Comparison of the bronchodilator effects of aerosol fenoterol and isoproterenol.

Aerosolized fenoterol in a dosage of 400 microgram was compared to isoproterenol 150 microgram in 31 asthmatic subjects during the course of a double-blind parallel 90-day study. Bronchodilator activities of the two drugs were evaluated for up to 6 hours on days 1, 45 and 90. Analysis of the data revealed that fenoterol consistently produced a significantly greater increase in FEV1, FEF25-75% and Gaw/VL. Specific airway conductance increased on each test day 25 percent or more above baseline for over three hours after use of fenoterol and for only one hour after use of isoproterenol. Fenoterol has less effect upon the cardiovascular and central nervous systems, but produced a greater incidence of shaking compared to isoproterenol. Patients used fenoterol less frequently than isoproterenol which can be attributed to the former having a greater peak effect and time course of bronchodilation. The therapeutic efficacy of fenoterol was sustained throughout this three-month study, and suggests that this relatively selective beta2 adrenergic drug will provide a well tolerated, alternative aerosol for chronic use in asthma.     

Bronchodilator effects of caffeine in coffee. A dose-response study of asthmatic subjects

Although caffeine is a universal drug and has multiple pharmacologic and physiologic actions in man, there are surprisingly few objective data about its effect on pulmonary function. We conducted a short-term, double-blind, randomized crossover study in nine asthmatic adults who ingested decaffeinated coffee containing varying amounts of added caffeine (mean of 0.2,2.5,5.6, and 7.2 mg/kg of body weight) on different days. The subjects also ingested decaffeinated coffee and aminophylline (200 mg) on a separate day of study. Baseline and post-drug determinations of serum levels of caffeine and theophylline, forced expired volume and flow, specific airway conductance (Gaw/VL), vital signs, and reported symptoms were obtained. Peak increases in serum caffeine concentrations (mean, 12.4 micrograms/ml +/- 1.5 micrograms/ml) occurred 45 minutes following the highest dose of caffeine (7.2 mg/kg), whereas the peak theophylline level (mean 3.8 micrograms/ml +/- 0.4 micrograms/ml) occurred 90 minutes following oral administration of aminophylline (mean theophylline, 2.6 mg/kg). Comparable peak increases in the forced expiratory volume in one second (FEV1), the forced expiratory flow during the middle half of the forced vital capacity (FEF25-75%), and Gaw/VL occurred at 120 minutes following aminophylline and the highest dose of caffeine, indicating that caffeine is an effective bronchodilator but is only 40 percent as active as an equivalent molar dose of theophylline. Regression analysis revealed statistically significant dose-response relationships between peak increases in serum caffeine concentrations and increases in FEV1, FEF25-75%, and Gaw/VL from baseline values. These findings have diagnostic and therapeutic implications regarding the use of caffeine prior to tests of pulmonary function and as a dietary agent, alone or in combination with theophylline.     

Factors that contribute to inhibition of methacholine-induced bronchoconstriction

To evaluate the factors that contribute to inhibition of airways reactivity, we compared the effect of inhaled isoproterenol, 125 micrograms, on the response to methacholine-induced bronchoconstriction in 10 normal and 10 asthmatic subjects. We measured in each subject baseline lung function, response to inhaled bronchodilator, dose of bronchodilator causing 50% maximal response, and degree of airways reactivity to inhalation of methacholine before and after isoproterenol. In asthmatics, but not normal subjects, inhalation of isoproterenol led to significant inhibition of methacholine-induced bronchospasm. In asthmatics, the greater the airways reactivity to methacholine the greater the inhibition by isoproterenol (p less than 0.05). In both groups, there was significant correlation between baseline lung function and level of airways reactivity. In neither normal subjects nor asthmatics did the maximal bronchodilator response to isoproterenol inhalation correlate with inhibition of airways reactivity. Studies evaluating inhibition of airways reactivity should take into account the population tested, baseline lung function, and baseline level of airways reactivity.     

