companies. All RCTs over four weeks in duration comparing treatment with long-acting beta-2 adrenoceptor agonists (salmeterol or formoterol) with placebo in patients with stable poorly-reversible COPD. Data extraction and study quality assessment was performed independently by two reviewers. Where further or missing data were required, authors of studies were contacted. Eight RCTs met the inclusion criteria review. Six were parallel group studies of 12-16 weeks in duration and two were cross-over studies with four week treatment arms. All eight assessed the efficacy of salmeterol in COPD compared to placebo. Few of the results could be combined in meta-analyses because of differences in methods of reporting data. Isolated trials reported an improvement in one or other outcome in favour of salmeterol, but the only possible meta-analysis of FEV1 showed no overall benefit (Standardised mean difference 0.14 (95% Confidence Interval -0.16, 0.44, n=4). There was no consistent effect on Health Related Quality of LIfe or symptoms scores. Overall, breathlessness was not reduced, but in one study more subjects in the salmeterol group had low Borg dyspnoea scores compared to placebo (Peto Odds Ratio = 0.60, 95% CI: 0.40; 0.88). There was no effect on COPD exacerbations over the short period of the studies. In the few studies that could be included in this review, treatment of patients with COPD with long acting beta-2 agonists produces only small increases in FEV1. The improvement in airways function does not seem to be associated with a consistent effect on other outcomes such as health related quality of life or reductions in breathlessness.

Comparison of the Bronchodilating Effect of Salmeterol and Zafirlukast in Combination with That of Their Use as Single Treatments in Asthma and Chronic Obstructive Pulmonary Disease

Background: It has been suggested that the effect of a β₂-agonist is additive with that of a cysteinyl leukotriene 1 receptor antagonist. Objectives: The present study was designed to answer the question of whether combined administration of inhaled salmeterol and oral zafirlukast at the standard doses would result in greater bronchodilation in patients with chronic airway obstruction than the use of either drug alone. Methods: The study was performed using a double-blind, double-dummy, crossover, randomised design, and was conducted on 4 non-consecutive days. Sixteen patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 10 non-smoker asthmatic patients received 40 mg of oral zafirlukast, 50 µg of inhaled salmeterol, 50 µg of inhaled salmeterol plus 40 mg of oral zafirlukast of placebo. Lung function was assessed before drug administration and 30, 60, 120, 180 and 240 min thereafter. At the end of the 4-hour period, each patient received 400 µg of inhaled salbutamol and spirometric testing was performed 30 min later. Results: In both asthmatic and COPD patients, the overall effect of salmeterol and zafirlukast on the forced expiratory volume in 1 s (FEV₁) was considered extremely significant (p < 0.0001), with a maximum bronchodilation above baseline after 180 min (20.7 and 11.0%, respectively) in asthmatics and after 2 h (21.7 and 11.2%, respectively) in COPD subjects. Zafirlukast did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone in either asthmatic or COPD patients. Nevertheless, 7 out of 16 COPD patients and 7 out of 10 asthmatic patients had a further improvement after the combination of salmeterol and zafirlukast. The mean difference in pre- and post-salbutamol FEV₁ values in both asthmatic and COPD patients after zafirlukast was significant (p < 0.05), but that after salmeterol and the combination of the two drugs was not significant (p > 0.05). The difference between placebo and zafirlukast was not significant following inhaled salbutamol given 4 h after each treatment. Conclusions: Both salmeterol and zafirlukast induced a significant increase in FEV₁, although salmeterol elicited a greater improvement in both asthmatic and COPD patients. Apparently, zafirlukast at the clinically recommended dose did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone, either in asthma or COPD. In any case, evaluation of the effect of the combination over a 12-hour period is mandatory.

