The inhibitory effect of long-acting beta-adrenergic agonists, mabuterol, clenbuterol and fenoterol on "morning dipping" in patients with asthma

We examined the inhibitory effect of the long-acting beta-adrenergic agonists, mabuterol, clenbuterol and fenoterol on "morning dipping" in ten patients with nocturnal asthma. On the first night, as a control experiment, the subjects received no beta-adrenergic agonist. On the succeeding three nights at 8:00 PM, each subject was orally administered 50 micrograms of mabuterol, 40 micrograms of clenbuterol and 5 mg of fenoterol in a randomized, crossover fashion. Pulmonary function tests (FVC, FEV1.0, PEFR, V50 and V25) were performed at 8:00 PM (just before administration of beta-adrenergic agonist), 9:00 PM, 10:00 PM, 6:00 AM and 8:00 AM. On the night when clenbuterol was administered, there was a significant inhibition of morning dipping at 6:00 AM in FVC (p less than 0.01), FEV1.0 (p less than 0.01), PEFR (p less than 0.01), V50 (p less than 0.01) and V25 (p less than 0.05) compared with the control night. On the nights when mabuterol and fenoterol were administered, there was a significant inhibition of morning dipping at 6:00 AM in FVC (p less than 0.01) and FEV1.0 (p less than 0.01) compared with the control night. Palpitations associated with clenbuterol administration were seen in two subjects. The effect of each beta-adrenergic agonist varied inconsistently among the subjects. These results indicate that clenbuterol is the most effective in inhibiting morning dipping among the long-acting beta-adrenergic agonists examined, but individualization in the choice of beta-adrenergic agonist is mandatory in order to achieve the maximum effect.     

Epinephrine improves expiratory flow rates in patients with asthma who do not respond to inhaled metaproterenol sulfate

One hundred patients with acute asthma and peak expiratory flow rates (PEFR) less than 150 L/min were randomized and treated in a double-blind treatment protocol with either metaproterenol sulfate aerosol (MPA) inhalation and placebo injection or epinephrine injection (EPI) and inhaled placebo at entry and at 30 and 60 minutes, and then were treated with the crossover comparison regimen at 120, 150, and 180 minutes. The two groups had similar entry PEFRs and FEV1 (MPA, 112 L/min; 0.94 L, respectively; EPI, 111 L/min; 0.85 L, respectively) and similar plasma theophylline levels (MPA, 12.2 micrograms/ml; EPI, 13.8 micrograms/ml). PEFR and FEV1 were measured every 30 minutes for 4 hours. Mean expiratory flow rates among both groups were similar at entry and at 120 and 240 minutes. At 120 minutes, flow rates had improved in 28/46 MPA-treated patients (61%) and 48/54 EPI-treated patients (89%). Among these improved patients, flow rates were significantly higher in the MPA-treated group. At 120 minutes, 18/46 MPA-treated patients (39%) and 6/54 EPI-treated patients (11%) had PEFRs less than 120 L/min and PEFR and FEV1 less than 120% of baseline values (p less than 0.01). In 13 of these 18 MPA-treated patients who did not improve compared to 1/6 EPI-treated patients who did not improve, PEFRs were greater than 120 L/min, and PEFR and FEV1 had increased 20% or more above baseline values after treatment with the crossover comparison regimen (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Late asthmatic reaction decreased after pretreatment with salbutamol and formoterol, a new long-acting beta 2-agonist.

The inhibitory effect of salbutamol and formoterol, a new long-acting beta 2-agonist for inhalation, on the late asthmatic reaction (LAR), was studied in 12 patients with allergic asthma. After a single-blind, placebo-treatment control, equipotent bronchodilating doses of inhaled salbutamol (500 micrograms) and formoterol (30 micrograms) were administered 30 minutes before bronchial allergen challenge in a double-blind randomized design. The early asthmatic reaction was completely inhibited by both drugs (p less than 0.01) but not by placebo. The LAR was also significantly inhibited by both drugs (p less than 0.01); formoterol was only slightly, but significantly, more effective than salbutamol (p = 0.04). In contrast to some earlier studies, the present study indicates an inhibitory effect of beta 2-agonists on the LAR.     