Lung deposition and efficacy of inhaled formoterol in patients with moderate to severe COPD

BACKGROUND: Little is known about the impact of COPD on lung deposition of inhaled drugs and the relationship between lung-dose and response of pulmonary function measurements. METHODS: Nineteen patients with varying degrees of COPD were randomized to inhale single doses of formoterol (Oxis) Turbuhaler 4.5, 9, 18, and 36 microg in a double blind, placebo-controlled, crossover design. Urinary excreted formoterol during 32 h was used to determine absolute lung deposition. Peak inspiratory flow (PIF) and inhaled volume (IV) were recorded to assess the patients' ability to use Turbuhaler. Efficacy was measured by spirometry, inspiratory capacity (IC), airway conductance (sG(AW)), and absolute lung volumes. RESULTS: Mean pulmonary bioavailability of formoterol was about 24% of the nominal delivered dose after inhalation for the different treatments. No significant correlations between lung deposition and baseline FEV(1), PIF or IV were shown. All formoterol doses produced statistically significant increases in FEV(1), FVC, IC, and sG(AW) relative to placebo. Linear dose/response relationships were observed for these variables, with more narrow limits of the slopes for the lung-dose/response relationships than for the nominal-dose/response relationships. Moreover, 36 and 18 microg formoterol statistically significantly decreased functional residual capacity (FRC) and residual volume (RV) relative to placebo. CONCLUSIONS: This study could not show any difference in lung deposition of formoterol inhaled via Turbuhaler between patients with moderate and severe COPD. Moreover, the effect of formoterol on various pulmonary function measurements were more closely related to lung deposition than the inhaled nominal dose.     

Dose-response effects of two sizes of monodisperse isoproterenol in mild asthma

The dose-response effect of monodispersed isoproterenol of two different sizes (diameters 2.5 and 5 microns) was examined in eight mild asthmatic subjects (baseline FEV, 81.5% of predicted). Pulmonary and cardiovascular variables were measured before and following 1, 2, 4, 8, and 16 cumulative min of aerosol inhalation. Subjects inhaled 1 to 30 micrograms (2.5-microns particles) or 2 to 50 micrograms (5-microns particles) of isoproterenol. Pulmonary but not cardiac responses were significantly greater for the 2.5-microns particles as compared to equivalent doses of 5-microns particles. Pulmonary dose-related response differences were particularly marked for variables associated with small airway function (FEF25-75 and FEF75-85). These findings suggest that small particles penetrate more deeply into the lung and thereby more effectively dilate small airways and that small amounts of appropriately sized inhaled bronchodilator may produce considerable therapeutic effects.     

Cumulative and single-dose design to assess the bronchodilator effects of beta2-agonists in individuals with asthma

With the development of different chlorofluorocarbon (CFC)-free metered dose aerosol and dry powder devices, it is necessary to study and validate the methods used for assessing and comparing their efficacy. This study evaluated the cumulative dose design by determining the bronchodilator response to salbutamol given according to either a high or a low cumulative dose regimen. Adults with asthma (n = 24) were studied in a placebo-controlled, randomized, double-blind, cross-over design. On separate days, cumulative doses of salbutamol (50+50+100+200 or 100+100+ 200+400 or 400+0+0+0 or 0+0+0+0 microg) were given via Turbuhaler with 30 min between doses. The two cumulative dose regimens produced almost identical bronchodilator responses at each time point. The relative dose-potency between the 800- and 400- microg cumulative dose regimens was 0.7 with a 95% confidence interval of 0.5-1.0, excluding the true value of 2. The 400-microg cumulative dose regimen resulted in a higher FEV1 at 115 min than the 400-microg single-dose regimen. There was no difference in the bronchodilator response to the single dose of 50, 100, or 400 microg of salbutamol after either 5 or 25 min. Thus, care should be exercised when using either a cumulative or single-dose design for comparing different beta2-agonists, or different inhalation devices, with respect to their relative dose-potency. In addition, this study provides further evidence that for short-acting beta2-agonists such as salbutamol, lower doses than those normally recommended may be used, and that repeated self-administration of low doses over a period of 60 min may give a better bronchodilator response than a single administration of a high dose.     

