Placebo Inhalation Research Articles

A Double-blind Trial of a Nicotine Inhaler for Smoking Cessation

To evaluate the efficacy of a new nicotine inhaler system for smoking cessation. A 1-year, randomized, double-blind, placebo-controlled study. Medical outpatient clinic with physicians experienced in smoking cessation assistance. A total of 286 volunteers who smoked at least 10 cigarettes daily recruited through a local newspaper. Subjects were randomly allocated to nicotine inhalers (n = 145) or placebo (n = 141) to be used for 3 months followed by tapering for 3 months in the context of minimal levels of advice and support. Continuous smoking abstinence at weeks 6, 12, 24, and 52, verified by measurements of carbon monoxide in expired air. Continuous smoking abstinence was significantly higher for the active nicotine inhaler group compared with the placebo inhaler group. The respective success rates were 28% and 12% after 6 weeks, 21% and 9% after 12 weeks, 17% and 8% after 6 months, and 15% and 5% after 1 year (P = .02 to .001). The mean nicotine substitution based on cotinine determinations after 2 weeks was 43% (SD, 45%) of smoking levels. The treatment was well tolerated, and no serious adverse events were reported. In this setting the nicotine inhaler appeared safe to use and increased success rates of smoking cessation attempts.

Duration of preventive effect of inhaled salbutamol on early airway response to allergen in asthmatic subjects

Salbutamol is known to effectively prevent early asthmatic response (EAR) after specific bronchial provocation test (sBPT) in asthmatic subjects, but the time-course of this protection is not known. In this study the effects of 200 μg salbutamol inhaled 2 h before sBPT were compared with 200 μg salbutamol inhaled 10 min before sBPT in eight asthmatic subjects sensitized to Phleum pratensis (PP) or Dermatophagoides pteronyssinus (DP). All subjects showed an EAR (% decrease in FEV 1 from baseline value: 30·4 ± 11%) in a preliminary sBPT performed with cumulated doses of extracts of PP or DP titrated in biological units (BU). Each subject performed, on two different days, in a random, double-blind, cross-over study, two puffs of placebo 2 h before sBPT and two puffs of salbutamol 10 min before sBPT (treatment A) or two puffs of salbutamol 2 h before sBPT and two puffs of placebo 10 min before sBPT (treatment B). Baseline FEV 1 were similar in both tests. In treatment B, 10 min, 1 h and 2 h after salbutamol inhalation, FEV 1 increased significantly with respect to placebo inhalation in treatment A. Ten minutes after salbutamol inhalation in treatment A, FEV 1 became similar to that obtained 2 h after salbutamol inhalation and 10 min after placebo in treatment B. Allergen inhalation induced an EAR in only one out of eight subjects after treatment A, and five of the eight subjects after treatment B. The severity of EAR was significantly greater after treatment A than after treatment B, and the FEV 1 after 10, 15, 30 and 60 min from the end of allergen inhalation was significantly different between two treatments. The protection index was significantly greater after treatment A than treatment B. In conclusion, although salbutamol induces the same bronchodilation either 2 h or 10 min after inhalation, the preventive effect on allergen-induced EAR is present when the drug is inhaled 10 min before sBPT, but is less effective when the drug is inhaled 2 h before sBPT.

Protective effect of loop diuretics, piretanide and frusemide, against sodium metabisulphite-induced bronchoconstriction in asthma

