Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency

Salmeterol and formoterol are two long-acting beta2-agonists for inhalation, currently being used in clinical practice. The aim of the present study was to investigate the onset of action, duration of effect and potency of these two beta2-agonists in asthmatic patients. Patients (n=28) were included on the basis of salbutamol stepwise reversibility (100, 100 and 200 microg, given cumulatively; total reversibility > or =15%). In a double-blind placebo-controlled crossover study, the bronchodilating properties of formoterol 6, 12 and 24 microg were compared with the effects of salmeterol 50 microg. Formoterol was given via Turbuhaler and salmeterol via Diskhaler, and forced expiratory volume in one second (FEV1) was monitored during 12 h. Formoterol at all doses had a more rapid onset than salmeterol as judged from bronchodilation at 3 min after the dose. Formoterol at all doses had a similar duration of effect to salmeterol 50 microg, as judged from bronchodilation at 12 h after dose administration. When the relative potency of the two drugs was compared, salmeterol 50 microg was estimated to correspond to formoterol 9 microg (95% confidence interval: 3-19 microg). We confirm that formoterol and salmeterol are both long-acting beta2-agonists, but with some differences in effect profile. We confirm the more rapid onset of action of formoterol compared with salmeterol, and furthermore, no difference in duration of effect is evident.     

Dose equivalence and bronchoprotective effects of salmeterol and salbutamol in asthma

BACKGROUND: Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio. METHODS: The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded. RESULTS: Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms. CONCLUSIONS: The data are compatible with a weight-for-weight dose ratio for salmeterol:salbutamol of < or = 1:4.     

Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia

OBJECTIVE: There are several reports of documented adverse cardiac effects during treatment with beta-agonists. Since one should be aware that this may be a problem in patients with preexisting cardiac disorders, we have conducted a randomized, single-blind, balanced, crossover, placebo-controlled study to assess the cardiac effects of two single doses of formoterol (12 microg and 24 microg) and one single dose of salmeterol (50 microg) in 12 patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia (PaO2<60 mm Hg). DESIGN: Each patient was evaluated at a screening visit that included spirometry, blood gas analysis, plasma potassium measurement, and 12-lead ECG. In following nonconsecutive days, all patients underwent Holter monitoring 24 h during each of the four treatments. Holter monitoring was started soon before drug administration in the morning. Plasma potassium level was measured before drug inhalation, at 2-h intervals for 6 h, and at 9, 12, and 24 h following administration. None of our patients took rescue medication during the 24-h period. RESULTS: Holter monitoring showed a heart rate higher after formoterol, 24 microg, than after formoterol, 12 microg, and salmeterol, 50 microg, and supraventricular or ventricular premature beats more often after formoterol, 24 microg. Formoterol, 24 microg, significantly reduced plasma potassium level for 9 h when compared with placebo, whereas formoterol, 12 microg, was different after 2 h and salmeterol, 50 microg, from 4 to 6 h. CONCLUSIONS: The results of this study suggest that if a COPD patient is suffering from preexisting cardiac arrhythmias and hypoxemia, long-acting beta-agonists may have adverse effects on the myocardium, although the recommended single dose of salmeterol and formoterol, 12 microg, allows a higher safety margin than formoterol, 24 microg.     

Proteins in uterine secretions of fertile and sterile patients using SDS polyacrylamide gel electrophoresis (SDS-PAGE)

The long-acting beta 2-agonist salmeterol has been shown in several in vitro studies to produce non-beta-mediated relaxant effects. The aim of the present study was to investigate whether these effects have any relevance in humans in vivo. Thirteen healthy individuals were studied in a randomized, double-blind, cross-over study on five separate days. The subjects were pre-treated orally with either propranolol 400 mg in order to block beta-adrenoceptor mediated effects or placebo. Two hours after drug intake, three increasing doses of salmeterol (25 + 50 + 100 micrograms), salbutamol (100 + 200 + 400 micrograms) or placebo were given from matched meter dose inhalers at 1-h intervals between doses. Specific airway conductance (sGAW) was measured in a body plethysmograph at the beginning of the experiment and 30 and 60 min after each inhaled dose of the beta-agonists. Salmeterol and salbutamol produced the same maximal increase in sGAW and had the same area under the dose-response curves. Pre-treatment with propranolol totally inhibited the effect of both drugs. In conclusion, salmeterol at clinically used doses did not produce any non-beta-mediated bronchodilating effect in normal individuals, measured as sGAW. Salmeterol and salbutamol showed the same efficacy but salmeterol was four times more potent than salbutamol.     

Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.     

The detection of cytochrome P450 2E1 and its catalytic activity in rat testis

The aim of this study was to compare the efficacy of 100 micrograms of salbutamol inhaled from a new metered-dose powder inhaler (MDPI, Leiras Taifun, Finland) with that of a same dose of salbutamol inhaled from a conventional pressurized metered-dose inhaler with a large volume spacer (pMDI + S) in protecting against methacholine (Mch) induced bronchoconstriction. This was a 3 day, randomized, cross-over, partly blinded, placebo-controlled multicentre study where the pMDI + S was used as an open control. Twenty-six asthmatic outpatients with a baseline FEV1 > or = 60% of predicted and with bronchial hyperreactivity (PD20 FEV1 < or = 890 micrograms of Mch) were studied. On each study day the patients underwent an Mch provocation 30 min after inhaling placebo from the MDPI or a dose of 100 micrograms of salbutamol from the MDPI and from the pMDI + S. PD20 FEV1 and dose-response slope [DRS; maximal change in FEV1 (%)/dose of Mch (mumol)] were used to evaluate efficacy. The median values of PD20 FEV1 were 250, 622 and 1737 micrograms after placebo MDPI, salbutamol pMDI + S and salbutamol MDPI, respectively. The corresponding DRS values were -11.0%, -4.5% and -2.0% mumol-1. With both parameters, all differences were statistically significant (P < 0.05). In conclusion, 100 micrograms of salbutamol inhaled from Leiras Taifun MDPI offers better protection against Mch-induced bronchoconstriction than 100 micrograms of salbutamol from a pMDI connected to a large volume spacer device.     

Effect of short- and long-acting inhaled beta2-agonists on exhaled nitric oxide in asthmatic patients

Increased concentrations of exhaled nitric oxide (NO) occur in patients with asthma, and exhaled NO may be useful for assessing the effect of drug therapy on airway inflammation. Beta2-agonists have been proposed to have both proinflammatory and anti-inflammatory effects. We therefore assessed exhaled NO after beta2-agonists in asthmatic patients. Two randomized, double-blind, placebo-controlled studies were conducted. Firstly, exhaled NO was measured in 18 asthmatics (9 taking inhaled glucocorticosteroids (GCS)) before and after nebulized salbutamol (5 mg), or identical placebo (0.9% saline). Exhaled NO and forced expiratory volume in one second (FEV1) were measured at 15 min intervals for 1 h (Study 1). Secondly, the effect of 1 week of treatment with the long-acting beta2-agonist, salmeterol (50 microg b.i.d.), added to either budesonide (800 microg b.i.d.) or placebo, was studied in eight mild asthmatic subjects (Study 2). Exhaled NO was measured by a chemiluminescence analyser, adapted for on-line recording. In Study 1, exhaled NO showed no significant change at any time-point in patients not taking inhaled GCS. In asthmatics on inhaled GCS, exhaled NO increased compared to placebo at 15 and 30 min, but this did not reach statistical significance. In Study 2, treatment with salmeterol increased FEV1, but exhaled NO levels were not significantly changed, either after budesonide treatment (143+/-35 to 179+/-67 ppb), or after placebo (201+/-68 to 211+/-65 ppb). Our results confirm that single high dose salbutamol does not increase exhaled nitric oxide in asthmatics not taking inhaled glucocorticosteroids. Salbutamol may increase exhaled nitric oxide in asthmatics taking inhaled glucocorticosteroids. However, regular use of salmeterol resulted in no change in exhaled nitric oxide, either used alone or in combination with inhaled glucocorticosteroids.     

Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group

BACKGROUND: The role of long-acting, inhaled beta2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. METHODS: After a four-week run-in period of treatment with budesonide (800 microg twice daily), 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 microg of budesonide plus placebo, 100 microg of budesonide plus 12 microg of formoterol, 400 microg of budesonide plus placebo, or 400 microg of budesonide plus 12 microg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma, symptoms, and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days. RESULTS: The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent, respectively, when formoterol was added to the lower dose of budesonide. The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent, respectively. Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent, respectively. Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide, but the improvements with formoterol were greater. CONCLUSIONS: In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial. The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma.     

Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids

The aim of the present study was to examine the efficacy of low-dose inhaled budesonide (BUD) administered via Turbuhaler once or twice daily on symptoms, lung function and bronchial hyperreactivity in children with mild asthma. One hundred and sixty-three children (mean age 9.9 yrs, 56 females/107 males) with mild asthma (forced expiratory volume in one second (FEV1) 103% of predicted, morning peak expiratory flow (PEF) 87% pred, reversibility in FEV1 3%, fall in FEV1 after exercise 10.4% from pre-exercise value) and not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. After a two-week run-in period, the children received inhaled BUD 100 microg or 200 microg once daily in the morning, 100 microg twice daily or placebo for 12 weeks. Exercise and methacholine challenges were performed before and at the end of treatment. After 12 weeks of therapy, the fall in FEV1 after an exercise test was significantly less in all three BUD groups (43-5.1%) than in the placebo group (8.6%). Bronchial hyperreactivity to methacholine with the provocative dose causing a 20% fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo (ratio at the end of treatment 156%). Changes in baseline lung function (FEV1 and PEF) were less marked than changes in bronchial responsiveness. In conclusion, low doses of inhaled budesonide, given once or twice daily, provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function.     

Salmeterol xinafoate as maintenance therapy compared with albuterol in patients with asthma

OBJECTIVE: To compare the efficacy and safety of inhaled salmeterol xinafoate, a long-acting beta 2-adrenoceptor agonist, with that of albuterol, a short-acting inhaled beta 2-agonist, in the treatment of asthma. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Eleven outpatient clinical centers. SUBJECTS: A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy. INTERVENTION: Patients were treated with salmeterol xinafoate (42 micrograms inhaled twice daily), albuterol (180 micrograms inhaled four times daily), or placebo (four times a day) for 12 weeks; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms. MAIN OUTCOME MEASURES: Serial 12-hour forced expiratory flow in 1 second (FEV1), peak expiratory flow (PEF), asthma symptoms, nocturnal awakenings due to asthma, episodes of asthma exacerbations, and electrocardiography. RESULTS: The mean area under the curve for FEV1 throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart (P < .001), with the difference ranging from 3.1 to 4.3 L.h. Salmeterol produced an average increase in morning and evening PEF of 26 and 29 L/min, respectively, over pretreatment values compared with decreases of -13 and -3 L/min, respectively, in the albuterol group and -2 L/min both in the morning and evening in the placebo group (P < .001). Patients in the salmeterol group had significantly fewer days and nights with symptoms than did either the albuterol or placebo group (P < .001). Responses to salmeterol were similar at day 1 and at week 12. Adverse events in all treatment groups were equally infrequent, and no clinically significant change in cardiac rhythm was observed with salmeterol treatment. CONCLUSION: Salmeterol inhaled twice daily is more effective than albuterol inhaled four times a day (or as needed) in patients with asthma requiring maintenance therapy. No deterioration of asthma control was observed with the use of salmeterol over a 3-month period.     

Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture

The effects of usual or low doses of inhaled corticosteroids on airway mucosal inflammation have not yet been examined. We therefore, compared the effects of inhaled beclomethasone dipropionate (BDP) 336 microg x day(-1) on asthma control outcomes and markers of airway inflammation. Twenty-four adult subjects with mild and moderate asthma were randomized to receive either BDP or placebo for four weeks; then subjects entered a single blind four week placebo run-in period. We found that the BDP group had significantly greater improvements in forced expiratory volume in one second (FEV1), morning peak flow, and rescue salbutamol use than the placebo-treated group. The improvement in FEV1 largely reversed one week after treatment was stopped. The decrease in the median percentage of eosinophils in induced sputum in the BDP group from 3.8% to 3.4% was not significant, but because eosinophils increased from 8.4% to 12.7% in the placebo group, there was a significant difference between treatment groups (p=0.03). There was no significant difference between groups during treatment in the levels of eosinophil cationic protein (ECP), tryptase mucin-like glycoprotein, or fibrinogen in induced sputum. The change in FEV1 in the BDP group did not correlate significantly with the change in eosinophil percentage or ECP levels. We concluded that four weeks of treatment with inhaled beclomethasone dipropionate 336 microg x day(-1) was associated with significant improvements in peak flow, forced expiratory volume in one second, and rescue salbutamol use in asthmatic subjects but was not associated with large reductions in markers of eosinophilic inflammation, bronchovascular permeability, or mucus hypersecretion.     

Additive effect of nitroglycerine inhalation on beta2-agonist-induced bronchodilatation in asthmatics

The current treatment of airway obstruction using beta-agonists and theophylline is designed to increase intracellular level of cAMP. Experimental data show that cGMP and cAMP induce functionally additive relaxation of airways. Nitrates relax smooth muscle through the activation of guanylate cyclase. We wondered whether an additive effect of nitroglycerin (NTG) on beta2-agonist-induced bronchodilatation was present in asthmatic patients. To this aim we evaluated the acute bronchodilating effect of inhaled salbutamol (200 mu g MDI) in 10 asthmatics, pre-treated with inhaled NTG or placebo, in a double-blind cross-over design. FEV1 after NTG was higher than that obtained after placebo (2197 +/- 175 vs. 1981 +/- 155 ml, P <0.001). Mean FEV1 obtained 5 min after salbutamol was higher when patients were pre-treated with NTG than placebo (2694 +/- 217 vs 2440 +/- 228 ml respectively, P <0.001). The bronchodilatation due to salbutamol was identical whether NTG or placebo was inhaled first, respectively at 458 +/- 68 and 497 +/- 44 ml after 5 min. After 15 min FEV1 was higher than baseline, but no significant difference was still present between the value observed after pre-treatment with NTG or placebo (2554 +/- 235 and 2551 +/- 205 ml respectively). In conclusion, in asthmatics nebulized NTG produces a moderate and short-lasting bronchodilatation, which is additive with that produced by salbutamol.     

Caring for AIDS patients at home--requirements for development of the concept

Exercise tolerance in chronic obstructive pulmonary disease (COPD) patients treated with oral aminophylline may be different from those treated with high-dose inhaled ipratropium bromide. The purpose of this study was to compare the effects of therapeutic doses of oral aminophylline with high-dose ipratropium bromide on spirometry and exercise tolerance. The study was conducted on three consecutive days in a double-blind, randomized, crossover fashion. Baseline studies obtained on each study day included vital signs, simple spirometry and a symptom-limited maximal cardiopulmonary stress test, after which patients received one of the following treatments on each day: Treatment 1, inhaled ipratropium (total dose of 144 micrograms) with placebo tablets; Treatment 2, inhaled placebo with oral aminophylline (400 mg); Treatment 3, inhaled placebo and placebo tablets. Simple spirometry was repeated at 60 and 120 min after baseline. Vital signs and cardiopulmonary stress testing was repeated at 120 min. Eighteen patients were enrolled in the study, and 17 of these completed the study. There was a significant (P < 0.05) increase in both forced expiratory volume in 1 s (FEV1), from 0.75 (0.21) to 0.92 (0.3), and forced vital capacity (FVC), from 1.8 (0.79) to 2.11 (0.84), with high-dose ipratropium despite prior beta-agonist therapy. Lack of improvement in exercise capacity was noted with ipratropium despite improvement in spirometry. These results suggest that elderly patients with severe COPD may have exercise limitation that is not directly dependent on severity of airflow obstruction. Ipratropium bromide and aminophylline demonstrated no acute effects on exercise capacity.     