Effect of inhaled atropine or metaproterenol in patients with chronic airway obstruction and therapeutic serum theophylline levels

Twenty-one patients with stable chronic obstructive pulmonary disease (mean FEV1 = 0.98 L) and high-normal serum theophylline levels (15-20 micrograms/ml) were evaluated in a randomized, double-blind fashion for additional bronchodilator response to aerosolized normal saline, atropine, or metaproterenol. Patients were classified as responders (R; n = 9) or nonresponders (NR; n = 12) to inhaled isoproterenol when they were taking no medications. Atropine and metaproterenol caused a significant additional increase in FEV1 for R (p less than .05), whereas only atropine resulted in a significant increase for NR (p less than .05). For R, the increase due to atropine was significantly greater compared to metaproterenol (p less than .05). We conclude that inhaled atropine (an anticholinergic drug) may be preferable to inhaled metaproterenol (a beta-adrenergic agonist) when additional bronchodilation is needed in patients with chronic obstructive pulmonary disease and high-normal serum theophylline levels.     

The bronchodilator test with increasing doses of terbutaline in chronic obstructive pulmonary disease patients

There is no uniform consensus on the dose of bronchodilator to be used in the bronchodilator test (BDT). The objective of the study was to determine the dose of inhaled terbutaline that can safely achieve a greater number of positive BDT in patients with chronic obstructive pulmonary disease (COPD). The study was prospective and single blinded. One-hundred and fifty patients with stable COPD were included. Their mean (+/-SD) age was 67.4 (8.8) years. Their mean forced expiratory volume in the first second (FEV1) was 1.14 (0.48) l (41% of the predicted value). A baseline spirometry was performed and a second 20 min after the inhalation of placebo. Three consecutive doses of 500 microg of inhaled terbutaline were administered and a new spirometry was performed after each one. A multivariate analysis based on the comparison of the repeated means was performed in order to analyse the spirometric changes achieved after the different doses of bronchodilator. The increase of FEV1 and forced vital capacity (FVC) with the two first doses of terbutaline was statistically significant; the increase of the peak expiratory flow (PEF) was significant after the three doses administered. The number of positive BDT were 40, 47 and 60 after each dose of terbutaline (P=0.004). The higher dose of terbutaline was more useful in identifying patients with significant bronchoreversibility and, moreover, was well tolerated. We suggest that this dose (1500 microg) should be routinely used in performing the BDT.     

Beta-blockers and asthma.

In a single-blind, randomised, crossover study in 10 asthmatic patients, the effects of approximately equipotent oral doses of 3 cardioselective beta-blockers-atenolol (100 mg), metoprolol (100 mg), and acebutolol (300 mg)-and 4 non-cardioselective beta-blockers-proranolol (100 mg), oxprenolol (100 mg), pindolol (5 mg), and timolol (10 mg) upon FEV1 were compared. All drugs, except pindolol, produced a significant reduction in standing pulse rate and prevented an increase in heart rate after inhaled isoprenaline (1500 microgram). All drugs caused a fall in FEV1 but only atenolol did not differ significantly from placebo in this respect. The bronchodilator response to inhaled isoprenaline was blocked by the 4 non-cardioselective drugs; the 3 cardioselective agents permitted some bronchodilatation, but only atenolol did not differ from placebo.     

Beta-blockers and asthma.

