Inhaled Beta Agonists Research Articles

Cutaneous vasoconstrictor response to glucocorticoids in asthma

The aim of the study was to find out whether asthma patients whose airways obstruction is sensitive (CS) or resistant (CR) to corticosteroid treatment also differ in their cutaneous vasoconstrictor response to a potent topical glucocorticoid. Corticosteroid resistance was defined by failure of forced expiratory volume in 1 s (FEV 1) and peak expiratory flow rate to improve by at least 15% after a 2-week trial of corticosteroids (prednisolone 20 mg daily for 1 week, then 40 mg daily for 1 week) despite more than 15% improvement with inhaled beta agonists. Beclomethasone dipropionate in concentrations of 3 μg/ml, 10 μg/ml, 30 μg/ml, and 100 μg/ml was applied to forearm skin; the site was occluded under plastic and the degree of blanching assessed after 18 h. CS asthmatic subjects (n=31), asthma patients with mild airways obstruction (n=26), asthma patients taking long-term prednisolone (n=13), and healthy volunteers showed similar vasoconstrictor responses. In CR asthmatic subjects (n = 15), the response (expressed in terms of either blanching intensity or the proportion of patients showing a positive response) was significantly lower than that in the CS group at concentrations of 3 μg/ml (p<0·01), 10 μg/ml (p<0·01), and 30 μg/ml (p<0·05), but not at 100 μg/ml. This resistance to glucocorticoids in the skin, together with reported evidence of glucocorticoid resistance in peripheral blood leucocytes, suggests a general defect in the ability of tissues to respond to glucocorticoids in CR asthma.

Evaluation of Three Theophylline Dosing Methods in Pediatric Patients

Three methods used for individualizing theophylline dosing were prospectively evaluated in 34 pediatric patients to compare the methods' ability to accurately predict steady-state serum theophylline concentrations (STCs) from non-steady-state data. Methods evaluated included a Bayesian weighted sum of squares regression program, an algebraic method developed by Chiou, and a commonly used population-based pediatric dosing algorithm. An expanded retrospective evaluation was also done to further compare the Bayesian and Chiou methods. Patients (aged 1-11 y) admitted to the hospital for acute bronchospasm refractory to inhaled beta agonists and with physician's orders to receive intravenous aminophylline were eligible for participation. Study patients received a 6-mg/kg loading dose aminophylline, followed by a 0.8-1.0 mg/kg/h constant aminophylline infusion. STCs were obtained 0.5 and 5.5 hours postinfusion. Subjects were randomized to one of three dosing method groups (Bayesian, Chiou, or pediatric algorithm). Doses were calculated using the assigned method to attain a target steady-state STC. Predictions from each dosing method were compared with actual serum concentrations for bias and precision. Additionally, analysis of fit-to-the-line-of-identity for predicted versus observed STCs was evaluated for each method. Precision of methods was also compared with regard to their ability to predict within 20 percent of their observed steady-state STC. Results from the prospective evaluation showed no significant difference between the three methods tested. Predicted STCs fell within 20 percent of their observed steady-state concentrations for 18 percent (2/11) of patients in the algorithm group, and 45 percent (5/11) of patients in the Chiou group and 17 percent (2/12) of the patients in the Bayesian group met this criterion. Retrospective analysis of all 34 patients demonstrated that the Bayesian and Chiou methods had similar bias and precision and no statistical difference was found between them. The results from this evaluation suggest that the pediatric dosing algorithm is equivalent in predictive bias and precision to the Bayesian and Chiou methods as well as in its ability to identify doses that result in steady-state STCs within 20 percent of their target values. Given the relative inaccuracy of these methods, cautious use of these techniques is recommended when evaluating non-steady-state STCs obtained from children during the acute stages of reactive airway disease.

Control of Breathing in Chronic Obstructive Pulmonary Disease Patients at Rest and after Beta-2 Agonist Inhalation

Ventilatory function tests, ventilatory cycle analysis, mouth occlusion pressure (P0.1) and effective inspiratory impedance (P0.1/Vt/Ti) were measured in 11 healthy subjects and in 26 patients with chronic obstructive pulmonary disease (COPD). In COPD patients these measurements were repeated 20 min after inhalation of 400 micrograms of fenoterol. In patients we observed an increase of mean inspiratory flow (Vt/Ti), and a decrease of inspiratory time (Ti) and inspiratory duty cycle (Ti/Ttot). P0.1 and effective inspiratory impedance were significantly increased. Moreover, we found a direct correlation between forced expiratory volume in 1 s (FEV1) and ventilatory cycle components (Ti/Ttot, Ti) and an indirect correlation between FEV1 and Vt/Ti.P0.1 was directly correlated with Vt/Ti and indirectly correlated with ventilatory cycle components. These observations lead us to speculate on the possible role of two opposite mechanisms acting on the control of breathing of COPD patients. While the 'intensity' component of the ventilatory cycle would be set to maintain the tidal volume at a constant level, the 'timing' component would act in order to prevent inspiratory muscle fatigue. Furthermore, in patients responsive to beta 2-agonist drugs, fenoterol inhalation would act in synergy with the timing component of ventilatory cycle, lowering P0.1 and the effective inspiratory impedance.