We determined whether the loop diuretic, piretanide, had a similar inhibitory action against sodium metabisulphite (MBS)-induced bronchoconstriction in asthmatic subjects as frusemide and, if so, its duration of action. In the first study, we compared the effect of inhaled placebo, piretanide (24 mg), or frusemide (40 mg), on the provocative concentration of MBS needed to cause a 20% fall in baseline forced expiratory volume in one second (FEV1) (PC20MBS) in 12 mild asthmatic subjects before, immediately after, and at 1.5, 3, 6, and 24 h, after inhalation. Both piretanide and frusemide induced a significant diuresis lasting at least 24 h. Frusemide caused a mean 3.8 fold (95% confidence interval: 2.3-6.3 fold), piretanide a 2.5 fold (1.8-3.4 fold) and placebo a 1.7 fold (1.5-1.9 fold) increase in PC20MBS. The effects of frusemide and piretanide were significantly greater than that of placebo. At later time points, tachyphylaxis to the bronchoconstrictor effects of MBS was observed during the placebo limb. In the second study, we measured PC20MBS at 90 min after inhalation of either placebo, piretanide (24 mg), or frusemide (40 mg). No significant difference in PC20MBS was observed. We conclude that piretanide in addition to frusemide significantly inhibits MBS-induced bronchoconstriction and that this action is short-lived over less than 90 min. Frusemide was more potent in inhibiting MBS-induced bronchoconstriction despite causing a smaller diuretic effect than piretanide. The basic mechanism of action of the loop diuretics in the airways remains unclear.

Bronchodilator Testing “Confidence Intervals” Based on the Level of Bronchial Responsiveness

"Confidence intervals" based upon inhalation of placebo have been proposed as criteria for defining a significant response to an inhaled bronchodilator. The published intervals were derived from a clinically heterogeneous population. We calculated the difference (delta) between spirometric data before and after placebo in 109 consecutive patients referred for methacholine bronchoprovocation challenge testing. The mean delta, expressed both as a percent change and as actual volume change for both the FVC and FEV1, was not significantly different in patients with bronchial hyperresponsiveness, as compared to subjects with a negative methacholine challenge test; however, the variance of measurements in hyperresponsive subjects was significantly greater than that of the normal population. In addition, as the category of responsiveness increased from mild to moderate to severe hyperresponsiveness, so did the variance within these groups. A negative correlation between the measured PC20FEV1 and the volume and percent change was noted. We conclude that patients with hyperresponsive airways may display increased spirometric variation before and after placebo. This general approach for establishing normal limits for defining a significant response appears to be valid, but the actual values used may vary, depending on the composition of the population tested and the goals of the study. Also, the use of the term, "confidence intervals," in this context is inappropriate; and we propose, instead, the use of percentiles and the simpler terms, upper 90th or 95th percentiles.

Effect of Inhaled Furosemide on the Bronchial Response to Lysine-Aspirin Inhalation in Asthmatic Subjects

It has been demonstrated recently that inhaled furosemide inhibits bronchoconstriction induced by cold air, physical exercise, various antigens, and metabisulfite. The goal of the present study was to determine if the inhalation of furosemide would inhibit the bronchoconstriction resulting from the inhalation of lysine-aspirin in aspirin-sensitive asthmatics. Six female subjects with known hypersensitivity to aspirin participated in this crossover study comparing 20 mg of inhaled furosemide and placebo. The volunteers inhaled increasing concentrations of lysine-aspirin after the inhalation of furosemide or placebo. The geometric mean provocative dose causing a 20 percent decrease in the FEV1 (PD20) after the inhalation of placebo was 30.4 mg/ml and the PD20 was equal or below 90 mg/ml in all patients. In contrast, the FEV1 did not decrease by 20 percent in any of the patients pretreated with furosemide when the inhaled concentration was increased to 360 mg/ml. From this study, we conclude that the administration of furosemide blocks the bronchospasm induced by the inhalation of lysine-aspirin in aspirin-sensitive asthmatics.

Short- and long-term retention of a nursing home education program on metered-dose inhaler technique.

To evaluate an education program on metered-dose inhaler (MDI) technique designed for nurses and trained medication aides (TMAs). The education program included a handout, a lecture incorporating a videotape on correct inhaler and device technique, and hands-on experience with placebo inhalers. The participants' ability to verbalize and demonstrate correct MDI technique was assessed by the same two-person teams before, immediately after, and two months after the program. Five nursing homes. Fifty-six nurses and TMAs practicing in nursing homes. Learning and retention. The participants' mean (+/- SD) verbal and demonstration scores increased immediately after the program by 68 +/- 18 points for verbalization and 47 +/- 16 points for demonstration. The participants were always better at demonstrating than verbalizing MDI technique. The participants' baseline verbal and demonstration scores correlated with the amount learned. Learning was influenced by the individual nursing home (verbal and demonstration) and personal use (demonstration only), but not by academic degree, previous training, past instruction of a patient, or current care of a patient who was receiving inhaler therapy. After two months, the scores were lower than immediately after the program test by 0-92 points for verbalization and 10-80 points for demonstration; however, the mean scores were still significantly greater (p less than 0.05) than the baseline scores. Retention of knowledge on the correct technique was greater for the demonstration component. Retention was influenced only by the nursing home in which the participant worked, and not any of the other variables. Our structured education program significantly improved inhaler technique; however, to maintain retention of the material, the program should be frequently repeated.