Administration of Aerosolized Antibiotics in Cystic Fibrosis Patients

High rates of colonization and the challenge of managing Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) have necessitated a search for safe and effective antibiotics. Currently, therapy with an aminoglycoside in combination with a beta-lactam or a quinolone antibiotic is the standard. Unfortunately, it is difficult to deliver high doses of these antibiotics via the IV route without significant systemic adverse events (AEs) (eg, ototoxicity and nephrotoxicity). Recently, a reformulation of the aminoglycoside antibiotic tobramycin has become available in a preservative-free, pH-adjusted solution for inhalation by jet nebulizer. A 96-week series of clinical studies including 520 patients, aged > or = 6 years, with moderate-to-severe CF has evaluated the long-term safety and effectiveness of this formulation. Patients received tobramycin solution for inhalation (TSI) or placebo, which was administered in alternating cycles of 28-days-on and 28-days-off therapy, plus their usual CF care for 6 months with open-label follow-up extended to 2 years. Most AEs declined in frequency with increasing TSI exposure. Patients receiving TSI spent 25 to 33% fewer days in the hospital. Following the initiation of TSI treatment, patients experienced significant increases in FEV(1). FEV(1) values were maintained above baseline for the duration of the study series. Antibiotic susceptibility of the bacterial isolates did not predict clinical response. TSI was safe, well-tolerated, and effective for long-term treatment (96 weeks) of P aeruginosa colonization and infection in CF patients.

Time-Dependent Changes in Orally Exhaled Nitric Oxide and Pulmonary Functions Induced by Inhaled Cortico-steroids in Childhood Asthma

Exhaled nitric oxide levels are elevated in asthmatic children and decrease after inhaled steroid treatment. We evaluated the time-dependent changes in fractional exhaled nitric oxide concentration (FENO) and pulmonary function parameters following inhaled steroid therapy. Thirty-nine steroid-naive atopic patients (age 11.92 ± 0.48 years) with mild intermittent asthma and 22 age-matched healthy controls were enrolled in the study; pulmonary functions and FENO levels were measured. Low doses of inhaled steroids were prescribed to all asthmatic patients who were reevaluated in a second visit (between 10 and 40 days after the beginning of the treatment). At the enrolment, asthmatic patients had similar forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) values (p > 0.05) but reduced forced expiratory flows at 25–75% of the vital capacity (FEF25–75%) values, as compared to controls (p < 0.05). In addition, FENO levels were significantly higher in asthmatics with respect to control subjects (30.8 ± 3.0 and 4.0 ± 0.5 ppb, respectively; p < 0.01). All asthmatics had FENO levels higher than 8.8 ppb (i.e., >2 standard deviations of the mean in controls). After steroid treatment, patients showed significant improvement of FEV1, FVC, and FEF25–75% (p = 0.0001; each comparison) and a reduction of FENO levels (p = 0.0001). A weak significant correlation was found between percent decrease in FENO levels and percent increase in FEV1 (r = 0.33, p = 0.04) or in FEF25–75% (r = 0.4, p = 0.01) after treatment. When changes in FENO levels and in pulmonary function parameters were corrected for days of treatment, significant correlations were still present between percent decrease in FENO levels and percent increase in FEV1 (r = 0.57, p = 0.0004) or percent increase in FEF25–75% (r = 0.45, p = 0.006). Sixteen of the 39 asthmatic patients were evaluated on two occasions after the beginning of treatment, at days 10 and 40. The significant reduction in FENO levels (p < 0.01) and the significant increase in FEV1 and FEF25–75% values observed (p < 0.05) after 10 days did not further improve at day 40. These data show that it is possible to demonstrate early effects of low-dose inhaled steroids in asthmatic children using objective measurements of airway caliber and inflammation.