Acute effect of intravenous magnesium sulfate on airway obstruction of asthmatic patients

The bronchodilating effect of magnesium sulfate (MgSO4) was studied in ten asthmatic patients with moderate to severe airway obstruction. Two grams of MgSO4 or saline in double-blind crossover design was administered IV for 20 minutes (0.40 mmol/min) and forced expiratory capacity and forced expiratory volume in one second (FEV1) were studied at intervals. Only at the end of MgSO4 infusion did FEV1 increase significantly (109% of initial values). The bronchodilating effect was short lasting and far less than that observed after salbutamol.     

Relationship between symptoms and objective measures of airway obstruction in asthmatic patients.

The objective of this study was to determine the relationship between asthma symptoms and the degree of airway obstruction as measured by the forced expiratory volume in one second (FEV1) and peak expiratory flow rate (PEFR) in a group of 64 asthmatic patients with clinically stable disease attending a university-based urban asthma clinic. Asthma symptoms did not correlate with the degree of airway obstruction as measured by prebronchodilator PEFR (total asthma symptom score vs PEFR: r = -0.214, p = 0.104, n = 59) and only correlated poorly with prebronchodilator FEV1 (total asthma symptom score vs FEV1: r = -0.256, p = 0.041, n = 64). These results lend support to the recommendation that airway obstruction should be measured objectively when assessing patients with chronic persistent asthma.     

A comparison of the effects of sodium cromoglycate and beclomethasone dipropionate on pulmonary function and bronchial hyperreactivity in subjects with asthma

After a run-in period of 2 weeks, receiving a regimen of inhaled beta 2-agonists and/or theophyllines, 38 atopic patients with asthma with perennial symptoms were randomly allocated to receive an 8-week treatment of additional inhalation treatment with either sodium cromoglycate (SCG), 2 mg four times daily, and placebo beclomethasone dipropionate (BDP), or BDP, 200 micrograms twice daily, and placebo SCG. After crossover, each group received the opposite treatment for the final 8 weeks. FEV1, FVC, and provocation concentration of histamine causing a 20% fall in FEV1 (PC20) were determined monthly and peak expiratory flow (PEF) daily throughout the study. A significant increase in FEV1, FVC, and PEF (p less than 0.01) was observed after BDP treatment was started, and likewise, in the second period, an increase in both FEV1 and PEF (p less than 0.05) was observed. The total effect on logarithm-natural (Ln) (PC20), i.e., the mean effects of the two periods, was also significant (p less than 0.01). SCG, however, was most effective when it was used as the first drug, indicated by a significant increase in FVC in the first period (p less than 0.05). Neither in the first nor in the second period did SCG treatment influence the Ln (PC20) value positively, and the SCG treatment administered in the second period could not maintain the improvement in the pulmonary function (i.e., FEV1, FVC, and PEF) obtained initially with the BDP treatment. When the effect of BDP on FEV1, FVC, PEF, and Ln (PC20) was compared to the effect of SCG in the first 8-week treatment period, no significant difference was observed (p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine-Induced Bronchospasm

The reproducibility of the histamine challenge in seven asymptomatic patients with extrinsic asthma, provoked four times each with 1-2 weeks interval, was investigated. The method was thereafter used in order to find the sub-threshold bronchodilating dose of a new beta-agonist KWD 2131 with a preferably anti-allergic property. Selection of patients and methodology of the histamine challenge procedure were carefully standardized. Histamine was administered during quiet breathing at 3-min intervals in a step-wise cumulative manner up to a point where greater than 20% decrease in FEV 1.0 was reached. The pooled intra-individual standard deviation was 4.6% in FEV 1.0, 5.0% in PEFR, and 4.7% in FVC. Pretreatment with KWD 2131, before histamine challenge, showed that the subthreshold dose for bronchodilatation was 0.5 mg in nine patients and 0.25 mg in three patients compared with 1 mg in patients with intrinsic asthma. It was important to perform individualized dose-titration of the sub-threshold bronchodilating dose of KWD 2131 before initiation of a subsequent allergen provocation study.     