Potential masking effects of salmeterol on airway inflammation in asthma

We hypothesized that regular use of long-acting beta-agonists could delay recognition of ("mask") increasing airway inflammation. We studied steroid-sparing and "masking" effects of salmeterol versus placebo in 13 asthmatic individuals requiring >= 1,500 microgram inhaled corticosteroid daily. Corticosteroid doses were reduced weekly until criteria were met for an exacerbation or the corticosteroid was fully withdrawn. Subjects were restabilized on their original dose of inhaled corticosteroid for 4 wk before crossover to the alternative treatment. Subjects maintained symptom and peak expiratory flow (PEF) diaries, and underwent weekly spirometric, methacholine challenge, sputum eosinophil, and serum eosinophil cationic protein (ECP) measurements. Mean corticosteroid dose was reduced by 87% during salmeterol treatment, versus 69% with placebo (p = 0.04). Sputum eosinophils increased before exacerbation despite stable symptoms, FEV1, and PEF. In the week before clinical exacerbation, sputum eosinophil counts were higher in the salmeterol-treatment arm (19.9 +/- 29.8% [mean +/- SD], versus placebo 9.3 +/- 17.6%; p = 0.006). Five subjects showed > 10% sputum eosinophilia before exacerbation during salmeterol treatment, as compared with two receiving placebo. In this model, salmeterol controlled symptoms and lung function until inflammation became significantly more advanced. We conclude that the bronchodilating and symptom-relieving effects of salmeterol can mask increasing inflammation and delay awareness of worsening asthma.     

Overnight protection by inhaled salmeterol on exercise-induced asthma in children

The main aim of the present study was to evaluate whether inhaled salmeterol given in the evening protected against exercise-induced asthma the next morning. Twenty three children (12 males and 11 females) with a mean age of 11 yrs and with exercise-induced asthma participated in a double-blind, randomized, placebo-controlled study. The children inhaled salmeterol 25 micrograms, salmeterol 50 micrograms and placebo by Diskhaler at 10 p.m. on 3 separate days. Next morning, half of the children ran on a motor-driven treadmill for 6 min at submaximal load at 8 a.m. and the remainder at 10 a.m. Lung function was measured by maximal expiratory flow-volume loops before running, immediately after, and 3, 6, 10 and 15 min after running. The mean maximum reduction in forced expiratory volume in one second (FEV1) after treadmill run was 34% before inclusion in the study. Mean maximum fall in FEV1 was significantly greater after placebo: 30% (23-36) 95% confidence interval) than after salmeterol 25 micrograms: 19% (12-23) or salmeterol 50 micrograms: 18% (12-25). In addition to the reduced postexercise bronchoconstriction, pre-exercise lung function (FEV1) was significantly higher both after salmeterol 25 micrograms: 2.4 L.s-1 (2.1-2.7) and salmeterol 50 micrograms: 2.5 L.s-1 (2.2-2.8) than after placebo: 2.2 L.s-1 (1.9-2.5). No significant differences in pre- and postexercise lung function were found between children tested at 8 or 10 a.m., or in relation to salmeterol dosage. Thus, inhaled salmeterol 25 and 50 micrograms offered similar overnight protection against exercise-induced asthma and improved baseline lung function in the morning as compared to placebo.     

Different effects of salmeterol, formoterol and salbutamol on cholinergic responses in the ferret trachea