Additive Effects of Salmeterol and Fluticasone or Theophylline in COPD

ss(2)-Agonists and corticosteroids or theophylline can interact to produce beneficial effects on airway function in asthma, but this has not been established in COPD. Eighty patients with well-controlled COPD were randomized to receive 3 months of treatment in one of four treatment groups: (1) salmeterol, 50 microg bid; (2) salmeterol, 50 microg, plus fluticasone propionate, 250 microg bid; (3) salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid; and (4) salmeterol, 50 microg, plus titrated theophylline bid. At each visit, a dose-response curve to inhaled salbutamol was constructed using a total cumulative dose of 800 microg. A gradual increase in FEV(1) was observed with each of the four treatments. Maximum significant increases in FEV(1) over baseline values that were observed after 3 months of treatment were as follows: salmeterol, 50 microg bid, 0.163 L (95% confidence interval [CI], 0.080 to 0.245 L); salmeterol, 50 microg, plus fluticasone propionate, 250 microg bid, 0.188 L (95% CI, 0.089 to 0. 287 L); salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid, 0.239 L (95% CI, 0.183 to 0.296 L); and salmeterol, 50 microg, plus titrated theophylline bid, 0.157 L (95% CI, 0.027 to 0. 288 L). Salbutamol always caused a significant dose-dependent increase in FEV(1) (p < 0.001), although the 800-microg dose never induced further significant benefit when compared with the 400-microg dose. The mean differences between the highest salbutamol FEV(1) after salmeterol, 50 microg, plus fluticasone propionate, 500 microg bid, and that after salmeterol, 50 microg, plus titrated theophylline bid or salmeterol, 50 microg bid, were statistically significant (p < 0.05). These data show that both long-acting ss(2)-agonists and inhaled corticosteroids have a role in COPD. The data also show that fluticasone propionate and salmeterol given together are more effective than salmeterol alone. Moreover, it suggests that the addition of fluticasone propionate to salmeterol allows a greater improvement in lung function after salbutamol, although regular salmeterol is able to improve lung function in COPD patients without development of a true subsensitivity to its bronchodilator effect. In any case, patients must be treated for at least 3 months before a real improvement in lung function is achieved.

Salbutamol via Easyhaler®is at least as effective as salbutamol via Turbuhaler®in the treatment of histamine-induced bronchoconstriction

The aim of this study was to compare the clinical efficacy and acceptability of salbutamol inhaled via Easyhaler®and Turbuhaler®multi-dose dry powder inhalers in the treatment of histamine-induced bronchoconstriction. Thirty-two adult patients with asthma and/or bronchial hyper-reactivity were included in the study, which was carried out according to a randomized, double-blind, double-dummy, cross-over design. Histamine challenge test was performed on 2 study days separated by at least 7 days. The challenge test was continued until a ≥20% fall in forced expiratory volume in 1 sec (FEV1) was achieved. The patients then inhaled a single 100 μ g dose of salbutamol from Easyhaler®, or from Turbuhaler®. FEV1was assessed by flow–volume spirometry before and after histamine challenge and 1·5, 3, 5, 10, 15, 20, 30 and 60 min after salbutamol inhalation. The primary efficacy variable was the maximum percentage change in FEV1from the post-challenge value. The secondary efficacy variable was area under the curve (AUC) of FEV1. At the end of the study, acceptability of salbutamol Easyhaler®was evaluated using a questionnaire and Easyhaler®was also compared with the inhalation device the patient had used earlier.Twenty-six patients completed the study. Both salbutamol Easyhaler®and salbutamol Turbuhaler®produced a rapid and significant increase in FEV1, with maximum percentage changes being 43·9% (±15·3) and 40·5% (±21·9) from the post-challenge value, respectively. There were no significant differences between the two inhalation devices in terms of changes in FEV1or AUC of FEV1. The use of Easyhaler®and getting a new dose from Easyhaler®was considered to be very easy by 65% and easy by 35% of the patients. None considered it difficult. Of 16 patients who had used Turbuhaler®earlier, 19% considered Easyhaler®much better, 44% better, and 38% the same as Turbuhaler®, and none considered it worse.In conclusion, the results show that salbutamol Easyhaler®was at least as effective as salbutamol Turbuhaler®in the treatment of histamine-induced bronchoconstriction. In addition, the patients considered Easyhaler®very easy or easy to use. The majority of patients who reported Turbuhaler®as their own inhaler considered Easyhaler®better or much better than Turbuhaler®.

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.

