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It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E2 (PGE2) is produced in the lung but unlike most other lipid mediators has potentially important antiallergic effects. Whether these properties are relevant to asthma has not been established. The effect of inhaled PGE2 on allergen-induced asthma was examined in a double-blind crossover study of eight subjects with asthma. In Study 1 subjects inhaled 100 micrograms PGE2 or placebo 5 min before a normal saline challenge, and FEV1 and bronchial reactivity to methacholine was measured at intervals for 7 h. In Study 2, which had a similar design, subjects inhaled the same dose of PGE2 or placebo followed by a dose of allergen previously shown to cause a fall in FEV1 of 20% or more. On the normal saline challenge day inhaled PGE2 caused a small increase in FEV1 that lasted for around 60 min; there was no difference in the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) at 4 and 7 h compared with placebo. PGE2 caused marked inhibition of the early and late response to allergen. The mean maximum fall in FEV1 0 to 2 h after allergen was 37.8 and 7.7% with placebo and PGE2 pretreatment, respectively (mean difference 30%; 95% CI 15, 45%; p < 0.005). The mean maximum fall in FEV1 from 4 to 7 h after allergen was 25.5 and 8.8% respectively (mean difference 16.7%; 95% CI 4, 29%; p < 0.02). The methacholine PD20 fell significantly after allergen with placebo but not with PGE2. The difference was 1.5 doubling doses at both 4 and 7 h (p < 0.01 and p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Inclusion of a standardized measurement of airway function is important in epidemiologic studies of asthma to facilitate comparison between different studies. Bronchial reactivity is widely used in such studies, but measurement of peak expiratory flow (PEF) variability has a number of potential advantages. We compared PEF variability with methacholine challenge tests in a community population sample. Subjects selected at random (n = 95) and on the basis of having experienced wheeze in the last 12 months (n = 130) performed a challenge test with methacholine to a maximum dose of 12.25 mumol and made serial PEF recordings every 2 h for a week. PEF variability was expressed as mean daily maximum amplitude as a percentage of the mean (amplitude % mean). Increased bronchial reactivity and PEF variability were arbitrarily defined as values above the 10th or below the 90th percentiles in the random sample. A measurement of amplitude % mean was available from all 225 subjects, whereas only 115 (51%) had a measurable PD20 methacholine. PD20 measurements correlated weakly but significantly with amplitude % mean (r = -0.44, p less than 0.001). Increased values of both bronchial reactivity and PEF variability were related to the presence of respiratory symptoms in the week before testing. Asthma was more strongly related to increased bronchial reactivity than to PEF variability. Both measurements showed a strong association with atopy and the intraclass correlation coefficients (ratio of between-subject to total variance) were similar for both.(ABSTRACT TRUNCATED AT 250 WORDS)

Salmeterol is a new beta 2-selective agonist with a long duration of action. We compared the effect of 50 micrograms salmeterol administered by metered dose inhaler (MDI) and dry powder inhaler (DPI), with 200 micrograms albuterol (by MDI) on FEV1 and histamine-induced bronchoconstriction in 12 asthmatic subjects in a double-blind, placebo-controlled crossover study. Subjects were studied for 12 h on four occasions with a histamine challenge test at 1, 4, 8, and 12 h, the response being measured as the dose of histamine causing a 20% fall in FEV1 (PD20). There was no difference in the mean +/- standard error of the mean maximum increase in FEV1 between salmeterol MDI, salmeterol DPI, or albuterol (0.57 +/- 0.078, 0.54 +/- 0.089, and 0.49 +/- 0.081 L, respectively); the increase following placebo was 0.25 +/- 0.082 L. The area under the 12-h time-response curve for FEV1 was greater for both formulations of salmeterol (MDI and DPI) than for albuterol. The three active drugs protected against histamine-induced bronchoconstriction. The increase in PD20 at 1 and 12 h and the area under the 12-h time-response curve for PD20 were greater following both formulations of salmeterol than after albuterol. The greater change in geometric mean PD20 values at 1 h after both formulations of salmeterol (2.21 and 1.88 mumol) relative to albuterol (0.98 mumol) suggests that despite similar effects on FEV1 the doses used do not have an equivalent effect on the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