In a single-blind, randomised, crossover study in 10 asthmatic patients, the effects of approximately equipotent oral doses of 3 cardioselective beta-blockers-atenolol (100 mg), metoprolol (100 mg), and acebutolol (300 mg)-and 4 non-cardioselective beta-blockers-proranolol (100 mg), oxprenolol (100 mg), pindolol (5 mg), and timolol (10 mg) upon FEV1 were compared. All drugs, except pindolol, produced a significant reduction in standing pulse rate and prevented an increase in heart rate after inhaled isoprenaline (1500 microgram). All drugs caused a fall in FEV1 but only atenolol did not differ significantly from placebo in this respect. The bronchodilator response to inhaled isoprenaline was blocked by the 4 non-cardioselective drugs; the 3 cardioselective agents permitted some bronchodilatation, but only atenolol did not differ from placebo.     

Acute postbronchodilator changes in pulmonary function parameters in patients with chronic airways obstruction

Pulmonary function studies were performed before and after one-time administration of an inhaled bronchodilator to ascertain the relative diagnostic value of using FVC, FEF25-75%, static lung volumes, Raw, and/or sGaw measurements, in addition to the FEV1, to assess the reversibility of chronic airways obstruction in nonasthmatic patients. A total of 517 patients underwent 686 spirometric tests, 264 (38 percent) of which disclosed a significant response to bronchodilators. In 247 (93 percent) studies, this response included a significant change in FEV1 and/or FEF25-75%, while in 17 studies (7 percent), the postbronchodilator improvement was seen exclusively in the FVC measurement. It is concluded that, in the clinical setting, analyzing static lung volumes, Raw, sGaw, and spirometric parameters other than the FEV1, seldom yields meaningful additional information regarding the reversibility of chronic airways obstruction in nonasthmatic patients. Finally, potentially misleading results can be seen in a relatively small proportion of studies due to errors in the FVC and/or FEF25-75% measurements.     

Patterns of response to bronchodilators in asthma

Twenty-eight asthmatics inhaled an isoprenaline aerosol on several occasions. The dose administered was constant for each subject on each occasion, yet the responses of each subject measured spirometrically differed on most of the separate occasions. The individual response patterns showed the following features. Spontaneous worsening of the asthma was associated with spirometric responses which in some cases increased directly and predictably with the corresponding fall in pre-treatment FEV1. In other cases the increase in response was less regular and in a few it bore no relation whatsoever to the pre-treatment FEV1. In three subjects a response occurred when the pre-treatment FEV1 was greater than the predicted value. There were variations between subjects in the magnitude of increase in spirometric response to inhaled bronchodilator occurring when there was a fall in pre-treatment FEV1. The great majority of subjects never achieved their predicted FEV1 after maximal doses of isoprenaline. The study of individual response patterns is of value in the selection of subjects for comparative trials of different bronchodilator drugs. The present study draws attention to an irreversible component in the reduction of airways calibre that occurs in asthma.     

Inhaled formoterol versus ipratropium bromide in chronic obstructive pulmonary disease

BACKGROUND: Short-acting anticholinergic bronchodilator, ipratropium bromide has been recommended as first-line drug in chronic obstructive pulmonary disease (COPD). More recently, long acting beta2-agonist (LABA) bronchodilators such as formoterol have been shown to be useful in COPD. Limited information is available on the relative efficacy of these two drugs in COPD. METHODOLOGY: A randomised, double-blind, cross-over, placebo-controlled study was carried out. Forty-four stable patients with COPD received single doses of formoterol (12 microg), ipratropium bromide (40 microg) or placebo, administered through a metered-dose inhaler on three consecutive days in a random order. Spirometry, static lung volumes, pulse rate and blood pressure, and assessment of sensation of dyspnoea at rest using a visual analog scale (Borg Scale) were recorded at baseline. Subsequently, these were repeated for assessment of response: spirometry at 5, 30 and 60 minutes and static lung volumes, pulse rate, blood pressure and dyspnoea measurement at 60 minute. RESULTS: Formoterol resulted in greater immediate improvement in lung function, with the change in FEV1 at 5 min being greater than that observed with ipratropium. The changes in static lung volumes were similar between the two but superior to placebo. Both the drugs reduced dyspnoea. Formoterol produced a significantly greater increase in heart rate and systolic blood pressure as compared to ipratropium, although the magnitude of these changes was small and clinically unimportant. CONCLUSIONS: Single therapeutic doses of formoterol and ipratropium bromide are equally effective in improving lung function and reducing dyspnoea. However, formoterol appears to be a better bronchodilator producing a faster improvement in lung function.     