The Effect of glucocorticoid on the change of nitric oxide and cytokine levels in induced sputum from patients with bronchial asthma

Background It has been well known that bronchial asthma is a chronic airway inflammatory disorder. Recently, sputum specimen induced with hypertonic saline was introduced as a simple and useful noninvasive medium to investigate airway inflammation and symptom severity in patients with asthma. We examined the eosinophil, cationic protein (ECP), interleukin(IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and nitric oxide (NO) derivatives in induced sputum from patients with bronchial asthma in order to determine the role of NO and various inflammatory cytokines as a useful markers of airway inflammation of changes in pulmonary function tests and symptoms. Methods A total 30 patients with bronchial asthma received oral prednisolone 30 mg daily for 2 weeks. Forced expiratory volume in one second (FEV), total blood eosinophil count, and induced sputum eosinophil count, ECP, IL-3, IL-5, GM-CSF, and NO derivatives were determined before and after the administration of prednisolone. Results Of the 30 patients, 13 (43.3%) were male and 17 (56.7%) were female. The mean age of patients was 41.8 years (range 19-64 years). Two patients could not produce sputum at the second study and 3 could not be followed up after their first visit. Two weeks after the prednisolone administration, there was a significant increase in FEV1 (% of predicted value) from 78.1±20.6% to 90.3±18.3% (P<0.001). The eosinophil percentages in induced sputum were significantly decreased after treatment with prednisolone, with values of 56.1±27.2% versus 29.6±21.3% (P<0.001), and ECP were 134.5±68.1 µm/L versus 41.5±42.4 µm/L (P<0.001) respectively. After the prednisolone treatments, the eotaxin concentration also showed a decreasing tendency from 26.7±12.8 pg/ml to 21.7±8.7 pg/ml. There was a decreasing tendency but no significant differences in total blood eosinophil count(425.7±265.9 vs 287.7±294.7) and in the concentration of NO derivatives (70.4±44.6 µmol%/L vs 91.548.3 µmol/L) after the predinisolone treatments. IL-3, IL-5, GM-CSF were undetectable in the sputum of most subjects either before the prednisolone treatments of after the treatments. Before the prednisolone treatments, a significant inverse correlation was observed between FEV1 and sputum ECP (r=-0.364, P<0.05) and there was a significant correlation between sputum eosinophils and eotaxin (r=0.369, P<0.05). Conclusion The eotaxin and ECP concentration in induced sputum may be used as markers of airway inflammation after treatments in bronchial asthma. In addition, the measurement of sputum eosinophil percentages is believed to be a simple method displaying the degree of airway inflammation and airway obstruction before and after the predinisolone treatment in bronchial asthma. However, unlike exhaled NO, the examination of NO derivatives with Griess reaction in induced sputum is considered an ineffective marker of changing airway inflammation and obstructing symptoms.

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 β₂-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 (FEV₁) 19.3 ± 3.1%] were evaluated after inhalation of 12 μg formoterol and 50 μg salmeterol. Results: Regarding the onset of bronchodilator action, the mean absolute increase of 0.20 liters in FEV₁ 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 FEV₁ 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 FEV₁ of formoterol (3.5 ± 1.3 l·h) and salmeterol (3.2 ± 1.2 l·h) averaged over 12 h were comparable and higher than placebo values (1.2 ± 0.5 l·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 μg formoterol and 50 μg salmeterol provided comparable bronchodilation within 12 h and had tolerable side effects in patients with mild to severe COPD having partially reversible airway obstruction.