Public screening for lung disease: Experience with the NIH lung health study

The Lung Health Study is the first major initiative of the National Heart, Lung, and Blood Institute in screening for and intervention in early lung disease. The objective of the study is to identify cigarette smokers who have early disease and determine whether an intervention program of smoking cessation and bronchodilator therapy will alter the course of their disease. After an extensive screening program, 5,887 participants have been randomized to one of three groups: usual care, intervention with smoking cessation and the use of a placebo inhaler, and intervention with smoking cessation and the use of ipratropium bromide. All participants will be followed for 5 years. Preliminary data from the screening indicate that chronic obstructive pulmonary disease is more prevalent than was previously recognized, that it is widespread in women as well as men, and that it is far more common in young individuals than was thought. Approximately twothirds of the study participants have hyperreactive airways. Preliminary data from the Lung Health Study indicate that screening for lung function can be carried out in a costeffective manner.

The effect of inhalation of the leukotriene receptor antagonist, SK&F 104353, on leukotriene C 4- and leukotriene E 4-induced bronchoconstriction in subjects with asthma

The effect of prior inhalation of the sulfidopeptide leukotriene receptor antagonist, SK&F 104353 (963 ± 43.7 μg; mean ± SEM), on (LTC 4)- and leukotriene E 4 (LTE 4)-induced bronchoconstriction has been studied in six subjects with asthma (six male subjects, aged 24 to 36 years). Inhalation challenges with either synthetic LTC 4 or LTE 4 were performed after prior inhalation of aerosolized SK&F 104353 or placebo in a double-blind, randomized fashion. Airway responsiveness to each agonist was determined by the cumulative dose of agonist required to induce a 35% fall in specific airway conductance (PD 35) as determined by linear interpolation of the log dose-response curve. There was no change in baseline specific airway conductance after inhalation of either placebo or SK&F 104353. LTC 4- and LTE 4-induced bronchoconstrictions were significantly inhibited by aerosolized inhalation of SK&F 104353 30 minutes before challenge. The geometric mean (GM) PD 35 of LTC 4 on the open-therapy and placebo-therapy days was 0.043 nmol (range, 0.01 to 0.1 nmol) and 0.036 nmol (range, 0.01 to 0.1 nmol), respectively. On the treatment day with SK&F 104353, it was not possible to obtain a GM PD 35 LTC 4 up to a maximum concentration of 0.52 nmol LTC 4 ( p < 0.01). The GM PD 35 of LTE 4 on the open-therapy and placebo-therapy days was 0.30 nmol (range, 0.13 to 0.76 nmol) and 0.39 nmol (range, 0.14 to 0.9 nmol), respectively. On the treatment day with SK&F 104353, it was not possible to obtain a GM PD 35 LTE 4 up to a maximum concentration of 5 nmol LTE 4 ( p < 0.005). Thus, LTC 4- and LTE 4-induced bronchoconstrictions are both inhibited by SK&F 104353.

Prolonged Protection against Methacholine-induced Bronchoconstriction by the Inhaled β2-Agonist Formoterol

