Treatment of adult asthma: controlled double-blind clinical trial of oxitropium bromide. Inhaled bronchodilator's in asthma: low or high dose? Synergism between ipratropium and theophylline in asthma. Home nebulizers: can optimal therapy be predicted by laboratory studies? Reduction of nocturnal asthma by an inhaled anticholinergic drug. Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study. Inhaled beclomethasone improves the course of asthma and COPD. A comparative study of the bronchodilatating effects of ipratropium and terbutalin inhaled with Monaghan IPPB-M 515 by 19 patients with chronic obstructive airways disease. Efficacy and compliance to prolonged Duovent treatment of bronchospasm. Comparison with salbutamol. Ipratropium bromide, salbutamol and prednisolone in bronchial asthma and chronic bronchitis. A long-term prospective assessment of home nebulizer treatment. Effect of four-week treatment with oxitropium bromide on lung mucociliary clearance in patients with chronic bronchitis or asthma. Continuous and on demand use of bronchodilators in patients with non-steroid dependent asthma and chronic bronchitis: four-year follow-up randomized controlled study. Comparison of Berodual and salbutamol in asthma: a multicenter evaluation. The development of subsensitivity to atropine methylnitrate. A double-blind, placebo-controlled crossover study. Terbutaline controlled-release tablets and ipratropium aerosol in nocturnal asthma. Density dependence of expiratory flow and bronchodilator response in asthma. Comparison of a combination of fenoterol with ipratropium bromide (Duovent) and salbutamol in young adults with nocturnal asthma. Comparison of the effect of oxitropium bromide and of slow-release theophylline on nocturnal asthma. Oral atropine in the treatment of chronic asthma. Comparison of ipratropium bromide and salbutamol in a long-term trial in asthmatic and bronchitic patients in a cold climate. Anticholinergic and sympathomimetic combination therapy of asthma. Use of ipratropium bromide in asthma. Results of a multi-clinic study. Effect of four weeks' high dose ipratropium bromide treatment on lung mucociliary clearance. Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis.
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. We studied the effect of regular inhalations of low-dose and high-dose fenoterol and low-dose and high-dose combinations of fenoterol and ipratropium bromide in maintenance treatment of 120 adults with moderately severe asthma. We used a double-blind, randomized, parallel group design comparing 12 weeks of treatment with four regimens: fenoterol, 100 micrograms/dose; fenoterol, 200 micrograms/dose; fenoterol, 50 micrograms; and ipratropium, 20 micrograms/dose in a single inhaler (Berodual) and fenoterol, 100 micrograms and ipratropium, 40 micrograms/dose in a single inhaler (Duovent). During the baseline and active treatment period the patients recorded PEFR in the morning and evening, symptoms and use of a rescue inhaler. Changes in twice daily peak expiratory flow rates or asthma symptoms did not show any significant differences among the four treatment regimens during the 12 weeks compared with the baseline period. Use of the rescue inhaler did not differ among the four groups during the active treatment. The patients' assessment of the efficacy of the active treatment favored the low-dose fenoterol and low-dose combination. More side effects were recorded in the high-dose combination group during the first 4 weeks compared with the other groups. We conclude that in maintenance therapy of chronic asthma high doses of fenoterol alone or in combination with ipratropium bromide offer no clinical advantage over low doses. On the contrary, the low-dose fenoterol and the low-dose combination are better accepted and tolerated by the patients. Ipratropium bromide is a bronchodilator whose effect has been compared with beta agonists but not with theophylline. Twelve asthmatics were given four two-week courses of the different combinations of ipratropium (40 micrograms in two puffs), theophylline capsules, and their corresponding placebos in a random, double-blind fashion. There was a significant increase in FEV1 and MMFR 60 minutes after theophylline was administered (p less than 0.05) when measured after one and two weeks of therapy. FEV1 and MMFR were significantly increased (p less than 0.05) 30 and 60 minutes after ipratropium inhalation and this increase was significantly greater when the patient had also been taking theophylline compared with placebo capsules (p less than 0.05). There was no toxicity associated with this combination. The synergism demonstrated may be related to the time sequence of drug administration, mechanical or cellular factors. Twenty patients (six severe asthma, 14 chronic obstructive pulmonary disease, COPD) were referred for consideration of domiciliary nebulized treatment. A double blind laboratory assessment demonstrated similar subjective and objective responses to nebulized salbutamol (5 mg), ipratropium bromide (IB) (0.5 mg) or a mixture of these medications in both groups of patients. The patients subsequently self-administered each treatment four times daily for one month. Fourteen patients requested long-term home nebulizer treatment (three salbutamol, four ipratropium bromide, seven mixture), and nine of these had their highest domiciliary peak flow recordings during home nebulizer treatment. However, subjective and objective laboratory assessments did not clearly predict the patients long-term choice of therapy in any case. There was little overall correlation between the laboratory response and the domiciliary response to treatment (Spearman correlation coefficient; subjective score, laboratory vs. home, r = 0.27, P = 0.03; peak flow response 30 min after treatment, laboratory vs. home, r = 0.31, P less than 0.02). The hospital study was also unreliable in predicting side effects during domiciliary nebulizer use. We conclude that prospective laboratory studies are of little value in the assessment of patients for home nebulizer therapy; these assessments must be made by carefully supervised domiciliary trials of nebulized treatment. 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. To determine if deterioration in patients with asthma or chronic obstructive pulmonary disease (COPD) during bronchodilator therapy could be slowed by additional treatment with an inhaled corticosteroid.