Monitoring of peak expiratory flow rates in subjects with mild airway hyperexcitability

Twenty-seven subjects with mild symptoms of bronchial hyperexcitability (cough, dyspnea, wheezing) and low to moderate degree of airway response to histamine monitored their peak expiratory flow rates (PEFR) for a mean +/- SD of 14.4 +/- 4.0 days. This assessment was performed without the use of any medication in 15 subjects, and before and after inhalation of salbutamol in 12 others. 100% and 52% of individuals, respectively, showed baseline FEV1 and maximum mid-expiratory flow rates greater than 80% of predicted. The improvement in FEV1 after salbutamol was less than 20% in every subject and from 10 to 20% in 15%. The mean daily percentage changes in PEFR were greater than the ones observed in normal individuals in only 21% and 50% of the subjects on no medication and on salbutamol, respectively. Diurnal changes in PEFR were significantly negatively correlated with the response to histamine (r = -0.51; p less than 0.01) and baseline FEV1 (r = -0.49; p less than 0.02). We conclude that there are minor fluctuations of PEFR in subjects with mild symptoms and low degree of airway excitability.     

Comparison of four weeks'' treatment with fenoterol and terbutaline aerosols in adult asthmatics : A double-blind crossover study

Fenoterol and terbutaline, two long-acting beta 2-adrenoceptor agonists in aerosol form, were compared in an 8-wk randomized double-blind crossover study in 22 mild to moderately severe asthmatics. Patients completed diary cards, recorded peak expiratory flow rate (PEFR) twice daily, and attended a clinic for measurement of PEFR, 1-sec forced expiratory volume (FEV1), and forced vital capacity (FVC) twice during each treatment period. Fifteen patients completed the study; 5 dropped out while using fenoterol, and 2 while using terbutaline. At clinic attendances, the patients had a significantly higher mean PEFR after 4 wk on terbutaline (385 L/min) than after fenoterol (316 L/min) (p less than 0.001). Similar results were found on analysis of the morning and evening PEFR recordings. On comparing each individual's PEFR recordings during the 2 treatments, it was found that there was no significant difference among the treatments in 3 patients, while 9 patients had a better response to terbutaline, and 3 patients had a better response to fenoterol. While similar number expressed a subjective preference for each treatment, the lung function data suggested that the effectiveness of fenoterol appeared to decline during the trial period.     

Once-daily budesonide via Turbuhaler improves symptoms in adults with persistent asthma.

BACKGROUND: Previous studies have demonstrated the efficacy and safety of twice-daily budesonide Turbuhaler (Pulmicort Turbuhaler, AstraZeneca, Wilmington, DE) for the treatment of mild to severe asthma. OBJECTIVE: To compare the efficacy and safety of budesonide Turbuhaler administered once daily each morning with placebo in inhaled corticosteroid-naive adults with persistent asthma. METHODS: In this randomized, double-blind, placebo-controlled, multicenter study, 177 adults (aged 18 to 70 years) received placebo or once-daily budesonide Turbuhaler (400 microg) for 12 weeks. Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second (FEV1) and AM/PM peak expiratory flow rate (PEFR), and nighttime/daytime asthma symptom scores, patient discontinuations, use of breakthrough medication (albuterol), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of FVC (FEF25%-75%), and quality of life assessments. Safety was evaluated based on adverse events, physical examinations, vital signs, and laboratory tests. RESULTS: Demographic and baseline characteristics were comparable between study groups. The mean percentages of predicted FEV1 at baseline were 71.9 +/- 9.8 in patients receiving budesonide Turbuhaler and 70.6 +/- 11.0 in patients receiving placebo. Mean changes from baseline over the 12-week treatment period in FEV1 were significantly (P = 0.007) improved in patients receiving once-daily budesonide Turbuhaler compared with placebo (0.31 L and 0.17 L, respectively). Significant (P < or = 0.037) improvements over placebo also were observed in AM PEFR, nighttime/daytime asthma symptoms, and albuterol use with budesonide Turbuhaler treatment. Adverse events were generally mild or moderate in intensity and similar between study groups. CONCLUSIONS: Budesonide Turbuhaler 400 microg administered once daily in the AM is efficacious and safe for inhaled corticosteroid-naive asthmatic adults.     