Formoterol fumarate is a new, high-affinity, beta 2-adrenergic receptor agonist that causes bronchodilation for at least 12 h. The purpose of this study was to compare the magnitude and duration of the effect of inhalation of formoterol (12 and 24 micrograms), albuterol (200 micrograms), and placebo in terms of protection against methacholine-induced bronchoconstriction. The 16 stable adult asthmatic subjects were studied on four separate study days. On each study day the subjects inhaled 2 puffs of the study medication, and methacholine tests were performed at 30 min and 4, 8, and 12 h later. Results were expressed as the provocative concentration of methacholine required to cause a 20% fall in FEV1 (PC20). At 30 min, 12 and 24 micrograms formoterol caused a mean 14- to 20-fold decrease in responsiveness, and albuterol a 12-fold decrease. However, albuterol had no significant protective effect at 4 h or thereafter, whereas there was still an 8-fold decrease in responsiveness for 24 micrograms formoterol and a 6-fold decrease for 12 micrograms formoterol at 12 h. This study has shown that both doses of formoterol were still actively protective against induced bronchoconstriction 12 h after inhalation, with minimal side effects. This suggests that formoterol may prove to be a very useful bronchodilator for the treatment of patients with asthma who have significant airway hyperresponsiveness or nocturnal symptoms and who require inhaled beta 2-agonists at least twice daily.

Dynamic T-Cell Changes in Peripheral Blood and Bronchoalveolar Lavage after Antigen Bronchoprovocation in Asthmatics

We previously demonstrated decrease of peripheral blood CD4+ cells 48 to 72 h after antigen-induced bronchoprovocation in asthmatic subjects. To determine if this was accompanied by reciprocal changes in bronchoalveolar lavage (BAL) fluid, we sampled BAL before and 48 h after antigen administration. Peripheral blood lymphocytes (PBL) and BAL T-cell subset composition were examined in eight extrinsic asthmatics during three different weeks. During control week (CW) BAL was preformed at baseline, and PBL subsets were followed for 3 days. During placebo week (PW) a placebo inhalation was followed by a BAL at 48 h and daily PBL for 3 days. Asthmatic attacks were induced by inhalation of a relevant antigen at the start of antigen week (AW) and followed by examining the BAL at 48 h and PBL daily for 72 h. We found that BAL as a stimulus had no effect on T-cell composition of the PBL after the procedure. After induction of an asthmatic attack there was a reduction of PBL CD4+ cells from a baseline mean of 52.6% to 38.8% at 48 h (p less than 0.05). At the same time BAL CD4+ cells increased from 35.6% at PW to 47.3% in AW (p less than 0.05). These data are compatible with specific recruitment of PBL CD4+ cells into the respiratory system in atopic subjects undergoing antigenic bronchoprovocation.

Inhaled Furosemide Prevents Both the Bronchoconstriction and the Increase in Neutrophil Chemotactic Activity Induced by Ultrasonic “Fog” of Distilled Water in Asthmatics

Inhaled furosemide has been shown to prevent bronchoconstriction induced by inhalation of ultrasonic nebulization of distilled water (UNDW) in bronchial asthma. To evaluate whether inhaled furosemide also prevents the increase in serum neutrophil chemotactic activity (NCA) observed during UNDW bronchoconstriction, we measured NCA during UNDW challenge without (control) and immediately after inhalation of furosemide (40 mg) or placebo (saline) in 10 asthmatics responsive to UNDW, in a randomized, double-blind study. NCA was assessed by measuring the maximal distance reached by neutrophils in a filter when challenged with the subject serum in a Boyden chamber ("leading front"). UNDW inhalation produced a significant increase in NCA in each subject. Gel filtration chromatography on S400 column indicated that the NCA released were 600 to 700 kD. Saline had no effect on bronchoconstriction nor on NCA increase induced by UNDW in nine patients. Furosemide did not change baseline FEV1, but it prevented bronchoconstriction and NCA increase in nine patients. In the whole group the maximal decrease in FEV1 after UNDW was -31.1%, SEM 4.7 after saline and -7.5%, SEM 5.2 after furosemide, p less than 0.001, the maximal increase in NCA after UNDW was +52.9%, SEM 9.2 after saline and +3.8%, SEM 3.1 after furosemide, p = 0.001. These results indicate that inhaled furosemide prevents both the bronchoconstriction and the NCA increase induced by UNDW inhalation in most asthmatic patients. This finding adds support to the suggestion that furosemide acts on mast cells.