                A 4-year prospective study.
                Twenty-nine general practices in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands.
                The study included 56 patients (28 with asthma and 28 with COPD) who showed an annual decrease in the forced expiratory volume in 1 second (FEV1) of at least 80 mL in combination with at least two exacerbations per year during bronchodilator therapy alone. Forty-eight patients completed the study.
                During the first 2 years of treatment, patients received only bronchodilator therapy (salbutamol, 400 micrograms, or ipratropium bromide, 40 micrograms). During years 3 and 4, they received additional treatment with beclomethasone dipropionate, 400 micrograms two times daily.
                Prebronchodilator FEV1 increased 458 mL/y (95% CI, 233 to 683 mL/y) during the first 6 months of beclomethasone treatment; FEV1 then decreased 102 mL/y (CI, 57 to 147 mL/y) during months 7 to 24. The annual decline in FEV1 during beclomethasone treatment was less than the decline of 160 mL/y seen before beclomethasone therapy (difference, 58 mL/y; 95% CI, 2 to 87 mL/y). Only in patients with asthma did beclomethasone treatment improve bronchial hyperresponsiveness (assessed by determining the concentration of histamine that provoked a 20% decrease in FEV1 [PC20]) by 3.0 doubling doses per year (95% CI, 0.8 to 5.2 doses per year). Beclomethasone treatment was associated with improvement in peak expiratory flow rate, alleviation of symptoms, and a decrease in the number of exacerbations in both patient groups.
                Adding beclomethasone, 800 micrograms daily, slowed the unfavorable course of asthma or COPD seen with bronchodilator therapy alone. This effect was most evident in asthmatic patients. The effects of inhaled beclomethasone dipropionate (BDP), 800 micrograms daily, on the long-term course of asthma and chronic obstructive pulmonary disease (COPD) were investigated in a prospective, controlled study, over three years. During the first two years, patients were treated with a bronchodilator only (salbutamol or ipratropium bromide). Fifty six patients (28 asthma, 28 COPD), with an unfavourable course of disease during bronchodilator therapy alone (an annual decline in forced expiratory volume in one second (FEV1) of > or = 80 ml.yr-1 in combination with at least one exacerbation.yr-1), were selected for additional treatment with inhaled beclomethasone dipropionate (BDP), 800 micrograms daily, during the third year. The FEV1 and provoking concentration of histamine producing a 20% fall in FEV1 (PC20-histamine) were assessed at six-monthly intervals. In asthma, the annual decline in prebronchodilator FEV1 of -158 ml.yr-1 during bronchodilator therapy alone was followed by a significant increase of 562 ml.yr-1 during months 1-6 of BDP treatment (p < 0.0005). During months 7-12 of BDP, the FEV1 declined slightly with -31 ml.yr-1, which was not statistically different from the annual decline before steroid therapy (p = 0.17). In COPD, the increase of 323 ml.yr-1 during months 1-6 of treatment with BDP was different from the annual decline of -156 ml.yr-1 before BDP (p < 0.05). The PC20-histamine improved by 308 doubling doses during 1-12 months of BDP in asthma (p < 0.05) but not in COPD.(ABSTRACT TRUNCATED AT 250 WORDS) The effect of ipratropium (Atrovent) 0.125 mg x 4 daily was compared to terbutalin (Bricanyl) 5 mg x 4 daily, given to 19 patients with chronic obstructive airways disease (15 with chronic bronchitis, 10 bronchial asthma, 7 pulmonary emphysema) as inhalation therapy with Monaghan IPPB-M 515, during 2 treatment periods of 3 days. The investigation was carried out as a controlled, double-blind, cross-over comparison. The effect of treatment was evaluated by measurement of PEFR, symptom scores, including the side-effects and the use of rimiterol MDI for the treatment of acute attacks. The PEFR values were all higher than the initial values (P less than 0.001) during the period of treatment (08.00-20,30 hrs). The highest values were recorded at 16.30 hrs, these