Localization of the bronchodilator effect induced by type A natriuretic peptide in asthmatic subjects

Type A natriuretic peptide (CDD/ANP99-126) in its circulating form was analyzed with respect to the localization of its bronchodilating effects in asthmatic subjects in vivo. The intravenous infusion of 5.7, 11.4, and 17.1 pmol kg^–1 min^– CDD/ANP-99-126 caused a significant bronchodilation of both central and peripheral airways. While the localization of the bronchodilating effects was similar to ₂-agonists, an improvement in lung function parameters comparable to these substances was not observed. But other members of the natriuretic peptide family may reveal a stronger bronchodilating potency.Abbreviations FEV forced expiratory volume in 1 s - FVC forced vital capacity - PEF peak expiratory flow - MEF₇₅, MEF₅₀, MEF₂₅ maximal expiratory flow at 75%, 50%, 25% of forced vital capacity Correspondence to: T. Edge     

Significance of area under the flow volume curve--useful index of bronchial asthma]

Some studies have reported that area under the flow volume curve (AUFVC) can be an index of pulmonary function. However, the significance of AUFVC remains to be clarified. We have clarified that AUFVC reflects the momentum of expired air. Size of flow volume curve (= AUFVC) has been commonly recognized to be changeable visually in patients with asthma. To clarify whether size of flow volume curve (= AUFVC) is a useful index of the course of bronchial asthma, we compared the rate of improvement forced expiratory volume in 1 second (FEV1.0), peak expiratory flow rate (PEFR) or forced vital capacity (FVC) to the rate of improvement in AUFVC after admission in 20 patients with bronchial asthma. The rate of improvement in AUFVC positively correlated with the rate of improvement in FEV1.0, PEFR or FVC. AUFVC demonstrated more marked improvement than other indices. Since AUFVC reflects the momentum of expired air, bronchial asthma's patients could understand visually that the momentum of expired air decreased due to airway stenosis by presenting flow volume curve. Therefore, visual size of flow volume curve helped patients with asthma to understand the condition of asthma. Size of flow volume curve (AUFVC) may be useful index of the course of bronchial asthma.     

Pulmonary function studies in healthy non-smoking men of Calcutta

Pulmonary function measurements were made in 104 healthy non-smoking men from Calcutta with an age range of 20-59 years. Except for peak expiratory flow rate (PEFR), all the measurements were made with the help of two 9L closed-circuit type expirographs using standard spirometric techniques. PEFR was recorded by two Wright peak flow meters. Prediction formulae were derived on the basis of age and height for all the ventilatory tests except for FEV1%, FET and PEFR. These were predicted from age only. The prediction equation for VC, FVC, FEV1, FEV1%, MVVF and PEFR were reliable, but those for forced expitatory flows and time were not. The FVC and FEV1 values of the present subjects, standardized for age and height, were much lower than those of Americans, Caucasians, Europeans and Canadians but similar to those of Pakistani healthy adults. On comparison with the data reported from other parts of our country, it was revealed that the VC and FEV1 values of the current study, after adjustment of age and height, were much higher than those of southern Indians but comparable with those of north-western Indians.     