1. In the present study, the inhibitory effects of the selective beta 2-adrenoceptor agonists, salmeterol, formoterol and salbutamol, have been investigated on contractions of ferret trachea induced both by endogenous and exogenous acetylcholine. The aim of the study was to evaluate quantitative and/or qualitative differences in response which may indicate both pre- and post-junctional sites of action. The non-selective beta-antagonist, sotalol, was used to estimate beta-adrenoceptor involvement. 2. Isometric tension was measured in ferret isolated tracheal strips. The inhibitory effects of the drugs were studied on tonic contractions induced by pre-junctional activation with electrical field stimulation (EFS) (2 Hz, 700 mA) or post-junctional activation with exogenous acetylcholine (ACh) (0.5 microM, about EC80), giving a similar degree of smooth muscle response. 3. Concentration-response experiments were performed with formoterol (0.3 nM-0.3 microM) and salmeterol and salbutamol (10 nM-10 microM). The experiments ended with the addition of sotalol (10 microM). 4. All three beta-agonists inhibited the contractions in a concentration-dependent manner. Salbutamol, formoterol and salmeterol inhibited the EFS-induced contractions by 66(8)%, 105(5)% and 103(8)% (mean(s.e. mean)) respectively. ACh-induced contractions were inhibited by 37(6)%, 72(11)% and 33(8)%. Theophylline (10 nM-3 mM) inhibited the contractions to the same degree. 5. beta-Adrenoceptor blockade by sotalol significantly antagonized the inhibitory effects of salbutamol and formoterol on both EFS- and ACh-induced contractions. The effect of salmeterol on ACh-induced contraction was also significantly antagonized, whereas the inhibition of EFS-induced contraction was virtually unaffected. 6. In conclusion, salbutamol, salmeterol and formoterol produced greater inhibitory effects in preparations contracted by EFS than in preparations contracted by exogenously-added ACh. In the case of formoterol and salbutamol, the effects on both levels are most probably due to beta-adrenoceptor stimulation, whereas for salmeterol the dominant pre-junctional effect is probably not mediated via beta-adrenoceptors. This non-beta-mediated effect could represent an additional relaxant mechanism for salmeterol.     

The preterm prediction study: risk factors for indicated preterm births. Maternal-Fetal Medicine Units Network of the National Institute of Child Health and Human Development

This study has compared the efficacy and tolerability of formoterol (FORADIL) dry powder and salbutamol in elderly patients with reversible obstructive airways disease (ROAD). A total of 262 elderly outpatients with clinically stable ROAD participated in a multicentre, double-blind, parallel study. Patients were randomized in equal numbers to receive formoterol 12 micrograms b.i.d. formoterol 24 micrograms b.i.d. or salbutamol 400 micrograms q.i.d. for a 3 month period. All study drugs were inhaled through an Aeroliser device. Daily morning and evening peak expiratory flow (PEF) values, symptom scores and additional bronchodilator use were recorded by the patients throughout the study. Clinic assessment which included spirometry and PEF measurements was made at 4, 8 and 12 weeks. Morning and evening PEF values were significantly higher with both doses of formoterol compared with salbutamol. This difference was statistically significant both for the overall study period and during the week preceding each of the clinic visits (4, 8 and 12 weeks). There was no significant difference for the two doses of formoterol with respect to PEF values. The FEV1 and FVC values between the three treatment groups were similar. The daily use of rescue medication was significantly lower for the formoterol 24 micrograms group compared with the salbutamol group. The percentage of patients rating the therapeutic effect as 'very good' was significantly higher for formoterol: 41% on 12 micrograms; 34% on 24 micrograms; 19% on salbutamol. All treatments were well tolerated. This study demonstrates that formoterol 12 micrograms and 24 micrograms b.i.d. by dry powder inhalation are equally effective and are both significantly superior to salbutamol 400 micrograms q.i.d. in the treatment of ROAD in the elderly.     

Bronchodilator response to salbutamol after spontaneous recovery from nonspecific bronchial provocation tests in asthma

Assessment of airway responsiveness by bronchoprovocation and bronchodilatation tests is important in the diagnostic work-up protocol of bronchial asthma and it would be convenient to undertake both tests on the same occasion. However, it is not known whether this can be done accurately. Therefore, this study evaluated the effect of a prior bronchial provocation test on the bronchodilator response to salbutamol after spontaneous recovery of the forced expiratory volume in one second (FEV1) in a group of asthmatic subjects. On two separate occasions at the same time of day, concentration-response studies with inhaled histamine or methacholine, or a sham challenge with normal saline were carried out in a blinded, randomized manner. Changes in airway calibre were followed as FEV1 and agonist responsiveness expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). After either spontaneous recovery or a fixed-duration wait of 45 min (when appropriate), the subjects received 2x100 microg of salbutamol from a metered dose inhaler with a spacer. The bronchodilator response to salbutamol was expressed as a percentage of initial FEV1 (deltaFEV1% init). Bronchial challenge with both agonists failed to alter significantly the airway response to salbutamol, with the deltaFEV1% init mean value (range) being 16.9% (9.0-31.9) and 17.5% (11.6-31.2) on the sham and histamine/methacholine challenge day respectively. It was shown that the degree of bronchodilatation achieved after salbutamol 200 microg is not affected by prior bronchoprovocation testing when enough time is allowed for the airways to recover spontaneously to baseline forced expiratory volume in one second. Thus evaluation of airway responsiveness by both bronchial provocation tests and bronchodilator testing can be assessed reliably within a few hours in asthmatic patients.     

Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids

Long-acting beta2-adrenoceptor agonists such as salmeterol reduce airway responsiveness for at least 12 h, but this effect seems to decrease with regular use. We evaluated the time-course of the protective effects of salmeterol on methacholine-induced bronchoconstriction, its modulation by inhaled corticosteroids (ICS) and its influence on asthma control. Thirty two subjects (13 males and 19 females) with mild to moderate stable asthma were divided into two groups according to their medication needs: bronchodilators (BD) alone (n=16) or with ICS (n=16). After a 2 week run-in period, a double-blind crossover study was conducted. Subjects from both groups received salmeterol 50 microg b.i.d. or a placebo for 4 weeks each in random order, separated by a 2 week washout period. The provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) was measured before and after each treatment period, 1 h prior to inhalation of salmeterol or placebo and 1 and 12 h after. Baseline forced expiratory volume in one second (FEV1) increased significantly after salmeterol, both after the first dose and at 4 weeks (BD group: 19 and 17%; ICS: 22 and 13%). On the first day of administration, salmeterol provided significant protection in both groups up to 12 h with a PC20 before and 1 and 12 h postdose of 2.2, 21.7 and 12.4, mg x mL(-1), respectively, in the BD group and 2.1, 11.6 and 55 mg x mL(-1), respectively, in the ICS group. After 4 weeks, this effect was significantly attenuated in both groups with a PC20 before, 1 and 12 h postdose of 3.3, 10.9 and 7.1 mg x mL(-1), respectively, in the BD group and 2.1, 5.0 and 2.3 mg x mL(-1), respectively, in the ICS group. This loss of protective effect was of similar magnitude in both groups. Respiratory symptoms, rescue beta2-agonist use and baseline FEV1 did not change significantly throughout the study in both groups. In conclusion, the bronchoprotective effect of salmeterol decreased with regular use both 1 and 12 h postdose; inhaled corticosteroids did not prevent this reduction. However, the development of tolerance was not associated with loss of asthma control.     

Flow-dependent effect of formoterol dry-powder inhaled from the Aerolizer

The output and size distribution of aerosols from dry powder inhalers are dependent on the flow rate through the device. Therefore, in an in vivo study, we examined the flow-dependency of the effect of formoterol when delivered from a dry powder inhaler, the Aerolizer, in a flow range relevant to schoolchildren. In a preliminary study comprising 126 asthmatic children aged 3-10 yrs, the relationship between age and peak inspiratory flow (PIF) rate through the Aerolizer was determined. Mean PIF was 104 L.min-1 and all children aged > 5 yrs performed a PIF > 60 L.min-1. Sixteen children aged 8-15 yrs with exercise-induced asthma (EIA) took part in the main trial comparing the protective effect of 12 micrograms formoterol inhaled at 60 and 120 L.min-1. The effect from high and low inspiratory flow was judged from the protective effect against EIA 12 h after drug administration. The decrease in forced expiratory volume in one second (FEV1) after exercise was 34% on the placebo day, but only 15% when formoterol was inhaled at the high flow rate. This difference was statistically significant. The decrease in FEV1 was 23% after treatment with formoterol inhaled at the low flow rate, that was not significantly different from placebo or from high-flow formoterol treatment. These clinical findings correspond with the in vitro findings of flow-dependent fine particle mass from the Aerolizer, and corroborate the relationship between fine particle mass of aerosol and clinical effect. The results indicate a flow-dependent effect of formoterol dry powder inhaled from the Aerolizer, within the range of inspiratory flow rate obtainable by school-children. This questions its applicability in children with asthma.