Time to onset of effect of fluticasone propionate in patients with asthma

Background: The effectiveness of inhaled glucocorticoids in the treatment of asthma is well documented; however, times to onset and maximal treatment effects of these agents have been poorly described. Objective: We sought to determine the time to onset of effect and the time to the best observed effect of inhaled fluticasone propionate (FP) in patients with asthma. Methods: Data from 8 randomized, double-blind, placebo-controlled clinical trials of at least 8 weeks’ duration were analyzed. Corticosteroid-naive patients (n = 1461) were treated with either FP (25 μg to 500 μg) or placebo twice daily. Efficacy evaluations included morning peak expiratory flow (PEF), asthma symptom scores, supplemental albuterol use, and FEV 1 . Results: Statistically significant improvements in PEF, asthma symptom scores, and supplemental albuterol use were observed beginning on day 1 of treatment in the FP group versus the placebo group ( P < .001); significant increases in FEV 1 were observed at the first measurement at week 1 ( P < .001). The best observed effect occurred within 3 weeks of the start of FP treatment for PEF (+36 L/min) and FEV 1 (+0.52 L) and within 2 weeks for reduction in supplemental albuterol use and asthma symptom scores. Patients with the most severe airflow obstruction had the greatest change in PEF (+56 L/min) and fastest time to 50% of best observed effect (3 days) compared with patients with mild or moderate airflow obstruction; however, time to best observed effect was similar in the 3 groups (20 to 27 days). Conclusion: In patients with asthma, the onset of significant benefit of FP on PEF, symptoms, and rescue albuterol use occurred within 1 day of the start of therapy. FEV 1 improved within 1 week of the start of therapy (the first measurement after randomization). There was no effect of sex, age, or dose of FP on the time to response. The best observed response in PEF varies with the degree of baseline airflow obstruction; however, the degree of airflow obstruction has no effect on the time to best observed response. (J Allergy Clin Immunol 1999;103:780-8.)

Forced expiratory maneuvers in very young children. Assessment of flow limitation.

The application of negative expiratory pressure (NEP) to the airway opening during forced expiratory maneuvers has recently been described as a noninvasive method to assess whether flow limitation is achieved in adults. This methodology has great potential for extending the measurement of forced expiratory maneuvers to young children who may not produce maximal efforts as reproducibly as adults. We used NEP to assess flow limitation in 10 children between 3 and 5 yr of age. NEP was well tolerated by all subjects. With the application of NEP, there was not a step increase in flow, a finding consistent with flow limitation for the subjects. In addition to visual inspection, we proposed a method to quantify the change in flow during a short NEP. The flow-volume curves obtained with and without NEP were visually the same, other than the flow transients produced by NEP. The calculated values of FVC and FEF25-75 were not significantly different when measured from flow- volume curves with and without NEP. There was a statistically significant increase in FEV1 with NEP; however, the group mean increase in FEV1 was less than 2%. We conclude that NEP may be a useful technique to determine whether flow limitation has been achieved in young children performing forced expiratory maneuvers.

Effects of Lung Volume Reduction Surgery on Exercise Pulmonary Hemodynamics in Severe Emphysema

To clarify the effects of lung volume reduction surgery (LVRS) on pulmonary hemodynamics in severe emphysema and to evaluate the role of pulmonary circulation in the increased exercise performance after LVRS. In eight male patients with severe emphysema, we measured pulmonary artery (Ppa) and occlusion (Pop) pressures and cardiac output through a Swan-Ganz thermodilution catheter, and we calculated cardiac index (CI), pulmonary vascular resistance index, and driving pressure. The study was performed at rest and during exercise using a supine bicycle ergometer at 25 W, under room air and O2 inhalation. Exercise performance was expressed as endurance time in minutes. Pulmonary function tests were performed. The patients underwent an identical study before and 6 months after LVRS. The patients' exercise performance was significantly increased after LVRS (5.9+/-1.8 min) compared with that before LVRS (3.6+/-0.9 min). LVRS resulted in a significant increase in FEV1 and a significant decrease in residual volume. Before LVRS, Ppa was increased both at rest and during exercise. LVRS did not change rest or exercise Ppa. LVRS significantly decreased Pop during exercise from 24+/-10 mm Hg to 18+/-7 mm Hg. CI at rest and during exercise were significantly increased after LVRS. O2 administration significantly decreased Ppa during exercise both before and after LVRS. These findings suggest that LVRS does not improve pulmonary hypertension at rest or during exercise in patients with severe emphysema and that elevated Pop during exercise before LVRS is probably related to lung mechanic abnormalities.