Activity of Erdosteine on Mucociliary Transport in Patients Affected by Chronic Bronchitis

The influence of erdosteine (a mucomodulator endowed with mucolytic and antioxidant properties) on human mucociliary transport (MCT) was investigated in a double-blind placebo controlled study. Sixteen former smokers affected by chronic bronchitis, preselected for their mucociliary responsiveness to an inhaled beta 2-agonist, were divided into two groups (matched by number, sex, age and FEV1%) and orally treated with placebo or erdosteine (300 mg t.i.d.) for 8 days. Their MCT was assessed by the bronchofiberscopy technique just before starting the treatment and at the end of the treatment. The pretreatment mucus transport velocity in these patients was significantly decreased with respect to healthy subjects. The erdosteine treatment induced a significant improvement of MCT while placebo was inactive (mean % variation +/- SE against their baseline values being +60.4 +/- 18.4 and -3.0 +/- 5.9, respectively). This peculiar activity of erdosteine on mucus transport may be of clinical usefulness in chronic bronchitic patients and it can be added to beta 2-agonist to restore the decreased MCT.

Psychosomatic study of inhalation therapy in patients with bronchial asthma. I. Evaluation by questionnaire

We investigated the use of metered-dose beta agonist inhalers (MDIs) by means of 17-item questionnaires from the standpoint of psychosomatic medicine in 56 subjects with bronchial asthma. The results can be summarized as follows: 1) Many asthmatics with neurotic characters used MDIs frequently; Thirteen percent of them suffered adverse effects. The number of times the inhalers were used increased in proportion to the severity and the duration of illness. Fifteen percent of the subjects used MDIs frequently because of anxiety. 2) Fifty percent of the subjects, most of them had neurotic or alexithymic characters, used MDIs without suffering from dyspnea or wheezes; the subjects who used MDIs because of anxiety increased in proportion to the duration of illness. 3) Seventy eight percent of the subjects were anxious about asthmatic attack when they did not carry any MDI; sixty two percent of the subjects, most of them had neurotic or alexithymic characters, actually experienced asthmatic attack. 4) Seventy three percent of the subjects used MDIs secretly; sixty percent of the subjects did not like to inhale in the presence of others. 5) There were some subjects who acted incorrectly on or after asthmatic attack when MDIs were not effective.

A placebo-controlled blinded comparison of nedocromil sodium and beclomethasone dipropionate in bronchial asthma

Two hundred and two patients aged 12-78 with chiefly moderate to severe asthma took part in a multicenter randomized blinded group comparison of nedocromil sodium (NS) 4 mg four times daily, beclomethasone dipropionate (BD) 0.1 mg four times daily, and placebo. Patients were assessed at the start and end of a two week baseline and after three and six weeks of treatment. Compared with placebo, both NS and BD significantly improved daytime dyspnoea and day and nighttime cough, as assessed by diary card scores. Lung function (FEV1) was significantly improved in the BD group. In the NS group there was also a significant reduction in concomitant use of inhaled beta 2-agonists. Overall opinions of efficacy by clinicians and patients were significantly in favor of both active treatments over placebo. There were no significant differences between the three treatments for peak expiratory flow rates, morning tightness or nighttime dyspnoea. Comparison between the two active treatments showed no significant differences in any of the variables.

Regular inhaled beta agonist therapy is associated with poorer asthma control compared with intermittent therapy

Regular inhaled beta agonist therapy is associated with poorer asthma control compared with intermittent therapy

Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol

Recently, it was suggested that long-term administration of an inhaled beta 2-agonist might increase bronchial hyperresponsiveness (BHR) to histamine, possibly as a consequence of subsensitization to the inhaled beta 2-agonist. To test this hypothesis, we studied two groups of patients with asthma or with chronic obstructive pulmonary disease. An experimental group of 15 patients, inhaling 400 micrograms of salbutamol four times daily during 1 year and subsequently 40 micrograms of ipratropium bromide four times daily for 6 months, and a control group, consisting of 22 patients with the opposite treatment regimen. The BHR, the response in FEV1 to cumulative doses of salbutamol, and the number of beta 2-adrenoceptors and antagonist affinity of these receptors on circulating lymphocytes were assessed at the start of the study and at 6-month intervals for 1 1/2 years. The BHR increased significantly (p = 0.001) during the year salbutamol was inhaled and returned to about the value at the start of the study after inhaling ipratropium bromide for 6 months. No change occurred in the bronchodilating responses to cumulative doses of salbutamol, nor was any change observed in the number and the affinity of beta 2-adrenoceptors on lymphocytes. It was concluded that long-term use of salbutamol caused a small but significant increase in BHR. The increase in BHR was not caused by subsensitization of beta 2-adrenoceptors to salbutamol.