Bronchodilator response in relation to beta2-adrenoceptor haplotype in patients with asthma

RATIONALE: Genetic variation of the beta2-adrenoceptor (ADRB2) influences receptor function in vitro. There are reports that, in vivo, bronchodilator response is related to ADRB2 genotype, and that clinical outcomes during chronic therapy with beta2-agonist drugs are also influenced by genotype. Whether these features are related to single nucleotide polymorphisms or to combinations (haplotypes) is unclear. OBJECTIVES: Our aim was to measure bronchodilator response in patients with asthma stratified by ADRB2 haplotype. This was done after eliminating the confounding effect of prior drug treatment with inhaled beta2-agonists and corticosteroids. METHODS: ADRB2 haplotype was determined in 176 patients with asthma, of whom 161 harbored the six most common combinations. Treatment with inhaled beta2-agonists and inhaled corticosteroids was withheld for appropriate intervals. Spirometric changes 20 minutes after a single dose of albuterol (2.5 mg by nebulizer) were then recorded. RESULTS: There were no significant differences in bronchodilator response (% improvement in FEV(1)) with respect to any of the major ADRB2 haplotypes or genotypes. CONCLUSIONS: Genetic variation of the ADRB2 does not influence the immediate response to inhaled beta2-agonist. The confounding effect of tolerance resulting from regular beta2-agonist use must be controlled when assessing the pharmacogenetic influences on clinical outcomes with beta2-agonists.     

Dose-response study of nebulized bitolterol mesylate solution in asthmatic patients

Bitolterol mesylate, a new beta 2 adrenergic bronchodilator, is a "pro-drug" which is activated by esterases in the lung. In order to determine the optimal bronchodilator dose of bitolterol, six doses, (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg and 3.0 mg), were administered by closed-port, intermittent-flow nebulization (CPIF) to asthmatic patients on different days. For most patients, the onset of bronchodilator activity (FEV1 increase of at least 15 percent above baseline) occurred within 5 minutes and lasted at least 8 hours. Maximum mean increases in FEV1 were 46-50 percent at the 1.0 mg to 3.0 mg doses. Beyond the 1.0 mg dose, there was no significant improvement in bronchodilator effect, but adverse effects, particularly tremor, increased at higher doses. The optimal dose of bitolterol administered by CPIF was determined to be 1.0 mg which is similar to the dose of bitolterol recommended for use by metered-dose inhaler (MDI) which is 0.7 mg to 1.1 mg. If continuous-flow nebulization is used, two-three times more drug may be needed for a comparable effect. Bitolterol appears to be a safe, effective and long-lasting bronchodilator when administered by jet nebulization.     

Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects

OBJECTIVE: The aim of the study was to investigate whether treatment using inhaled corticosteroids decreases airway responsiveness to inhaled mannitol in asthmatic subjects. METHODOLOGY: Before treatment or a change in treatment with inhaled corticosteroids, 18 asthmatic subjects had measurements of lung function and airway sensitivity to mannitol taken and they completed a self-administered questionnaire on asthma symptoms. The procedure was repeated 6-9 weeks after taking 800-2400 microg/day of budesonide. RESULTS: There were significant reductions in airway sensitivity (provoking dose to induce a 15% fall in FEV1 (PD15)) and airway reactivity measured by the response dose ratio (RDR; final percentage fall FEV1/total dose of mannitol administered). The PD15 (Gmean (95%CI)) increased from 78 mg (51, 117) before treatment to 289 mg (202, 414) following treatment (P < 0.001). All subjects had a significant increase beyond the repeatability of 0.9 doubling doses with seven subjects becoming unresponsive. There was a 4.2 (3.4, 4.9)-fold improvement in the RDR with the value before the treatment period 0.18 (0.12, 0.28) decreasing to 0.04 (0.03, 0.08) following treatment (P < 0.001). These improvements were associated with significant improvements in lung function and symptom severity. CONCLUSION: Treatment with the inhaled corticosteroid budesonide caused a decrease in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms.     