The Impact of Smoking on Clinical and Therapeutic Effects in Asthmatics

Smoking is associated with poor symptom control and impaired therapeutic responses in asthma. A total of 843 patients with asthma were recruited. The patients received treatment for 1 yr according to the severity of their asthma. We compared the forced expiratory volume in 1 sec (FEV1), the ratio of FEV1 to forced vital capaity (FVC), atopy, total IgE, emphysema on high-resolution computed tomography (HRCT), the number of near-fatal asthma attacks, and physiological fixed airway obstruction between the smoking and nonsmoking groups. The study population consisted of 159 (18.8%) current smokers, 157 (18.7%) ex-smokers, and 525 (62.5%) nonsmokers. Although the prevalence of atopy was not different between the smoking and nonsmoking groups, the total IgE was higher among the smokers than the nonsmokers. Compared with the nonsmoking group, the smokers had a lower FEV1 % predicted and forced expiratory flow between 25 and 75% of FVC. A greater prevalence of emphysema and a significantly higher number of asthmatic patients with fixed airway obstruction were detected in the smoking versus nonsmoking group. The 37.5% of asthmatic patients who were former or current smokers showed decreased pulmonary function and increased IgE, emphysema on HRCT, and fixed airway obstruction, indicating that smoking can modulate the clinical and therapeutic responses in asthma.     

Spirometric response to a bronchodilator. Reference values for healthy children and adolescents

The spirometric response to inhaled salbutamol was assessed in 492 healthy volunteers 6 to 20 yr of age. Mean and standard deviation of the changes, expressed as percentage of prebronchodilator values, were as follows: forced vital capacity (FVC): 1.7 +/- 2.8; forced expiratory volume in one second (FEV1): 3.3 +/- 3.4; (FEV1/FVC): 3.1 +/- 3.2; peak expiratory flow: 6.4 +/- 8.6; maximal mid-expiratory flow: 10.1 +/- 8.8; maximum expiratory flow at 50% of FVC: 8.8 +/- 9.5 and maximum expiratory flow at 25% of FVC: 14.0 +/- 14.7. The changes were significant (p less than 0.005) for all parameters and similar to those observed in adults.     

Comparative study of cloprednol versus placebo in asthma.

This double-blind parallel trial evaluated the efficacy of cloprednol, a new synthetic glucocorticoid, in 40 patients with asthma. Patients kept daily records of wheezing, chest tightness, shortness of breath and cough. Analysis of these records showed cloprednol to be statistically significantly better than placebo for the relief of these symptoms (p values ranged from less than 0.01 to less than 0.0001). Weekly physician evaluations of asthma severity, symptoms since last visit and number of asthma attacks also showed a significant drug effect in favor of cloprednol. These subjective findings were confirmed by objective pulmonary function tests (FEV1.0, FVC and PEFR). There was a statistically significant difference favoring cloprednol for all the pulmonary function measurements. Previous studies have suggested that at equipotent anti-inflammatory doses cloprednol is less suppressive of hypothalamic-pituitary-adrenal axis function. Although plasma cortisol levels were not measured in this trial, none of the patients manifested clinically important side effects which required termination of their participation in the study.     

Correlation between nasal symptoms and asthma severity in patients with atopic and nonatopic asthma.

BACKGROUND: The association between allergic rhinitis and asthma has been well recognized, and it has been postulated that rhinitis may worsen asthma. OBJECTIVE: To investigate the severity of asthma among patients with atopic and nonatopic asthma with and without nasal symptoms. METHODS: Atopic asthmatic patients and nonatopic asthmatic patients were identified from the records of a university-based asthma clinic. A comparison of demographic clinical features was made within and between these 2 asthmatic groups, dichotomized according to the presence or absence of rhinitis. RESULTS: A total of 178 patients were classified as having atopic asthma and 218 as having nonatopic asthma. The atopic asthmatic patients with nasal symptoms compared with those without had a higher mean forced expiratory volume in 1 second (FEV1), a higher forced vital capacity (FVC), and a higher FEV1/FVC ratio, used fewer oral steroids, and had fewer hospitalizations. The nonatopic asthmatic patients with nasal symptoms compared with those without used more inhaled steroids (and they were also more likely to have nasal polyps on examination). Atopic, relative to nonatopic, asthmatic patients were younger, had a longer duration of asthma, had a higher FEV1/FVC ratio, and took fewer oral steroids. CONCLUSION: Contrary to current hypotheses, in this study the severity of asthma among atopic asthmatic patients was less in those with nasal symptoms. Conversely, among the nonatopic asthmatic patients, asthma was more severe among those with nasal symptoms than those without nasal symptoms.     