Inhaled beta agonists improve the condition of patients with asthma on ventilator support

Inhaled beta agonists improve the condition of patients with asthma on ventilator support

Pharmacological differences exist between inhaled beta agonists

Pharmacological differences exist between inhaled beta agonists

The daily variability of bronchial responsiveness to methacholine

Ten mild atopic asthmatics on inhaled beta 2-agonists alone were studied in order to determine the repeatability of methacholine inhalation provocation tests at 24 h intervals over a period of 5 days. Such patients are most frequently studied in therapeutic trials of anti-asthmatic medications. There were no significant differences in results obtained on any of the days and no evidence for the development of tolerance to methacholine in this group of patients at one day intervals. The 95% confidence interval for repeatability of the results was +/- 1.05 doubling doses of methacholine, and 95% range +/- 2.36 doubling doses, comparable to the results obtained by other investigators on similar patients. Some investigators have produced more highly repeatable results but these have generally been obtained using highly selected groups of patients.

Inhaled Salmeterol and Salbutamol in Asthmatic Patients: An Evaluation of Asthma Symptoms and the Possible Development of Tachyphylaxis

Salmeterol (SM) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients. In the present study, evaluating efficacy and possible development of tachyphylaxis after SM, 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15% to 200 micrograms salbutamol (SB) or 20% to 500 micrograms SB. At inclusion all patients were receiving treatment with inhaled beta 2-agonists, and 11 of the 12 patients were also receiving inhaled corticosteroids. The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day, following a double-blind, double-dummy, randomized design. The treatment periods were separated by a washout period of 1 wk. Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period. On each of these days, basal FEV1, tremor, heart rate, and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve. During the treatment periods, as well as during the washout week after each treatment, the patients recorded their morning and evening peak expiratory flow (PEF) each day before the inhalation of the study drug. Subjective asthma symptoms were monitored by a visual analog scale after each treatment period. The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments, but significant increases in basal FEV1 and FVC were seen after the SM period (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Children aged &lt; 2 years can respond to inhaled beta agonists

Children aged &lt; 2 years can respond to inhaled beta agonists

A Double-Blind Multicenter Group Comparative Study of the Efficacy and Safety of Nedocromil Sodium in the Management of Asthma: North American Tilade Study Group

To determine the efficacy of nedocromil sodium in adult asthma patients using bronchodilators alone to control their disease, a consecutive sample of 127 patients with long-term asthma was studied for 16 weeks. The patients were maintained on sustained release theophylline preparations (SRT) and inhaled and oral beta-adrenergic bronchodilators (beta 2). One hundred sixteen patients (90 percent) completed the study; one placebo-treated patient withdrew owing to throat irritation and wheezing. Nedocromil sodium provided an additional benefit to adult patients receiving SRT and inhaled beta 2-agonists. With the exception of night-time asthma, nedocromil sodium maintained this improvement for the final 12 weeks of the study despite a reduction in concomitant bronchodilator therapy.

Paradoxical bronchospasm associated with the use of inhaled beta agonists

Adverse reaction reports for inhaled relatively β 2-rselective, adrenergic-agonist bronchodilators submitted to the Center for Drug Evaluation and Research of the Food and Drug Administration between 1974 and 1988 were reviewed. There were 126 reports associated with the use of these drugs by metered-dose inhaler, which were consistent with a diagnosis of paradoxical bronchospasm. In addition, 58 such reports were received for these drugs delivered as a solution for nebulization between 1983 and 1988. Increased reporting of reactions consistent with paradoxical bronchospasm generally correlated with increased availability of these products during the same time period, although there has not been a steady upward trend in such reports for metered-dose inhalers during the past 3 years, despite increasing distribution figures. Despite the apparent infrequency of inhaler-induced paradoxical bronchospasm, the potentially life-threatening nature of such reactions makes awareness of this possibility essential. Patients who report that an inhaled β-adrenergic agonist makes their asthma worse, as well as the patients who fail to demonstrate expected improvement with this form of therapy, should be suspected of having developed paradoxical bronchospasm.

Assessment of reversibility of airway obstruction in patients with chronic obstructive airways disease.