Inhaled Epinephrine and Oral Theophylline—Ephedrine in the Treatment of Asthma

Inhaled and oral over-the-counter bronchodilators are used for self-therapy by asthmatic patients. To evaluate their safety and efficacy, we compared epinephrine and theophylline combined with ephedrine with inhaled metaproterenol and the placebo. Twelve asthmatic patients were studied in a randomized, double-blind, placebo-controlled, crossover trial comparing forced expiratory volume in 1 second (FEV1) after two inhalations of epinephrine (0.2 mg/inh), 1 minute apart, followed in 15 minutes by theophylline (130 mg) with ephedrine (24 mg) versus two inhalations of metaproterenol (0.65 mg/inh), 1 minute apart, versus placebo inhaler and tablets. Onset of FEV1 greater than 15% above baseline values occurred within 15 seconds after inhalations for 100% of epinephrine-treated patients, 92% of metaproterenol-treated patients, and 33% of placebo-treated patients. FEV1 responses were significantly greater (P less than .05) for epinephrine at 0.66 to 1.66 minutes compared with the responses of metaproterenol, and epinephrine and theophylline that was combined with ephedrine compared with metaproterenol beginning at 2 hours. Mean duration of activity was 5.7 hours for the epinephrine- and theophylline with ephedrine-treated patients, 4.9 hours for metaproterenol-treated patients, and 2 hours for the placebo group. There were statistically significant differences for patients receiving epinephrine and theophylline with ephedrine versus the placebo group (P less than .001), metaproterenol patients versus the placebo group (P = .02), and patients receiving epinephrine and theophylline with ephedrine versus metaproterenol-treated patients (P less than .05). Compared with inhaled metaproterenol, inhaled epinephrine followed in 15 minutes by a theophylline-ephedrine tablet had a significantly earlier onset, longer duration of action, numerically greater peak effect, and patient preference.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-induced T-cell changes: Modulation by pharmacologic agents

To determine the effect of pharmacologic modulation of alterations of peripheral blood T-cell subsets caused by antigen-induced bronchoconstriction, we administered albuterol immediately after antigen-induced bronchoconstriction in a double-blind to protocol to 12 atopic asthmatic subjects. We also administered cromolyn sodium before antigen to 7 of the same subjects. Peripheral blood T-cell subset composition (CD4, CD8, Ia) of a highly purified T-cell preparation was determined before, 24, 48, 72, and 168 h after bronchoconstriction. We found that placebo inhalation immediately after antigen-induced bronchoconstriction did not affect subsequent peripheral blood T-cell subset changes (decrease in CD4+ and increase in Ia+ T lymphocytes). In contrast, inhaled albuterol abolished these T-cell subset changes. Although cromolyn sodium significantly decreased the severity of antigen-induced bronchoconstriction, it did not affect T-cell subset composition changes at the dosage used. We conclude that albuterol can ablate T-cell subset changes associated with antigen-induced bronchoconstriction. Cromolyn sodium ameliorates bronchoconstriction, but has no affect on T-cell subset composition changes. This implies that T-cell changes and bronchoconstriction caused by antigen inhalation are mediated through different pathways.

Effect of Sodium-Transport Inhibitors on Bronchial Reactivity in Vivo

1. We have recently shown that ouabain, an inhibitor of Na+/K(+)-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K(+)-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 mumol after amiloride and 0.54 mumol after placebo (95% confidence intervals for the difference: 0.9 to -0.2 doubling doses of histamine; P = 0.2). 5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10(-2) mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 mumol and 4.3 mumol, respectively, in the normal subjects (95% confidence intervals for the difference: -0.53 to 1.52 doubling doses, P = 0.2), and 0.33 mumol and 0.29 mumol in the asthmatic subjects (95% confidence intervals for the difference: -0.95 to 0.57 doubling doses; P = 0.6).(ABSTRACT TRUNCATED AT 250 WORDS)

Nasal inhalation of the glucocorticoid budesonide from a spacer for the treatment of patients with pollen rhinitis and asthma