Chest physical therapy management of patients with cystic fibrosis. A meta-analysis.

The purpose of this overview is to quantitatively assess the conflicting body of literature concerning the efficacy of physical therapy modalities for clearing bronchial secretions in the treatment of patients with cystic fibrosis (CF). The modalities examined included positive expiratory pressure (PEP) mask, forced expiratory technique (FET), exercise (EX), autogenic drainage (AD), and standard physical therapy (STD), consisting of postural drainage, percussion, and vibration. Computerized searches of the MEDLINE and Cumulative Index for Nursing and Allied Health databases were performed for the years from 1966 to 1993. The authors of relevant papers were contacted for unpublished information. Studies were considered relevant if they met the following criteria: randomized trials in patients with a definite diagnosis of CF; an intervention of any combination of PEP, FET, STD, AD, or EX; and an outcome of FEV1, sputum weight, or sputum clearance. A review of 456 citations yielded 65 potentially relevant trials and 8 review articles; of these, 35 met the inclusion criteria and were incorporated into the overview. These studies evaluated different combinations of physical therapy modalities; therefore, we performed seven separate meta-analyses comparing the independent techniques using the pooled effect size technique. Standard physical therapy resulted in a significantly greater sputum expectoration than no treatment (effect size of 0.61 SD units, p < 0.0001). The combination of standard therapy with EX with associated with a statistically significant increase in FEV1 over STD alone (effect size of 0.48 SD units, p = 0.04). No other differences between physical therapy modalities were found.

LONG TERM EFFECTS OF A LONG-ACTING B2-ADRENORECEPTOR AGONIST, SALMETEROL, ON AIRWAY HYPERRESPONSWENESS IN PATIENTS WITH MILD ASTHMA

Purpose of the Study. To investigate long term effects of long-acting β2 agonist (salmeterol) on bronchodilation and bronchoconstriction caused by methacholine (MCH). Study Population. Twenty-four adult asthmatics (average age 25, range 19-36 yrs) who had not required any regular medication for 6 months. Methods. Parallel double blind study where either salmeterol 50 µg twice daily or placebo was administered during an 8-week trial. A complete dose response curve for MCH was recorded on days 0, 28, 56, and 2 and 4 days after the study ended. The PC20 (concentration required for 20% drop in FEV1) was recorded. Albuterol in an aggregate dose of 400 µg/day was allowed as rescue medication. Findings. Salmeterol caused a significant increase in FEV1 which did not change throughout the study. On the first treatment day salmeterol afforded protection against bronchoconstriction with 10-fold increase in PC20. After 4 and 8 weeks of therapy the change in PC20 returned to baseline after 4 days of washout. Reviewer's Comments. The regular use of long-acting beta agonist leads to tolerance to its protective effect against a bronchoconstrictor stimulus, although bronchodilator properties remain unchanged. Although the mechanism is unknown, this data suggests that long-term monotherapy with beta agonist may not be optimal.

Auranofin in the treatment of steroid dependent asthma: a double blind study.

Long term administration of oral corticosteroids in patients with asthma may be associated with serious side effects. Non-steroidal anti-inflammatory drugs, including gold salts, have been shown to reduce the need for systemic corticosteroid treatment in uncontrolled studies. The effect of oral gold (auranofin) on asthma symptoms, lung function, and the need for oral prednisone treatment was investigated. A 26 week randomised, double blind, placebo controlled, parallel group trial of auranofin was performed in 32 patients with moderately severe chronic asthma who required an oral corticosteroid dose of at least 5 mg prednisone a day (or equivalent) or 2.5 mg/day prednisone plus more than 800 micrograms/day inhaled corticosteroids. Auranofin was given orally in a dose of 3 mg twice daily. Asthma symptoms, lung function, and adverse effects were assessed at regular intervals. After 12 weeks of treatment prednisone dosage was tapered down by 2.5 mg every two weeks if the patient was clinically stable. Asthma exacerbations were treated with short courses of high doses of oral steroids. Twenty eight of the 32 patients, 13 in the placebo group and 15 in the auranofin group, completed the study. The total corticosteroid reduction achieved after 26 weeks of treatment was significantly greater (4 mg) in the auranofin group than in the placebo group (0.3 mg). The number of exacerbations requiring an increase of steroids was greater in the placebo group (2.1) than in the active group (0.9). A significant increase in FEV1 of 6.4% predicted occurred in the auranofin group during the study and there was a reduction of asthma symptoms such as wheezing and cough. There was no difference between the groups in peak flow measurements or in the number of asthma attacks. The incidence of side effects of auranofin was low, but exacerbations of constitutional eczema were noticeable. Auranofin provides an effective adjunct to treatment for steroid dependent asthma, leading to a reduction of oral steroid dose.