Spirometry before and after an inhaled beta agonist or a course of oral prednisolone is widely used to detect reversible airflow limitation in patients with chronic obstructive lung disease. How many of these patients have a response and how the response to beta agonists relates to the response to corticosteroids is not clear. In 127 outpatients (mean (SD) FEV1 0.92 (0.38) 1) who had a clinical diagnosis of chronic obstructive lung disease (continuous breathlessness for more than six months and an FEV1/forced vital capacity (FVC) ratio less than 60%) and who appeared to be stable, the change in FEV1 was measured after salbutamol 200 micrograms from a metered dose inhaler and 5 mg from a nebuliser. Symptoms and spirometric values were recorded before and after two weeks of oral prednisolone 30 mg. Reversibility was defined as a response in FEV1 of 15% or more from baseline alone and as a 15% change and a minimum increase of at least 200 ml. The latter gave results that showed greater internal consistency between the drug regimens. On the basis of this criterion 56 patients (44%) had no response to salbutamol or prednisolone, 71 responded to salbutamol (including all 27 steroid responders), and 25 patients had a response to salbutamol 5 mg but not to 200 micrograms. In general, the largest increase in FEV1 after salbutamol occurred in the subjects with greatest improvement after prednisolone. Subjects showing a response in FEV1 after two weeks' prednisolone had a fall in total symptom score, unlike those who had no response to any treatment or a response to salbutamol only. These data show that reversibility in response to beta agonists is common in patients diagnosed on clinical grounds as having stable chronic obstructive lung disease, that it can be substantial, and that it is best detected by using a larger dose of salbutamol. Salbutamol responders were those most likely to improve after a trial of oral prednisolone. Allowance should be made for the variability of FEV1 in the calculation of the percentage response at low baseline values (less than 1 litre).

The Effect of Osmolarity of Respiratory Salbutamol Solutions on Exercise-Induced Asthma in Children

The effect of an inhaled beta2 agonist (Salbutamol) in two solutions was studied in 17 asthmatic patients by comparing its blocking effect on exercise-induced bronchoconstriction. Salbutamol 0.5 ml was given by inhalation either with 2 ml 0.9% saline (230 mOsm) or with 2 ml of sodium cromoglycate (38 mOsm). The mean FEV1 after exercise, pretreated with Salbutamol in sodium cromoglycate solution, was 94 ± 14% of predicted values, and the mean FEV1 after exercise pretreated with Salbutamol in normal saline was 97 ± 14%. There was no statistically significant difference (p < 0.1) between these values. The conclusion of this study is that there is no advantage for any of these solutions when used as a diluent for Salbutamol.

Should we stop using theophylline for the treatment of the hospitalized patient with status asthmaticus?

Recent reviews and editorials have indicated that theophylline may not be effective for the therapy of acute severe asthma. This judgment is primarily based on data comparing the efficacy of theophylline to inhaled beta 2-agonists in the emergency room treatment of asthma. The authors believe that it is inappropriate to extrapolate data from short-term studies in the emergency room setting to the hospitalized patients with status asthmaticus. Studies of hospitalized patients in which the patients were monitored for at least 24 hours all demonstrate a positive therapeutic effect for theophylline. The possible reasons for the discrepancies between hospitalized patients and emergency room patients are discussed. Theophylline is still recommended for the management of the hospitalized patient with status asthmaticus.

Is theophylline use justified in acute exacerbations of asthma?

Despite widespread use of theophylline in the hospital management of asthma, supportive data justifying its use are sparse. Clinical research in the 1980s has forced a serious new examination of the drug's role in acute exacerbations of asthma. Because of the morbidity, mortality, questionable value, and overall cost of theophylline therapy, this reevaluation is of particular importance. Enhanced knowledge of the value of treatment with intensive inhaled beta agonists, systemic glucocorticoids, and inhaled ipratropium should prompt elimination of the routine, initial use of theophylline in emergency room care of most asthmatics. Further research is necessary to justify the routine, initial use of the drug in hospitalized asthmatics.

Asthma

Asthma is an extremely common disease that the emergency physician handles on a daily basis. Accurate clinical assessment from the history and physical examination is very important to assess the severity of the disease. Some measure of airway resistance of either FEV1 or PEFR should be done in every patient initially, at repeated intervals, and at discharge, to have a parameter to follow in therapy as well as a tool to use to warn the physician of a severe amount of airway obstruction. The inhaled beta agonists are the first line of therapy in acute asthma and can be delivered by either the nebulizer or the MDI with or without a spacer. Aminophylline will be continued to be used acutely even though it appears there is no improvement in bronchospasm in the first few hours of treatment when aminophylline is added to therapy. Anticholinergic agents will gain a wider role in acute asthma, especially when used in combination with a beta agonist. Corticosteroids continue to have a role in severe attacks of asthma, and earlier use may prevent relapse. Fatal asthma still occurs, however, and the emergency physician must use strict criteria to recognize status asthmaticus or the patient who is not doing well and admit them to the hospital. Using a stepwise, logical approach to the treatment of the asthmatic patient will lead to better patient satisfaction and fewer errors on part of the emergency physician.