Glucocorticoid sprays are increasingly used for the treatment of allergic rhinitis and asthma. This therapy is highly effective, and side effects are few and mild. It was the aim of the present study to evaluate a physiological nasal inhalation technique, which results in airway deposition of the steroid molecule similar to that of inhaled allergen particles. Thirty adults with grass pollen-induced rhinitis and asthma inhaled the steroid molecule budesonide through the nose from a pressurized aerosol attached to a spacer device. Compared with inhalation of placebo, the treatment resulted in a significant reduction of nasal symptoms (P = 0.005), of bronchial symptoms (P = 0.005), but not of eye symptoms. In addition, nasal peak inspiratory flow (P = 0.0003) and oral peak expiratory flow (P = 0.02) increased. There was no difference between budesonide and placebo with regard to local side effects, such as nose bleeding, hoarseness, and irritation in mouth and throat. It is concluded that nasal inhalation of a steroid from a spacer offers effective therapy of pollen rhinitis and asthma without significant local side effects. This therapeutic modality may have advantages over the ordinarily used nasal and bronchial spray treatment in patients with both rhinitis and asthma, especially when conventional spray therapy is associated with local side effects.

The effect of inhaled fenoterol, administered during the late asthmatic reaction to house dust mite ( Dermatophagoides pteronyssinus)

A double-blind, placebo-controlled crossover study was set up to investigate the effect of fenoterol (400 μg) during the late asthmatic reaction (LAR). Twenty young subjects with asthma (mean age, 11.8 years; range, 8.3 to 20.6 years) were selected on the basis that they developed an LAR after bronchial challenge with Dermatophagoides pteronyssinus. After the LAR occurred, a placebo and fenoterol were administered blindly by a metered-dose inhaler, with an interval of 15 minutes and in alternating, random sequence. At the start of the study, that is, a documented LAR, the two groups of subjects had the same severity of LAR, as expressed by the fall of the FEV 1 (mean, −34.5% versus −33.5%). The mean FEV 1 of the 10 patients who received placebo first changed only −1.1% (±5.0), whereas after fenoterol, the FEV 1 increased by 20.7% (±10.8). In the 10 patients receiving fenoterol first, the mean FEV 1 rose by 18.8% (±8.0), whereas the placebo inhalation resulted in a supplementary increase of 3.1% (±7.0). The paired Student's t test between these differences (placebo versus fenoterol) was highly significant ( p < 0.001). Although it was demonstrated in some studies that β-agonists did not prevent the LAR, the present study demonstrates that the administration of fenoterol can reverse the FEV 1 significantly, although it was not reversed completely, during an allergen-induced LAR.

Airways Responses to Ipratropium Bromide Do Not Vary with Time in Asthmatic Subjects: Studies of Interindividual and Intraindividual Variation of Bronchodilatation and Protection Against Histamine-lnduced Bronchoconstriction

Bronchial histamine provocation tests were performed in nine patients with nonallergic asthma on four consecutive days 45 minutes after inhalation of placebo or ipratropium bromide in a dose-response manner (40 micrograms, 200 micrograms, and 800 micrograms). The drugs were administered double-blind, one dose on each day. This procedure was repeated identically after three to nine months to investigate whether the bronchial responses to ipratropium bromide are constant or change with time. Ipratropium bromide induced a significantly better bronchodilation and protection against histamine-induced bronchoconstriction than placebo with no differences between the three doses. No correlation between bronchodilatation and protection was found. In six asthmatic patients ("responders") ipratropium bromide induced a significant protective effect against histamine-induced bronchoconstriction but no dose-response relationship was found. In three patients none or a very poor protective effect was found at all dose levels ("nonresponders"). The protective effect of ipratropium bromide against histamine-induced bronchoconstriction did not differ between the first and second occasion. Thus, the bronchoprotection differed between different asthmatic subjects but did not vary with time (three to nine months) within the same subject. This finding seems to be of clinical importance since it implicates that the effect of anticholinergic agents on the airways is predictable.