The time course of change in FEV1, bronchial reactivity, and daily measures of asthma control (peak expiratory flow, symptoms, and beta 2-agonist inhaler use) was determined during 6 wk of treatment with inhaled budesonide, 800 micrograms twice a day, and for 2 wk following cessation of treatment in 40 asthmatic subjects in a double-blind, placebo-controlled, parallel group study. Histamine reactivity, expressed as the provocative dose of histamine causing a 20% fall in FEV1 (PD20), was measured at intervals during the 8 wk of the study, with more frequent measurements after the first and last dose of drug to provide a detailed profile of change at the start and end of treatment. The first dose of budesonide caused a small increase in median values of FEV1 (0.2 L) and PD20 (1.0 doubling dose of histamine), which was maximum at 6 h. There was a further increase in FEV1 and PD20 over the 6 wk in the budesonide group relative to placebo, the maximum increases (0.53 L, 3.4 doubling doses of histamine) being recorded 6 h after the last dose on Day 42. Following cessation of treatment, FEV1 and PD20 declined and PD20 returned to placebo values at 1 wk. Median PEF increased by 40 and 30 L/min in the morning and evening, respectively, with budesonide treatment. Symptom scores and beta 2-agonist inhaler use were lower in the budesonide group than the placebo group during treatment but tended to be similar (symptom scores) or higher (beta 2-agonist) in the 2 wk following cessation of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The changes in airway caliber and plasma cyclic-AMP levels after intravenously administered aminophylline, and the effect of DL- and D-propranolol on these responses have been investigated in a double-blind manner in normal subjects. Aminophylline 5.6 mg/kg was given intravenously over a 10-min period and the airway response was measured as change in specific airway conductance (delta SGaw) in the body plethysmograph. In the initial study in 6 subjects, orally administered placebo or propranolol was followed 2 h later by intravenously administered aminophylline. Neither placebo nor propranolol alone caused any change in SGaw at 2 h. After placebo, intravenously injected aminophylline produced a 30% increase in SGaw, reaching a peak 5 min after injection. This response was equivalent to 77% of the maximal response to 400 micrograms inhaled albuterol in the same subjects. After propranolol, the airway response to aminophylline was attenuated, with a 53% reduction in delta SGaw at the time of peak response. In a further study on 6 subjects, intravenously given aminophylline produced a 25% increase in SGaw and a 51% increase in plasma cyclic-AMP levels after placebo tablets. Pretreatment with 40 and 80 mg DL-propranolol caused a dose-dependent reduction of both the airway and plasma cyclic-AMP response to aminophylline. The airway response to aminophylline was not attenuated by D-propranolol so the effect of DL-propranolol is thought to be due to beta-adrenoceptor blockade. The absence of any detectable change in SGaw after DL-propranolol suggests there is little resting sympathetic tone to the airways in normal subjects. In the absence of sympathetic stimulation, the rapid response to aminophylline is unlikely to be due to phosphodiesterase inhibition. The attenuation of the airway and cyclic-AMP response by propranolol suggests that part of the action of aminophylline may be due to beta-agonist activity.

The effect of suggestion on the airway response to 10 inhalations of normal saline followed by doubling concentrations of isoproterenol was assessed in 12 normal and 30 asthmatic subjects. It was suggested that the first 5 saline solutions contained a bronchoconstrictor and that the second 5 contained a bronchodilator, or vice versa, and that the first 4 isoproterenol solutions were inert, whereas the last was a bronchodilator. Nine asthmatic, but no normal subjects, bronchoconstricted after saline inhalation, with a mean fall in specific airway conductance (SGaw) of 40%. This was dose-dependent and was abolished when inhalations were carried out at 37 degrees C 100% relative humidity. Suggestion did not affect the airway response to saline or isoproterenol in either group, but it did influence the subjective impression of airway caliber recorded on a visual analogue scale. In this study, the bronchoconstriction after saline inhalation, previously attributed to the effect of suggestion, was caused by airway cooling.

Although serial peak expiratory flow (PEF) measurements are often used to assess the variability of airflow obstruction, the range of values to be expected in the general population has never been defined, nor is there any consensus as to how PEF variability should be expressed. We have compared PEF recordings made by 121 subjects selected at random from the population of a small town (Group A) and 221 subjects selected because of wheeze in the last year (Group B). Subjects were asked to record PEF every 2 h during waking hours for 7 days using a mini-Wright peak flow meter. Seven indices of PEF variability were derived for each subject and the range for each index determined. All indices showed a positively skewed distribution in the random sample. Two variability indices, standard deviation percent mean and amplitude percent mean, provided the greatest separation between subjects with both a diagnosis of asthma and wheeze in the last year and subjects with neither feature and also provided the highest intra-class correlation coefficients. We conclude that amplitude percent mean and standard deviation percent mean provide the best means of expressing PEF variability for epidemiological purposes, but that amplitude percent mean is more easily derived and appears to be the index of choice. PEF variability has a continuous distribution in the general population and no clear-cut division between asthmatic and nonasthmatic subjects can be defined.

Airway reactivity is known to increase in relation to the severity of asthma, and, in the community, hyperreactivity has been shown to be associated with respiratory symptoms such as wheezing and shortness of breath. However, the relation between change in airway reactivity and change in the severity of respiratory symptoms and change in the use of asthma medications within subjects has not been studied. We have investigated this relationship in a community population. In September 1984 and March 1985, the provocative dose of histamine producing a 20% fall in FEV1 (PD20) was measured, and respiratory symptoms and medication use assessed by questionnaire in 78 subjects taking part in a study of seasonal changes in airway reactivity. On both occasions, PD20 was negatively correlated with current frequency of wheezing, with the amount of asthma medication in regular use, and with the current general assessment of breathing problems. In the 45 subjects who had a PD20 value of 8 mumol or less on at least one of the two occasions tested, PD20 increased between September and March by 0.46 (SEM, 0.32) doubling doses of histamine (p = 0.16). Within subjects, change in PD20 was negatively correlated with change in the frequency of wheezing in the past month (p less than 0.005) and with change in medication use (p less than 0.05). This study demonstrates that PD20 is related to the severity of respiratory symptoms and medication use, and that change in airway reactivity within subjects in a community population is associated with changes in the frequency of wheezing and in the use of asthma medication.

