Anticholinergic and sympathomimetic combination therapy of asthma. Reduction of nocturnal asthma by an inhaled anticholinergic drug. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Treatment of adult asthma: controlled double-blind clinical trial of oxitropium bromide. Combined treatment with ipratropium bromide and beta-2-adrenoceptor agonists in childhood asthma. Long-term effect of ipratropium bromide and fenoterol on the bronchial hyperresponsiveness to histamine in children with asthma. A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Dutch Chronic Non-Specific Lung Disease Study Group. Bronchodilatory effects of salbutamol, ipratropium bromide, and their combination: double-blind, placebo-controlled crossover study in cystic fibrosis. The effects of ipratropium bromide and fenoterol nebulizer solutions in children with asthma.
The role of the anticholinergic drug, ipratropium bromide, in maintenance antiasthmatic therapy was evaluated in a double-blind crossover trial of three bronchodilator regimens: (1) inhaled ipratropium, placebo, and oral oxtriphylline; (2) inhaled fenoterol, placebo, and oral oxtriphylline; and (3) both inhaled ipratropium and fenoterol plus oral oxtriphylline. Twenty-two asthmatics were treated with all three regimens, each for 1 mo, allocated in random sequence. On the first and last treatment days of each month, spirometric measurements were performed before and 0.5, 1, 2, 3, 4, and 6 hr after administration of the test drugs. On the first treatment day of each month, all regimens produced significant bronchodilatation at 30 min after dose, an improvement that declined between 3 and 6 hr after dose. After continuous administration for 1 mo the two combinations employing fenoterol showed a decline in bronchodilator responsiveness from the initial treatment day, measured as the level of response (V50) or duration of response (FEV1, VC). Ipratropium plus oxtriphylline showed no such decline, suggesting the development of tolerance to long-term administration of fenoterol. Overall benefit at the end of 1 mo, measured as the area under the curves of FEV1, VC, or V50 vs time after dose, was greatest for the triple drug regimen. There were no differences in heart rate, blood pressure response, or side effects among the three treatments. It is concluded that when the anticholinergic drug ipratropium is administered concurrently with an inhaled beta 2 agonist and an oral theophylline derivative, increased bronchodilatation occurs with no detectable additional side effects. Although the mechanisms of nocturnal asthma are still uncertain, increased vagal cholinergic tone may be contributory factor. To examine this hypothesis, we have studied the effect of an anticholinergic drug, oxitropium bromide, on the early morning fall in peak expiratory flow (PEF) in patients with nocturnal asthma. Eighteen patients (aged 18 to 76 years; seven men) with documented nocturnal asthma were studied in a double-blind randomized cross-over study in which they received either oxitropium bromide (200 micrograms or 400 micrograms) or placebo in a single dose at night for two-week periods. With placebo the mean (+/- SE) fall in PEF (expressed as percentage of evening PEF) was 17.3 +/- 2.0 percent, which was significantly reduced to 10.3 +/- 3.3 percent after oxitropium (400 micrograms) (p less than 0.05; ANOVA). Closer analysis revealed that nine of the 18 patients had responded in a dose-dependent manner, with the mean percentage decreases with placebo, 200 micrograms, and 400 micrograms of oxitropium being 19.1 +/- 3.2, 11.5 +/- 4.4, and 5.0 +/- 4.5 percent, respectively (p less than 0.01 between each treatment). The remaining patients were unaffected by therapy. There were no differences between "responders" and "non-responders" in terms of age, atopic status, duration of asthma, severity of asthma, or bronchodilator response to albuterol (salbutamol). There were no differences in nocturnal symptoms between periods of treatment, and no side effects were recorded. We conclude that anticholinergic drugs may protect against nocturnal asthma in some patients, indicating the involvement of vagal cholinergic mechanisms. The effectiveness of nebulized anticholinergic and sympathomimetic regimens was evaluated in a double-blind study of 199 patients with acute airways obstruction. Patients were assigned to one of three treatment regimens according to a randomized schedule: 0.5 mg of ipratropium bromide, 1.25 mg of fenoterol hydrobromide, and 0.5 mg of ipratropium plus 1.25 mg of fenoterol. In 148 patients with acute exacerbations of asthma (mean one-second forced expiratory volume, 1.18 +/- 0.64 liters), all three regimens produced significant improvement in one-second forced expiratory volume (p less than 0.001). The greatest improvement followed treatment with