Formoterol, a new long-acting selective β 2-adrenergic receptor agonist: Double-blind comparison with salbutamol and placebo in children with asthma

We compared the protective effect and duration of action of inhaled formoterol, a new, long-acting, selective β 2-agonist, to inhaled salbutamol and placebo in a double-blind, randomized, crossover study in 16 children with asthma with a mean age of 10.3 ± 0.4 years. Mean baseline FEV 1 was 96 ± 3% predicted and mean provocative concentration of methacholine (milligrams per milliliter) required to decrease FEV 1 by 20% (PC 20) was 0.81 ± 0.25 mg/ml of methacholine. On the 4 study days, baseline FEV 1 was within 10% of the FEV 1 on visit 1, and baseline PC 20 was within one doubling dose of visit 1. Each day patients inhaled either placebo, salbutamol, 200 μg, formoterol, 12 μg, or formoterol, 24 μg. FEV 1 and PC 20 were measured repeatedly during 12 hours. After placebo inhalation, mean FEV 1 did not change significantly during 12 hours. After salbutamol inhalation, the mean FEV 1 was significantly increased for less than 3 hours, but after formoterol inhalation, 12 or 24 μg, the mean FEV 1 was significantly increased for 12 hours. After placebo treatment, mean PC 20 did not change significantly. After salbutamol inhalation, mean PC 20 was significantly increased for only 3 hours, but after formoterol inhalation, 12 or 24 μg, mean PC 20 was significantly increased for 12 hours. Protection by formoterol, 12 and 24 μg at 12 hours, was equivalent to protection by salbutamol at 3 hours. Inhaled formoterol is a potent, long-acting bronchodilator and provides significantly better antiasthma protection than inhaled salbutamol.

Bradykinin‐induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.

1. The effects of inhaled nedocromil sodium and sodium cromoglycate on bradykinin-induced bronchoconstriction have been studied in a double-blind, placebo controlled study, in eight mild asthmatic subjects. 2. The subjects attended on four occasions. Fifteen minutes after drug pre-treatment a bradykinin challenge was performed. Increasing concentrations were inhaled until a greater than 40% fall in expiratory flow at 30% of vital capacity from a partial flow volume manoeuvre (V p30) was demonstrated. 3. Inhaled bradykinin (0.06-8.0 mg ml-1) caused dose-related bronchoconstriction with the geometric mean cumulative dose causing a 40% fall in V p30 (PD40) of 0.035 (95% CI: 0.02-0.07) mumol, after placebo inhalation, which was similar to that measured before the trial (0.04: 0.02-0.09 mumol). 4. Both nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) gave significant protection (P less than 0.05) against bradykinin-induced bronchoconstriction (PD40 0.37: 0.19-0.72 mumol after nedocromil sodium and 0.22: 0.11-0.49 after sodium cromoglycate). 5. Since bradykinin-induced bronchoconstriction is probably neurally mediated we conclude that both nedocromil sodium and sodium cromoglycate have an action on neural pathways which may be useful in the control of asthma symptoms.

Rimiterol and the prevention of exercise-induced asthma

The potential for rimiterol to protect athletes from exercise-induced asthma (EIA) has not been fully established. Ten athletes with asthma (15 to 30 years of age) undertook 8 minutes of submaximal exercise (80% of anaerobic threshold) on the treadmill ergometer, once after inhaling rimiterol and once after inhaling a placebo. Treatment with all bronchodilator drugs was stopped for the 12 hours preceding each exercise test. Two puffs (400 μg) of rimiterol or placebo were administered in a double-blind crossover manner 2 minutes before each exercise test. Lung function measurements were made before exercise and immediately, 5, 10, 15, 20, 25, and 30 minutes after completion of exercise. The results of a two-way analysis of variance revealed significant ( p < 0.01) difference in the FEV 1 scores obtained after rimiterol inhalation and placebo inhalation, 5, 10, 15, 20, 25, and 30 minutes after cessation of exercise. After inhalation of rimiterol, there were no significant changes in FEV 1. After inhaling the placebo, significant reductions ( p < 0.01) in FEV 1 occurred after cessation of exercise (5, 10, 15, and 20 minutes). All subjects exhibited EIA after placebo, and none after rimiterol. The mean maximum drop after exercise in FEV 1 after inhalation of rimiterol (2.807 ± 5.55) and placebo (24.54 ± 8.4) was significantly different (t = 6.849). It was concluded that inhalation of rimiterol 2 minutes before exercise afforded significant protection from EIA in all subjects tested.