Effects of celiprolol, a cardioselective beta-blocker, on respiratory function in asthmatic patients

The aim of this study was to compare the pulmonary effects of a single dose of celiprolol 400 mg, versus bisoprolol 20 mg and the combination of celiprolol 400 mg plus propranolol 40 mg versus placebo plus propranolol 40 mg. We conducted a double-blind randomized cross-over study in 10 stable asthmatic patients (mean age +/- SD 31 +/- 7 yrs) with forced expiratory volume in one second (FEV1): 2.5 +/- 0.7 l. A three-day washout period preceded each treatment period. Measurements of respiratory function were done before treatment and after 90, 120 and 180 min. There was a significant increase of FEV1 (+12%) and forced vital capacity (FVC) (+8%) after celiprolol (p less than 0.05) and a decrease of FEV1 (-9%) after propranolol. Concerning the combination, celiprolol inhibits the bronchoconstrictor effects of propranolol. We conclude that celiprolol has bronchosparing properties in asthmatic patients, and even improves some of the ventilatory parameters.

A Comparison of the Effects of Anticholinergic and ß2-Agonist and Combination Therapy on Respiratory Impedance in COPD

The effects of three different regimens of inhaled bronchodilators on spirometry and respiratory impedance as measured with the technique of forced oscillations were compared in a double-blind crossover study in 22 patients with stable chronic obstructive pulmonary disease (FEV1 less than 70 percent predicted). On three trial days, patients inhaled, in random order, 40 micrograms ipratropium bromide, 200 micrograms fenoterol hydrobromide, or a combination of 40 micrograms ipratropium and 100 micrograms fenoterol from a powder inhaler, followed by a second dose of the same drug after 60 min. The effects were measured at baseline and 20, 40, 60, and 120 min after the first inhalation. No significant decrease in total respiratory resistance at 8 Hz (Rrs [8]) was observed after ipratropium, whereas Rrs (8) decreased significantly 20 min after fenoterol and 40 min after the combination regimen (p less than 0.05). All three studied drugs resulted in a significant increase in the reactance (p less than 0.01) and decrease in resonant frequency. Both fenoterol (delta FEV1 34 percent, p less than 0.0001) and the combination regimen (delta FEV1 38 percent, p less than 0.0001) resulted in a significantly larger increase in FEV1 than ipratropium alone (delta FEV1 17 percent, p less than 0.0001). A second dose of fenoterol and of the combination regimen resulted in a further significant increase in FEV1 after 120 min (p less than 0.05). A second dose of ipratropium did not result in a further significant increase in FEV1. The changes in respiratory impedance were qualitatively similar for all three drug regimens, but larger in absolute terms after fenoterol and the combination regimen than after ipratropium. The similar effect of these drugs on the reactance can be explained by an increase in the capacitance of the respiratory system, and in combination with a decrease in frequency dependence of resistance, by assuming a decrease in peripheral airway resistance.