the ipratropium-fenoterol combination (0.53 +/- 0.40 liters at 45 minutes; 0.57 +/- 0.51 liters at 90 minutes) and was significantly greater than that following either ipratropium alone (p less than 0.001) or fenoterol alone (p less than 0.05). In 51 patients with acute exacerbations of chronic obstructive pulmonary disease (mean one-second forced expiratory volume, 0.67 +/- 0.29 liter), each regimen produced significant improvement in one-second forced expiratory volume at both 45 and 90 minutes (for all, p less than 0.05), but there was no significant difference among the three treatment regimens. It is concluded that, in patients with acute asthma, combination therapy with sympathomimetic and anticholinergic agents is more efficacious than either one alone. In patients with acute exacerbations of chronic obstructive pulmonary disease, although either sympathomimetic or anticholinergic therapy provides bronchodilatation, no further benefit could be demonstrated from combination therapy. Sixteen young adult sufferers from extrinsic paroxysmal asthma with pollen hypersensitivity took part in a therapeutic trial of the synthetic anticholinergic agent oxitropium bromide administered by a metered dose inhaler. The study comprised three 3-week periods. The first, run-in period was carried out to confirm the ability of the patients to maintain a daily record of symptoms. During the second and third periods, the patient received 3 X 2 inhalations of drug or placebo in a cross-over design. The medical staff was blind to the nature of the aerosol (drug or placebo), which was given in random order. The run-in clinical score was high. Asymptomatic days were relatively infrequent and daily drug consumption was high. Functional studies between the cross-over periods showed flow-rate values close to normal, with an increase in residual volume and functional residual capacity. During treatment either with placebo or oxitropium, there was a statistically significant decrease in clinical scores. Results for oxitropium bromide treatment were significantly better than the run-in values (p less than 0.005) and the placebo period (p less than 0.02). There was no significant change in non-trial drug consumption. Functional values showed no difference in terms of flow rate, although oxitropium did cause a significant improvement in the RV/TLC ratio (p less than 0.05). No adverse reactions were reported. The effect of adding ipratropium bromide to treatment with beta-2-adrenoceptor agonists was studied in 13 asthmatic children in a double-blind cross-over trial. In the acute phase of the study inhalation of salbutamol 0.1 mg/kg followed by inhalation of 0.25 mg of ipratropium bromide was found to improve pulmonary function variables to a significantly greater extent than salbutamol followed by placebo. The combined therapy also provided significantly better protection than salbutamol plus placebo against exercise-induced asthma. Maintenance treatment with ipratropium bromide (two inhalations four times daily, 20 micrograms per inhalation) in combination with oral terbutaline and aerosolized salbutamol did not alleviate asthmatic symptoms or pulmonary function variables to a degree beyond that achieved with the beta-stimulants alone. There were no side effects associated with the ipratropium bromide treatment. These data suggest that higher doses of ipratropium bromide than are presently used should be tested for maintenance treatment of chronic asthma. We studied the effects of the anticholinergic ipratropium bromide (40 micrograms three times daily) and the beta-agonist, fenoterol (0.2 mg three times daily), both administered by powder inhaler, on bronchial hyperresponsiveness (BHR) to histamine in children, aged 7 to 15 years with mild stable asthma and limited bronchoconstriction who had a highly increased BHR. The double-blind, randomized, parallel study was conducted and performed in spring and early summer. BHR and FEV1 were measured on two occasions, before the start of treatment and monthly thereafter for 4 months. Symptoms, peak expiratory flow, and concomitant medication were registered daily. Nine of the 12 patients receiving ipratropium bromide and all eight patients receiving fenoterol completed the study. Patients completing treatment had few symptoms and were in a stable condition throughout the treatment period. Neither the administration of ipratropium bromide nor fenoterol resulted in a significant change of BHR. We concluded that long-term treatment with ipratropium bromide or fenoterol had no effect on BHR in children with mild stable asthma. The morbidity from obstructive airways disease (asthma and chronic obstructive pulmonary disease) is considerable, and the mortality rate is rising in several countries. It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy.
                In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist (terbutaline, 2000 micrograms daily) was combined with a corticosteroid (beclomethasone, 800 micrograms daily), an anticholinergic bronchodilator (ipratropium bromide, 160 micrograms daily), or placebo. Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years.
                Of the 274 patients enrolled, 56 percent had allergies. The mean forced expiratory volume in one second (FEV1) was 64 percent of the predicted value. The mean PC20 (the concentration of inhaled histamine causing a 20 percent decrease in FEV1, a measure of hyperresponsiveness) was 0.26 mg per milliliter. Withdrawal from the study, due mainly to pulmonary symptoms, was less frequent in the corticosteroid group (12 of 91 patients) than in the anticholinergic-drug group (45 of 92 patients) or the placebo group (44 of 91 patients; P < 0.001). The mean FEV1 (+/- SE) increased by 10.3 +/- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter, whereas it did not change in the other two groups (P < 0.001). The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups (P < 0.001). In the corticosteroid group, patients who did not smoke, who had allergies, or who were less than 40 years old benefited more from their treatment than did those who smoked, did not have allergies, or were over 40, but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group.
                The addition of an inhaled corticosteroid--but not an inhaled anticholinergic agent--to maintenance treatment with a beta 2-agonist (terbutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease. The efficacy of inhaled sympathomimetic and anticholinergic agents on airway obstruction in cystic fibrosis (CF) has been proven in several studies. However, studies comparing combined therapy with monotherapy led to divergent results, probably due to different study designs, different dosages, and the small numbers of patients investigated. Therefore, we wanted to answer the question which inhalation has the best short term effect: a sympathomimetic or an anticholinergic agent, or the combination of both. We investigated 17 patients with CF on 4 successive days in the morning, using pulmonary function testing before and 30 min after inhalation. Each patient received aerosolized salbutamol (SB, maximum dose (max.) 2.5 mg), ipratropium bromide (IB, max. 0.5 mg), the combination of both, or placebo (normal saline) in a randomized, double-blind crossover design. The mean forced expiratory volume in the first second improved significantly (adjusted P-value < 0.017) after each treatment compared to placebo. Analysis of variance showed that SB and combination therapy with SB and IB were superior to IB alone, without significant difference between SB and combination therapy. Response of a patient to combined therapy was usually associated with response to SB. Long-term efficacy and side effects of treatment with bronchodilators still remain to be investigated after this short term study. We conclude that in CF patients bronchodilator therapy with sympathomimetic agents is usually sufficient. Only in cases with proven additional benefit from inhalation by anticholinergics should combination therapy be recommended. The effects of nebulized solutions of ipratropium bromide and fenoterol combined were compared with the response to either preparation alone in single dose and longer-term administration in children who had asthma. The combination produced a slightly greater response than either alone, especially in peak expiratory flow. Over a 1-month period, there were no significant differences in symptom scores or lung function parameters between the combination of ipratropium bromide and fenoterol and fenoterol alone in a group of children who had asthma. It is possible that the addition of ipratropium bromide to a sympathomimetic drug may be useful in a subgroup of asthmatics, particularly if there is a considerable large airway contribution to bronchial narrowing.
Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there may be a sub-group of patients who derive some benefit and a trial of treatment in individual patients may still be justified. The role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma and any future trials might draw on the messages derived from this review.