Reversibility of airway obstruction in asthma and chronic bronchitis (author transl)

Our purpose was to determine whether, in patients with airway obstruction, the change in the forced expiratory volume in one second (FEV1) which occurs after a bronchodilator drug, is helpful in differentiating asthma from chronic bronchitis. Two groups of patients (48 with asthma and 42 with chronic bronchitis) having a comparable level of initial airway obstruction were selected according to clinical criteria. After salbutamol (200 microgram inhaled) the number of subjects showing a change in FEV1 of at least 20 percent of its initial value or 10 percent of its predicted value was significantly greater (p less than 0.01) in the asthmatic than in the bronchitic group. Lesser changes in FEV1 did not significantly separate the two groups. When the changes in FEV1 were expressed as percentages of both initial and predicted values, the number of positive responses increased in the asthmatic group. However, there were still 20 asthmatics with little or no change in FEV1 after salbutamol who could not be distinguished from the patients with chronic bronchitis. From these data we conclude that, in patients with airway obstruction, a large bronchodilator-induced change in FEV1 strongly suggests the diagnosis of asthma but that the presence of "irreversible" airway obstruction does not disprove it.     

Clinical evaluation of the "Siriraj Spacer" in asthmatic Thai children.

We designed a new, washable, and collapsible bag spacer (the Siriraj Spacer) for use with metered-dose inhalers (MDI) by Thai asthmatic patients. The Siriraj Spacer consists of a mouthpiece, a front panel to which any type of MDI could be attached and a collapsible 800 mL ringed-plastic bag. Fifteen asthmatic children (6-13 years of age) were enrolled into a randomized, double-blind, triple crossover study (spanning a period of three days) to compare the clinical effectiveness of the Siriraj Spacer with that of the Volumatic Spacer (Glaxo, Inc., Research Triangle Park, NC, U.S.A.) and with the use of MDI alone. Medication used with the active method of administration was 2 puffs of albuterol (100 micrograms/puff) while 2 puffs from placebo MDI were used with the other two methods in succession. All children were stable asthmatic patients, and had been instructed how to use MDI properly by an open mouth technique just before the initiation of the study. Spirometry (FEV1, FVC, PEFR, and FEF25-75%) was followed for six hours after the administration of albuterol. The baseline FEV1s of the three study days were within 50% to 70% of the predicted values (with baseline variability of less than 20%). Data were expressed as percentage of improvement from baseline. By an analysis of variance with repeated measures, no significant differences were observed between pulmonary function data obtained with any of the three methods of bronchodilator administration (P > .05) at any time point throughout the 6-hour period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of azelastine on allergen- and exercise-induced asthma

The effects of the new anti-allergic drug, azelastine, on allergen- and exercise-induced asthma were studied. In six allergen inhalation tests for five asymptomatic asthmatic patients, the maximum percentage fall in FEV1.0 immediately after inhalation of allergen extract was 37.2 +/- 6.4 per cent (mean +/- SEM). As compared with a placebo, the maximum percentage fall in FEV1.0 with azelastine after inhalation of allergen extract in the same manner as with the placebo was 17.3 +/- 6.9 per cent. The difference was statistically significant (p less than 0.05). The percentage fall in FEV1.0 with placebo and azelastine in late asthmatic response (n = 4) was 36.0 +/- 5.3 per cent and 10.0 +/- 5.2 per cent, respectively. The difference was also statistically significant (p less than 0.01). An exercise test was carried out on seven asymptomatic asthmatic patients using an inclined treadmill. The maximum percentage fall in FEV1.0 without drugs, with diphenhydramine and azelastine was 38.9 +/- 5.0 per cent, 20.1 +/- 3.8 per cent and 11.3 +/- 3.1 per cent, respectively. Significant differences were found among each group (p less than 0.05). Azelastine was regarded as having sufficient potency to inhibit exercise-induced asthma; however, placebo effects cannot be ruled out with regard to the effects of diphenhydramine. These results suggests that chemical mediator release is involved not only in allergen-induced asthma but also in exercise-induced asthma, suggesting the clinical utility of azelastine.