Long-term, double-blind comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and adults with asthma

This parallel-group study compared the safety and efficacy of controlled-release albuterol versus sustained-release theophylline, both administered every 12 hours. One hundred twenty-four adolescent and adult patients with asthma and with chronic reversible obstructive airway disease were studied. All patients qualified with an FEV 1 ⩽80% of predicted (not receiving treatment) and ⩾15% reversibility in FEV 1 or ⩾25% reversibility in FEF 25–75% after inhaled isoproterenol. All patients were known to be able to take theophylline without unacceptable adverse effects. Theophylline was titrated for patients to receive, unblinded, theophylline serum concentrations of 10 to 20 μg/ml. With subsequent randomization, 62 patients continued to receive theophylline and 62 patients started taking albuterol in the 12-week, double-blind, double-dummy portion of the study. Pulmonary function was measured during a pretreatment visit (unmedicated) and serial assessment was made starting just before the morning dose and continuing for 12 hours after the dose at the end of 1, 6, and 12 weeks of treatment. Both treatment groups exhibited statistically significant increases in FEV 1 from the pretreatment visit to all times of observation at weeks 1, 6, and 12. The increases in FEV 1 were not significantly different between albuterol and theophylline administration. There was no evidence of tolerance to the bronchodilatory effect during 12 weeks in either treatment group. Only one patient in the study stopped treatment because of an adverse effect. This patient had tremor during albuterol administration. All other adverse events were tolerated or resolved during treatment. Controlled-release albuterol proved to be a safe and effective alternative to sustained-release theophylline for management of patients with asthma.

Bronchodilator action of inhaled fenoterol and ipratropium in normal subjects: a teaching exercise for medical students.

1. A pharmacology practical class for preclinical medical students was designed as a placebo-controlled, double-blind trial of two bronchodilator drugs. 2. Fenoterol hydrobromide (800 micrograms), ipratropium bromide (80 micrograms) and placebo (propellant only) were given by metered dose inhaler to 79 non-asthmatic volunteers. Their effects on FEV1, heart rate and tremor (assessed by the time taken to thread five sewing needles) were compared. 3. Both drugs caused a significant increase in FEV1: the largest group mean increase was 77 ml, recorded 15 min after fenoterol, and 103 ml, recorded 60 min after ipratropium. 4. Fenoterol also caused a mean increase of 8.7 beats min-1 in heart rate, 5 min after inhalation. This effect was still apparent after 60 min. 5. Fenoterol appeared to prolong needle threading time in some individuals. 6. In subjects who inhaled fenoterol, there were no correlations between the increase in FEV1, the increase in heart rate, or the development of tremor. 7. It is concluded that inhaled fenoterol and ipratropium both cause bronchodilation in normal subjects. Systemic absorption of fenoterol is indicated by the rapid increase in heart rate. The bronchodilator effect of ipratropium suggests that resting airway calibre is governed partly by parasympathetic tone in normal subjects. 8. The bronchodilator and systemic effects of these drugs can be used to demonstrate pharmacological, therapeutic and statistical principles to medical students.

Comparison of terbutaline, isotonic saline, ambient air and non-treatment in patients with reversible chronic airway obstruction

The increase in forced expiratory volume in one second (FEV1) seen in asthmatics after inhalation of isotonic saline was studied in a blind, cross-over investigation of 24 consecutive out-patients presenting with reversible chronic airway obstruction. Forced expiratory manoeuvres allowing the measurement of FEV1 and forced vital capacity (FVC) were performed at six time intervals during a period of one hour according to the following regimes: inhalation of terbutaline by means of a Pari-inhalier Boy for 10 min; inhalation of isotonic saline under the same conditions; inhalation of ambient air under the same conditions (placebo with noisy nebulizer); inhalation of air without the nebulizer (non-treatment) in order to determine whether the impact of treatment by a nebulizer influences the measured lung function. A statistically significant increase in FEV1 was observed after each of the four regimes. The increase was large following terbutaline inhalation. After the other three regimes, it was significantly smaller and of about the same magnitude in each case. The increase in FEV1 after the non-treatment regime was unexpected and could possibly be due to the repeated dynamic spirometry. The increase in FEV1 after isotonic saline and ambient air (noisy nebulizer) did not differ from the increase after the non-treatment regime. We conclude that neither isotonic saline nor the impact of treatment with a noisy nebulizer have a measurable effect on lung function.