Inhaled adenosine causes bronchoconstriction in asthmatic patients. Antagonism of the bronchoconstrictor effect of endogenous adenosine has been proposed as a possible mechanism of action of theophylline in asthma. To directly investigate this, we have compared the airway responses to inhaled adenosine and histamine, with and without the prior administration of inhaled theophylline in 8 allergic asthmatic subjects. Airway response was measured both as forced expiratory volume in one second (FEV1) and as specific airway conductance (SGaw). Inhaled adenosine was less potent than histamine in producing bronchoconstriction, with geometric mean concentrations required to produce a 20% fall of FEV1 (PCf20) and a 40% fall of SGaw (PCs40) being 0.27 and 0.25 mg/ml for adenosine and 0.10 and 0.09 mg/ml for histamine. In a total nebulized dose of 37.5 mg, inhaled theophylline was a weak bronchodilator that caused maximal increases in FEV1 of 2 +/- 2% (mean +/- SE, p less than 0.05) and in SGaw of 8 +/- 4% (p greater than 0.05). However, theophylline significantly inhibited adenosine-induced bronchoconstriction, increasing the PCf20 and PCs40 values for adenosine to 1.66 (p less than 0.001) and 2.34 (p less than 0.005) mg/ml, respectively. Inhibition of histamine-induced bronchoconstriction was less marked, with PCf20 and PCs40 values of 0.19 (p greater than 0.05) and 0.21 (p less than 0.05) mg/ml. Thus, adenosine is a bronchoconstrictor in asthma whose effects are preferentially antagonized by concentrations of theophylline that cause little change in baseline airway caliber.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostacyclin (PGI2) is one of several prostanoids released after antigen challenge of human lung fragments. To define its activity on human airways, we studied the effect of inhaled PGI2 in 10 normal and 8 asthmatic subjects. In random order, PGI2, 1 mg/ml, its hydrolysis product, 6-oxo-PGF1 alpha, 1 mg/ml, and glycine vehicle were given on separate occasions by nebulizer. Measurements of specific airway conductance (SGaw), blood pressure (BP), heart rate (HR), plasma 6-oxo-PGF1 alpha, and cyclic AMP levels were made at frequent intervals for as long as 45 min after nebulization. Prostacyclin and 6-oxo-PGF1 alpha caused cough and retrosternal discomfort. None of the drugs had any significant effect on SGaw in either the normal or asthmatic subjects, though 2 asthmatics showed consistent bronchodilatation with prostacyclin. Prostacyclin caused a marked fall in diastolic blood pressure (mean 20 +/- 3 mmHg) and increase in heart rate (29 +/- 3 beats X min-1) with a small late fall in systolic blood pressure (8 +/- 2 mmHg). This was associated with a 12- to 15-fold increase in plasma 6-oxo-PGF1 alpha levels maximal at 1 min, and in normal subjects only, a later twofold increase in plasma levels of cyclic AMP maximal at 5 min. Thus, inhaled PGI2 at concentrations that had pronounced cardiovascular activity produced no consistent effect on airway caliber in normal or asthmatic subjects.

Higher doses of inhaled albuterol have been shown to cause slightly more bronchodilatation than standard doses from a metered-dose inhaler in patients with severe chronic airflow limitation. Higher doses, however, carry an increased risk of side effects, and the optimum dose balancing benefit and adverse effects have yet to be established. We have therefore looked at objective and subjective evidence of beneficial and adverse effects after 4 doses of albuterol in 30 patients with chronic bronchitis, severe airflow limitation, and less than 200 ml increase in FEV1 after 200 micrograms inhaled albuterol. Subjects were given placebo, 400 micrograms, 1 mg, 2 mg, and 4 mg albuterol by dry powder inhaler in random order on separate days in a double-blind study, and FEV1, relaxed VC, PEFR, 12-min walk distance, finger tremor, oxygen saturation, heart rate, and arrhythmias were measured at intervals over 6 h. With increasing doses of albuterol, there was a significant dose-related increase in FEV1, VC, and PEFR, the maximal mean changes being 196 ml, 480 ml, and 50 L/min, respectively. The duration of effect was longer with the higher doses. There was a dose-related increase in heart rate, tremor amplitude, and supraventricular ectopic beats and a dose-related fall in oxygen saturation. There was no drug-related effect on the frequency of ventricular ectopic beats either at rest or during the walk tests. The largest increases in walk distance occurred after the 1 and 2 mg doses and the least after the 4 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)