were PEFR + 31.7% for the Atrovent period and PEFR + 28.0% for the Bricanyl period. No statistically significant difference was observed in the PEFR, symptom scores, side-effects and the use of rimiterol during the Atrovent and Bricanyl treatment periods. The authors suggest that Atrovent is a wellsuited alternative bronchodilatator, particularly for patients with tremor, muscle cramp, and "inner restlessness" following treatment with a beta 2-stimulator. Duovent and salbutamol were compared in 15 patients with stabilized, but partially reversible chronic bronchospasm to verify the persistence of therapeutic effect, bronchodilator efficacy and patient compliance to prolonged treatment with these drugs. Results showed: Clinical efficacy; good protection from bronchospasm. Cough, day-time and nocturnal dyspnoea and the number of additional sprays required were better controlled with Duovent. Activity and bronchodilator efficacy: FVC and even more so FEV1 were sufficiently stable in baseline conditions with negligible variations at the various control times with both drugs, although Duovent was slightly more favourable. Bronchodilator efficacy was maintained more significantly with Duovent compared to salbutamol even after 5 h. Patient compliance: this was better with Duovent, both from the patient's personal opinion and because of the fewer number of daily administrations which the patient received (3 instead of 4). Eleven patients with bronchial asthma and 10 with chronic bronchitis were treated over four consecutive 3-day periods, firstly with aerosols either of ipratropium bromide (40 microgram four times a day) or of salbutamol (200 microgram four times daily) by random allocation, then the alternate drug, next by both drugs together, and finally with prednisolone (10 mg three times daily) in addition to both drugs. The effects of these four treatment periods were assessed both clinically and by measuring ventilatory capacity, nitrogen slope and progressive exercise testing. Ipratropium bromide and salbutamol produced approximately equal improvements in both diseases, with salbutamol showing a marginal advantage in patients with asthma. The combination of both drugs together more than doubled the FEV1 change in both groups of patients. The addition of prednisolone to both drugs produced a marginal advantage only in those with asthma. Forty-nine patients (15 asthma, mean FEV1/FVC 1.3/2.1; 34 COPD, mean FEV1/FVC 0.7/1.8) were referred for consideration of home nebulizer treatment. All were monitored for 2 weeks while using their usual inhaled treatment followed by 2 weeks using a 'Nebuhaler' spacer to deliver 1 mg of terbutaline and 80 micrograms of ipratoropium bromide (IB) four times daily. They then borrowed a System 22 nebulizer to self-administer salbutamol nebulizer solution (5 mg), IB unit dose vials (0.5 mg) or a mixture of these drugs four times daily for 1 month each. Both asthmatic and bronchitic patients had a significant rise in their mean daily peak flow rate (PFR) during home nebulizer treatment (P < 0.03) and the COPD patients also had a significant PFR rise during Nebuhaler treatment (P = 0.0004). The mean daily peak flow rates (PFR 1 min-1 were: baseline 179, Nebuhaler 195, salbutamol nebulizer 200, IB nebulizer 198, mixed nebulizer 216). Four patients failed to respond subjectively or objectively to either Nebuhaler or nebulizer treatment. Five patients responded well to Nebuhaler treatment and did not proceed to a home nebulizer trial. Eight further patients preferred Nebuhaler to nebulizer treatment or could not tolerate nebulizer treatment (two cases). Thirty-two patients requested home nebulizer treatment for long-term use (nine salbutamol, five IB, 18 mixture). Twenty-seven of these patients had an increased mean daily PFR (compared to their usual therapy) while using their chosen nebulized treatment. The mean increase in PFR for all 32 patients was 191 min-1 (11%).(ABSTRACT TRUNCATED AT 250 WORDS) The effect of oxitropium bromide on lung mucociliary clearance, pulmonary function and viscoelastic properties of sputum was investigated in 10 asthmatics and 10 chronic bronchitics. A controlled, double-blind, crossover study was performed. Following a baseline (B) measurement the patients were, in a random order, allocated placebo (P) or oxitropium bromide (O; 0.1 mg/puff), administered from metered dose inhalers, which they used for 4 weeks at a dose of 2 puffs t.d.s. This test medication was used in conjunction with their normal medication. At the end of the treatment period the patients were assessed, the treatments were then crossed over and a final assessment made 4 weeks later. The administration of oxitropium bromide resulted in (1) small but statistically significant increases in pulmonary function (less than 10% vs. placebo); (2) increased penetrance of radioaerosol into the lungs (mean +/- SEM alveolar deposition: 35 +/- 3, 26 +/- 3 and 24 +/- 3% for the O, P and B runs respectively; p less than 0.025); (3) no significant change in particle clearance rate from the lungs despite their deeper penetration (mean +/- SEM area under the tracheobronchial clearance curves between 0 and 6 h: 317 +/- 26, 324 +/- 25 and 287 +/- 25%.h for the O, P and B runs respectively; p greater than 0.1); (4) no alteration in sputum production, and (5) no significant changes in apparent viscosity (mean +/- SEM: 640 +/- 162, 446 +/- 79 and 557 +/- 115 mPa.s for the O, P and B runs, respectively; p greater than 0.1) and elasticity (mean +/- SEM: 3,682 +/- 1,383, 1,779 +/- 353 and 2,061 +/- 366 mPa for the O, P and B runs, respectively; p greater than 0.1) of sputum. When the two groups, i.e. the chronic bronchitics and asthmatics, were studied separately, no significant differences in any parameter measured (other than radioaerosol penetrance which was significantly enhanced on oxitropium bromide in chronic bronchitics) were noted between the three assessments. A previous two-year study of continuous and on demand bronchodilator therapy in patients with moderate asthma and chronic bronchitis showed a deterioration in lung function in those on continuous therapy.
                A two-year follow-up study was undertaken of patients who had been shown in the previous study to have non-steroid dependent (mild) asthma and chronic bronchitis, in order to investigate the effect of continuous and on-demand treatment with bronchodilator therapy.
                Patients for the study were drawn from 29 general practices in the catchment area of the University of Nijmegen, the Netherlands. A total of 83 patients (27 with asthma and 56 with chronic bronchitis) were selected from a group of 160 patients who had completed the previous two-year bronchodilator trial. During these first two years the selected subjects had been shown to be non-steroid dependent (no rapid decline in lung function and a low number of exacerbations of their condition per year), and they were followed up for another two years of treatment with bronchodilator therapy. At the start of the four-year study, patients were randomly assigned to one of two parallel treatment groups: continuous treatment (dry powder inhalations of either salbutamol 1600 micrograms or ipratropium bromide 160 micrograms daily) or treatment on demand (only during exacerbations or periods of dyspnoea). Outcome parameters were the annual decline in lung function, changes in peak flow rate, bronchial hyper-responsiveness, exacerbation rate, respiratory symptoms and reported health.
                After correction for possibly confounding variables and for regression to the mean, the decline in lung function was 49 ml year in patients taking bronchodilators continuously and 51 ml year in patients using bronchodilators on demand, irrespective of the drug use. Continuously treated patients, whether suffering from asthma or chronic bronchitis, did not differ from patients treated on demand with respect to mean morning peak flow rate, diurnal (and week to week) variation of the peak flow rate, bronchial hyper-responsiveness, exacerbation rate and reported health. There was no difference between the long-term effects of salbutamol and ipratropium.
                Continuous use of bronchodilators over four years in patients with non-steroid dependent asthma or chronic bronchitis does not increase the decline in lung function which had been observed previously in patients with moderate asthma or chronic bronchitis during two years of continuous treatment with bronchodilators. A 2-month study was carried out to compare the efficacy and safety of Berodual (B) (Boehringer Ingelheim) and salbutamol (S) in asthma. B is a combined agent with 20 micrograms of ipratropium bromide and 50 micrograms of fenoterol in each metered aerosol puff. Each puff of S contained 100 micrograms of drug. 196 patients were included in the study and received 4 x 2 puffs a day of either B or S. FEV1 and FVC were measured every month, and peak expiratory flow rate (PEFR) 4 times a day, i.e. morning and evening before and after administration of drug. Improvement of PEFR was the same in the two groups. No tachyphylaxis occurred. No difference was observed between the two drugs with regard to heart and respiratory rate, dyspnea and blood pressure. Tremor seemed less frequent with B but this difference was not statistically significant. B achieved the same effects as S though containing less beta-2-agonist agent. This is a double-blind, placebo-controlled crossover study designed to assess the effectiveness of nebulized atropine methylnitrate (AMN) with chronic use. We studied 22 patients with asthma, 10 receiving theophylline and inhaled beta-agonists and 12 who were receiving corticosteroids as well. All had demonstrated at least a 15% change in FEV1 either spontaneously or after bronchodilator. Bronchodilator effect was measured serially for 4 h after inhalation of the initial dose and again after 2 wk of four-times-daily use. Significant bronchodilator effect was seen initially with AMN when compared to placebo (p less than 0.01). After 2 wk of use, the bronchodilator effect of AMN was significantly diminished as compared to the initial effect (p less than 0.01) but was still better than placebo (p less than 0.05). Subsensitivity did develop to varying degrees in the patients, but we were unable to identify any clinical parameters that would allow prediction of subsequent subsensitivity. We conclude that the development of subsensitivity to AMN occurs in certain patients with chronic administration but does not reflect a total loss of bronchodilator effect. The effect of oral terbutaline (controlled-release [CR] tablets) was compared with that of inhaled ipratropium bromide (aerosol) in 21 patients with nocturnal asthma. In a randomized, double-blind, crossover study, the patients were treated with terbutaline CR 10 mg twice daily, ipratropium 40 micrograms four times daily, and the two drugs in combination. Each treatment was given for 3 weeks. Before the start of the study, the patients participated in a 1-week run-in period. The mean nocturnal decline in peak expiratory flow rate (PEFR) was 29% in the run-in period and was reduced to 22% in the terbutaline CR period, 27% in the ipratropium period, and 23% in the period with the combination of the two drugs. The mean night PEFR was significantly (P < 0.05) higher in the period with terbutaline CR, as compared with the period with ipratropium. The mean morning PEFR was also highest in the terbutaline CR period. The mean evening PEFR was significantly (P < 0.05) higher during treatment with terbutaline CR alone and with the combination, as compared with treatment with ipratropium alone. Treatment with terbutaline CR alone or the combination was preferred by as many patients as was treatment with ipratropium alone. When present, adverse reactions were judged to be mild or moderate. Treatment with terbutaline CR alone and the combination significantly improved the evening and night PEFR, as compared with treatment with ipratropium alone. Change in the magnitude of density dependence of the maximal expiratory flow (D/MEF) following inhalation of isoproterenol was used as a test for predicting the long term response to isoproterenol vs atropine in 24 adult patients with longstanding asthma. Eleven subjects showed a decrease in D/MEF manifested by increase in volume of isoflow (VisoV) and/or decrease in Vmax50 Helox/air following isoproterenol inhalation (group 1). Thirteen subjects manifested an opposite response (group 2). Atropine sulphate (0.08 mg/kg) and isoproterenol hydrochloride (2.5 mg) were then administered by inhalation, each four times a day for seven days in a randomized double-blind cross over fashion to all subjects. One of group 1 but ten of group 2 subjects had a greater subjective and objective improvement with atropine than with isoproterenol (P less than .005). An increase in D/MEF following isoproterenol can be used as a test to predict a better response to atropine than to isoproterenol over a one week period. Such a response occurs in almost half of the adult chronic asthmatic patients. The results are consistent with a preferential dilatation of the large airways by atropine. In a randomized, double-blind, double-dummy, crossover study consisting of two 1-month periods with a 2-week 'run-in' we compared the effects of a combination of fenoterol with ipratropium bromide (Duovent, Boehringer Ingelheim) and salbutamol administered by standard metered dose inhalers in conventional dosage in young adults with nocturnal asthma. Seventeen patients were studied, all were aged between 19 and 35 years and showed 'morning dip' associated with nocturnal symptoms of cough, wheeze and breathlessness. They recorded morning and evening peak flows and symptoms of nocturnal asthma on diary cards. Over the 10 weeks of the study there was no difference between Duovent and salbutamol in any of the parameters measured. The effects of a new inhaled antimuscarinic drug, oxitropium bromide, and of a slow-release theophylline preparation upon nocturnal asthma were compared in a placebo-controlled double-blind study. Two samples were studied: 12 patients received oxitropium at 600 micrograms (6 subjects) or at 400 micrograms t.i.d. (6 subjects) whereas 11 received theophylline at 300 mg b.i.d. Morning dipping, assessed by the fall in peak flow overnight, was significantly reduced in the periods when either active drug was taken, whereas no difference was noticed during the placebo administration. No significant difference was noticed between results obtained with either active drug, as well as with either dosage of oxitropium. No subject reported side effects of oxitropium, as compared to three subjects reporting nausea, vomiting and tremors after theophylline. Oxitropium proves to be a valuable alternative to theophylline in nocturnal asthma, since it is equally potent, safer and does not require the titration of dosage. Six adult patients with chronic asthma were treated with oral atropine sulfate 0.5 mg or placebo four times a day in a double-blind, crossover trial lasting eight weeks. Subjects returned at weekly intervals for spirometry and clinical evaluation. The baseline pulmonary functions did not differ significantly between the atropine and placebo periods. The only side effects noted were slight dryness of the mouth in three patients. The three patients who complained of mouth dryness felt that they were better while they were taking oral atropine in that they had fewer acute episodes of asthma. The administration of 0.5 mg oral atropine four times a day is ineffective in improving baseline pulmonary functions in chronic asthmatics, although it may decrease the incidence and severity of acute asthmatic episodes. nan 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. A multi-center, double-blind, 90-day study compared an ipratropium bromide metered-dose inhaler (40 microgram four times a day) with a metaproterenol metered-dose inhaler (1,500 micrograms four times a day) in 164 patients with asthma; of the 144 patients who completed the study, 71 received ipratropium and 73 received metaproterenol. Our results suggest that both drugs were equally effective bronchodilators. Although the shape of the pulmonary function response curves suggested that ipratropium has different bronchodilator kinetics than metaproterenol (in that it has a slower onset of action and a more prolonged duration), comparison of the areas under the curves for the two drugs showed that there was no statistical difference between ipratropium or metaproterenol. The only significant side effects noted with ipratropium were cough and exacerbation of symptoms; no anticholinergic side effects were noted. In a randomised, double blind crossover study the effect of high dose ipratropium bromide (200 micrograms three times daily given by metered dose inhaler for four weeks) on lung mucociliary clearance and on the wet weight and mean apparent viscosity of sputum was compared with that of placebo. Six smokers, six ex-smokers, and three non-smokers (12 men and three women, median age 60 years) were studied. Eight subjects had chronic obstructive lung disease (median FEV1 46% predicted) and seven had asthma (FEV1 70% predicted). Seven subjects produced sputum regularly, two of whom had asthma. Clearance of secretions was measured by an inhaled radioaerosol technique. The number of coughs and the wet weight, radioactive content, and mean apparent viscosity of sputum produced during the six hour observation period were recorded, as was the mean wet weight of sputum produced during the last two 24 hour periods ending each treatment. Comparison with placebo showed that treatment with high dose ipratropium bromide was associated with a significant increase in the penetration index of inhaled particles, but there was no significant change in alveolar deposition of particles or in tracheobronchial clearance, uncorrected or corrected for sputum expectorated. The wet weight of sputum produced, its radioactive content, and mean apparent viscosity were similar after treatment with ipratropium bromide and placebo. These results show that high dose inhaled treatment with the synthetic anticholinergic bronchodilator ipratropium bromide for four weeks is not associated with detectable modification of the clearance of secretions from the lungs, or of sputum volume or viscosity. The bronchodilating responses to 400 micrograms salbutamol and 80 micrograms ipratropium bromide were studied in 188 patients with chronic bronchitis (n = 113) or asthma (n = 75) and mild to moderate airflow obstruction (forced expiratory volume in one second (FEV1) above 50% but below 2 SD of predicted value) in a crossover study on two days a week apart. Both the patients with asthma and the patients with chronic bronchitis varied considerably in their responses to the salbutamol and the ipratropium bromide. The mean increase in FEV1 in the subjects with asthma was higher after salbutamol (0.371 or 18% of the prebronchodilator value) than after ipratropium bromide (0.26 1 or 13%). In chronic bronchitis there was no difference between the increase in FEV1 after salbutamol (0.161 or 7%) and after ipratropium bromide (0.191 or 8%). When patients were categorised into those with a better response to salbutamol 400 micrograms and those with a better response to ipratropium bromide 80 micrograms, patients with chronic bronchitis responded better in general to ipratropium bromide whereas asthmatic patients responded better to salbutamol. The response pattern was also related to allergy and age, allergic patients and patients under 60 being more likely to respond better to salbutamol 400 micrograms than non-allergic patients and older patients, who benefited more from ipratropium bromide 80 micrograms. The response pattern was not related to sex, smoking habits, lung function, bronchial reactivity, respiratory symptoms, or number of exacerbations during the preceding year.
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.