Unusual presentations of tuberculosis of the pleura

Rimiterol hydrobromide (Pulmadil) has been shown to have a dose-related bronchodilator effect; the optimum dose by inhalation appears to lie between 200 and 1,000 microgram. When given to a group of asthmatic patients at 'recommended' and 5--10 times 'recommended' dose by aerosol, cardiovascular effects were minimal and of a magnitude similar to that of salbutamol given in the same dosages to the same patients. The very rapid bronchodilator effect of rimiterol would appear to make the drug particularly suitable for the treatment of patients with intermittent asthmatic attacks, before exercise in patients with exercise-induced asthma and for bronchodilatation before using inhaled sodium cromoglycate or corticosteroid aerosols.     

Bronchodilator response in residual volume in irreversible airway obstruction

BACKGROUND: Although airway obstruction, as defined by improvement of forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC), is irreversible in patients with COPD, they clearly seem to benefit from treatment with inhaled bronchodilators. AIMS: To assess the response pattern of residual volume (RV) compared to FEV1 after bronchodilation in patients with reversible and irreversible airway obstruction. METHODS: Changes in static lung volumes were compared with improvement in dynamic lung volumes in 396 consecutive patients undergoing reversibility testing with repeat bodyplethysmography. Reversibility was defined as improvement of FEV1 >200 ml and >12% after inhalation of fenoterol hydrobromide. RESULTS: Irreversibility was found in 297 out of 396 patients with airway obstruction. Except for total lung capacity (TLC), all parameters (residual volume [RV], vital capacity [VC], forced inspiratory vital capacity [IVC], forced vital capacity [FVC], forced expiratory volume in one second [FEV1] and the FEV1/VC ratio) showed statistically significant changes after bronchodilation in 396 patients. The multiple linear regression model adjusted for age, sex and BMI showed a non-linear relationship between DeltaFEV1 or DeltaVC compared to DeltaRV after bronchodilation. If the increase in DeltaFEV1 is lower than 0.1 L, DeltaRV remains constant. However, if the increase in DeltaFEV1 is more than 0.1 L, DeltaRV decreases too. The same is found at an increase in VC of 0.3 L. CONCLUSION: In summary, in patients with irreversible airway obstruction DeltaRV cannot be predicted by DeltaFEV1 or DeltaVC after bronchodilation. Therefore, spirometric assessment should be complemented by bodyplethysmography.     

Prolonged effect of inhaled glycopyrrolate in asthma

Glycopyrrolate, a quaternary ammonium anticholinergic compound is a potentially useful bronchodilator. To determine the efficacy, optimal dose, and duration of action of inhaled glycopyrrolate, we gave the drug to 11 asthmatic patients. Each subject received placebo or glycopyrrolate (100, 200, 600, or 1,200 micrograms) by inhalation in a double-blind, randomized, crossover design. Measurements included FEV1, FVC, heart rate, and blood pressure before administration of the drug and periodically for 12 hours. For eight hours following all doses of glycopyrrolate, both FEV1 and FVC (both as percent of predicted) were significantly greater for drug than for placebo. Glycopyrrolate may be a useful long-acting drug for the treatment of asthma.     

Tolerance to beta-agonists during acute bronchoconstriction.

Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction. Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 microg, b.i.d.), both drugs or placebo in a randomized, double-blind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 microg at 5 min intervals) was then measured. Dose-response curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates. There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide. Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations.