Pharmacological effects and determination of the morphological distribution of powder aerosols containing fenoterol hydrobromide and ipratropium bromide

The bronchospasmolytic effects of fenoterol hydrobromide and ipratropium bromide, with some cardiovascular side effects by fenoterol, and the topographic morphological distribution of the powder aerosol particles in the respiratory tract were clearly demonstrated with the aid of ethidium-induced fluorescence in anaesthetised dogs.     

The duration of action of the combination of fenoterol hydrobromide and ipratropium bromide in protecting against asthma provoked by hyperpnea

We compared the duration of the protective effect of two beta-adrenoceptor agonists, fenoterol (200 micrograms) and salbutamol (200 micrograms), the anticholinergic agent ipratropium (80 micrograms), and the combination of fenoterol (200 micrograms) and ipratropium (80 micrograms) against challenge by eucapnic voluntary hyperventilation (EVH). Twelve patients with asthma performed EVH for two or four min at 60 percent maximal voluntary ventilation, 30 min, 2 and 4 h after treatment. All treatments (Rx) produced significant bronchodilation after 30 min. The Rx containing a beta-adrenoceptor agonist maintained this bronchodilation for at least 2 h. While all the Rx with a beta-adrenoceptor agonist significantly reduced the fall in forced expiratory volume in one second after EVH at 30 min, only the combination of fenoterol and ipratropium provided significant protection after 2 h. We advise that the duration of protective effect of beta-adrenoceptor agonists is short and patients with moderate to severe exercise-induced asthma may be better controlled by combination therapy.     

Comparison of a combination of fenoterol with ipratropium bromide (Duovent) and salbutamol in young adults with nocturnal asthma

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 bronchodilator effect of a fixed-combination metered aerosol (fenoterol and ipratropium bromide)

The fixed-combination metered aerosol lK6 (fenoterol 0.05 mg/puff, ipratropium bromide 0.02 mg/puff--Berodual, Boehringer-Ingelheim Ltd., Ridgefield, Conn.) was administered to 12 children (8 boys, 4 girls) aged 3 1/2 to 6 2/12 years who had extrinsic bronchial asthma. Three forms of administration, each with a different site of action, were compared: Two puffs during inspiration. Probable site of action: oral cavity, pharynx, larynx, trachea, and bronchi. Two puffs using an inhalational aid during inspiration. Probable site of action: pharynx, larynx, trachea, and bronchi. Two puffs in the breathing interval after deep inspiration. Probable site of action: oral cavity and pharynx. The resistance of the respiratory system (Rrs) was measured using oscillometry for up to 360 minutes after administration. A significant decrease of the median resistance was found with all three forms of administration. The changes were Form 1-48% of baseline after 120 minutes; Form 2-47.9% of baseline after 60 minutes; Form 3-44.4% of baseline after 30 minutes. The greatest decrease was observed with form 1. The study indicates that significant bronchodilation was achieved in small children using the combination of fenoterol and ipratropium bromide administered by metered aerosol even when inhalation and the release of the puff were not synchronized. A significant bronchodilator effect was also observed in cases of severe bronchial obstruction in which transport of the active ingredients to the lower airways could not be sufficiently guaranteed.     

Site of bronchodilatation with inhaled ipratropium bromide and fenoterol in normal subjects

To assess the effectiveness and site of action of bronchodilatation with an inhaled anticholinergic bronchodilator, ipratropium bromide, and a beta adrenergic agonist, fenoterol, we measured the density dependence of maximal flow and the density dependence of pulmonary resistance using a digital computerized averaging circuit. Eight normal subjects were studied on two separate days, before and after the bronchodilators were administered in a double blind manner. Both drugs resulted in significant and equivalent bronchodilatation. However, there were no significant changes in the density dependence of maximal flow or pulmonary resistance with either agent. These results in normal subjects, therefore, do not support the hypothesis of a preferential site of action of inhaled anticholinergic agents and beta-adrenergic agents.     

Effect of ipratropium bromide and fenoterol on airway obstruction in chronic pulmonary tuberculosis.

Single-blind, cross-over comparison of standard doses of ipratropium bromide (2 puffs of 0.02 mg each) and fenoterol (2 puffs of 0.2 mg each) in 36 pairs of experiments in 6 patients with partially reversible airway obstruction, presumably secondary to chronic widespread pulmonary tuberculosis, revealed no difference between the drugs in bronchodilating effect, evaluated by peak-flow measurements and spirometry. The inhalation of isoprenaline at the end of the experiment induced no further improvement in the lung function variables measured. The results suggest that a vagal reflex mechanism plays a major role in bronchoconstriction connected with severe chronic pulmonary tuberculosis.     

Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler.

Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat, a soft mist inhaler, and to establish the Respimat dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 microg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV1) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 microg delivered via Respimat; F/I 50/20 or 100/40 microg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV1 than placebo. A log-linear dose-response was obtained for the average increase in FEV1 up to 6 h (AUC0-6 h) and peak FEV1 across the dose range administered by Respimat. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat compared with the MDI. However 12.5/5 and 25/10 microg F/I administered via Respimat were closest (slightly superior) to the F/I dose of 100/40 microg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat, is as effective and as safe as higher doses given via a metered dose inhaler.     

Treatment of acute wheezing and dyspnea attacks in children under 2 years old: inhalation of fenoterol plus ipratropium bromide versus fenoterol.

Two treatment regimens for the initial treatment of acute wheezing were evaluated in 61 wheezing infants. Thirty-one patients received fenoterol (F) (0.1 mg/kg) and placebo (P) and 30 patients received fenoterol (F) (0.1 mg/kg) plus a fixed dose of ipratropium bromide (IB) (50 micrograms). Both groups received the drugs by inhalation using an ultrasonic nebulizer and face mask. A clinical score system based on wheezing and rib cage retraction was established and evaluations were performed before and at 15, 30, and 45 minutes after treatment. After the last evaluation based on the clinical score, it was decided whether to repeat or not to repeat the treatment. Our results showed that a combination of a beta agonist and ipratropium bromide (FB) was more effective than a beta agonist alone (F) in reducing wheezing and dyspnea during an acute attack (63.4 versus 25.8%; p less than 0.05).     

溴化异丙托品与氨茶碱片对支气管扩张作用的对比观察

目的比较定量雾化吸入溴化异丙托品与口服氨茶碱片对支气管扩张的作用。方法对２６例稳定期慢性阻塞性肺疾病（ＣＯＰＤ）患者采用安慰剂控制的双盲交叉试验，于试验前及试验后３０分，１，２，３，４，５，６小时分别测定第一秒用力呼气容积（ＦＥＶ１）。结果使用溴化异丙托品及氨茶碱后ＦＥＶ１平均峰值较基础值增加分别为３４％及１９％（Ｐ＜０．０１）；达峰时间分别为１～２小时及２～３小时；ＦＥＶ１较基础值增加＞１５％的患者分别为９０％及５０％（Ｐ＜０．０１）；ＦＥＶ１＞１５％的平均持续时间为３．６小时及１．６小时，６小时内ＦＥＶ１较基础值平均增加分别为１８％及８％（Ｐ＜０．０１）。结论对ＣＯＰＤ患者雾化吸入溴化异丙托品较口服氨茶碱片能更有效的扩张支气管作用     

Bronchodilator effect of fenoterol and ipratropium bromide in infants with acute wheezing: use of MDI with a spacer device

Twenty-eight infants admitted to Exequiel González Cortes Children's Hospital because of acute wheezing (AW) were randomly assigned to three study groups. Fenoterol (FNT), ipratropium bromide (IB), and placebo were administered respectively to children in the different groups by means of metered dose inhalers (MDI) with spacers, using doses of 3 puffs every hour, for 4 hours. The degree of bronchial obstruction was assessed clinically and scored with the single-blind method every hour prior to each treatment. The criterion of a bronchodilator effect was a significant decrease in the degree of bronchial obstruction at subsequent scorings. The scores of the three groups were compared using the Student's t test for matched samples. The same test was also applied to the independent samples for determining the superiority of one treatment, FNT or IB, over the other. The results indicated a significant decrease in the scores of the groups receiving FNT and IB (P less than 0.05); this did not occur in the group in which placebo was used. FNT produced a more rapid and sustained effect than IB (P less than 0.05). Significant bronchodilator effect was obtained in infants with AW when repeated doses of FNT or IB were administered with MDI and spacers. This effect was significantly greater in the group treated with FNT.     

Improved delivery of ipratropium bromide/fenoterol from Respimat Soft Mist Inhaler in patients with COPD

We performed a multicentre, randomised, double-blind (within-device), placebo- and active-controlled, parallel-group study to compare the efficacy and safety of ipratropium bromide plus fenoterol hydrobromide (IB/FEN; Berodual) delivered via the novel, propellant-free Respimat Soft Mist Inhaler (SMI) and from a chlorofluorocarbon (CFC)-metered-dose inhaler (MDI) in moderate-to-severe chronic obstructive pulmonary disease (COPD) patients. After 2-weeks' run-in (CFC-MDI [IB 20 microg/FEN 50 microg per actuation] two actuations q.i.d. [MDI 40/100]), 892 patients were randomised to Respimat SMI containing IB 10 microg/FEN 25 microg (Respimat SMI 10/25), IB 20 microg/FEN 50 microg (Respimat SMI 20/50) or placebo (one actuation q.i.d.), or a CFC-MDI containing IB 20 microg/FEN 50 microg (MDI 40/100) or placebo (two actuations q.i.d.) for 12 weeks. Analysis of the primary endpoint (change in forced expiratory volume in 1 s [FEV1] in the first 60 min after dosing [area under the curve; AUC0-1h]) on day 85 showed that the efficacy of Respimat SMI 20/50 (but not Respimat SMI 10/25) was not inferior to that of MDI 40/100. The safety profile of Respimat SMI was comparable to CFC-MDI. Switching from MDI 40/100 to Respimat SMI was well tolerated. Respimat SMI enables a 50% reduction of the nominal inhaled dose of IB/FEN in COPD patients while offering similar therapeutic efficacy and safety to the CFC-MDI.     

Therapeutic equivalence of a fenoterol/ipratropium bromide combination (Berodual) inhaled as a dry powder and by metered dose inhaler in chronic obstructive airway disease.

A randomized double-blind cross-over study was performed to compare the bronchodilator effects of a fenoterol/ipratropium bromide combination (Berodual) when inhaled as a dry powder and by metered dose inhaler (MDI) in an equal doses (fenoterol 100 micrograms + ipratropium bromide 40 micrograms). Thirty-eight patients (29 male, 9 female, mean age 53 years) with reversible chronic obstructive airway disease were studied on 2 separate days by employing the double-dummy technique. The effects of the two modes of administration of the fixed combination were followed by pulmonary function tests [forced expiratory volume (FEV1), forced vital capacity (FVC)] from 15 min up to 6 h after administration. In addition, the pulse rate was recorded just before each pulmonary function test. The FEV1 and FVC time-response curves showed that the dry powder had an overall efficacy profile similar to MDI. Both formulations produced clinically significant improvements in FEV1 in approximately 10 min. Peak effects occurred in 1 h while at 6 h after test drug inhalation there was still an increase in FEV1 of 14%. No safety problems were observed after the use of the test drugs and no clinically significant changes in pulse rate were found. It is concluded that the dry powder of the fenoterol/ipratropium bromide combination provided effective bronchodilation of similar degree and duration to that achieved with the MDI. It would appear, therefore, to be a valuable alternative to MDI.     

Standard and double dose ipratropium bromide and combined ipratropium bromide and inhaled metaproterenol in COPD

Inhaled ipratropium bromide (IPR) is effective in the management of COPD. The purpose of this study was to determine if doubling the standard dose of IPR resulted in greater bronchodilation and if the addition of an inhaled beta-agonist was superior to standard dose IPR alone. Twelve male patients with stable COPD completed a double blind, randomized trial. On each of three consecutive days, following baseline spirometry, all patients inhaled two puffs of IPR. This was followed by either two additional puffs of IPR, two puffs of metaproterenol (META), or two puffs of placebo. All inhalants were delivered by an InspirEase spacer. Spirometry was repeated at 30, 60, 120, and 180 minutes. The group mean percentage increases in the FEV1 and FVC from baseline were similar at all times tested for the three protocols. In conclusion, for the group, there was no objective benefit to doubling the standard dose of IPR or combining IPR with META. Two of 12 patients benefited from combining the two bronchodilators. A potential sequence for bronchodilator testing is suggested.     

Bronchodilatory effects of salbutamol, ipratropium bromide, and their combination: double-blind, placebo-controlled crossover study in cystic fibrosis

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.     

Early bronchodilating effect of oxitropium bromide in comparison with ipratropium bromide

The bronchodilating effects of a metered aerosol dose of 40 micrograms ipratropium bromide and of 200 micrograms oxitropium bromide are similar 15 min. after administration. The bronc hodilating activity of ipratropium bromide appears earlier (i.e., 75-90 s after administration) than that of oxitropium bromide but later than that of ibuterol, a beta2-agonist. Ipratropium bromide administered at the close of 80 micrograms provokes a bronchodilation about double of that obtained with 40 micrograms. An adaptation of the usual dosage should be considered.     

Efficacy and safety of ipratropium bromide plus fenoterol inhaled via Respimat Soft Mist Inhaler vs. a conventional metered dose inhaler plus spacer in children with asthma

The objective of this study was to compare the efficacy and safety of ipratropium bromide/fenoterol hydrobromide (IB/FEN; Berodual) delivered from the novel propellant-free Respimat Soft Mist Inhaler (SMI) with that from a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) plus spacer in children with asthma. The study followed a multicenter, randomized, double-blind (within Respimat SMI), parallel-group design. During the 2-week run-in period, patients received two actuations of CFC-MDI tid (IB 20 microg/FEN 50 microg per actuation) via a spacer (Aerochamber) (MDI 40/100). Patients (n=535) were then randomized to: Respimat SMI containing IB 10 microg/FEN 25 microg (Respimat SMI 10/25), IB 20 microg/FEN 50 microg (Respimat SMI 20/50), one actuation tid or CFC-MDI containing IB 20 microg/FEN 50 microg per actuation (in total 1B 40 microg/FEN 100 microg), or two actuations tid via Aerochamber (MDI 40/100), for 4 weeks. The primary endpoint was the change in forced expiratory volume in 1 second (FEV1) during the first 60 min after dosing (area under the curve from 0-1 h [AUC(0-1 h)]) on day 29. Analysis of the primary endpoint demonstrated that the efficacy of Respimat SMI 10/25 and 20/50 was equivalent to or greater than that of MDI 40/100. Similar results indicating that Respimat SMI 10/25 and 20/50 were not inferior to MDI 40/100 were also found on days 1 and 15. Analyses of other secondary endpoints supported these results. The safety profile of Respimat SMI was comparable to that of the CFC-MDI plus spacer. In conclusion, IB/FEN delivered via Respimat SMI is at least as effective as, and is as safe as, when delivered via CFC-MDI plus Aerochamber in children with asthma. Use of Respimat SMI thus enables a 2-4-fold reduction in the nominal dose of IB/FEN, and obviates the need for a spacer.     

Nebulized salbutamol and ipratropium bromide in asthmatic children

Varying doses of nebulized salbutamol, ipratropium bromide and a combination of both were given to 20 asthmatic children. All therapies produced effective bronchodilation. Ten mg salbutamol caused elevation of pulse rate and finger tremor whilst the duration of action of 0.6 mg salbutamol was too short. Dose-response effects were clearly seen with salbutamol but not with ipratropium bromide. A summation effect was not demonstrated when the medications were combined.