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Purpose: To compare the efficacy of nifedipine and fenoterol in the management of threatened preterm labor (TPL)., Methods: A randomized and multicenter study assessing the tocolytic effect of nifedipine versus fenoterol in patients admitted to the participating maternity units with a diagnosis of TPL and a cost-savings study for economic assessment. For a power of 80% and an α error equal to 0.05, 132 consecutive patients were recruited during the study period; 66 patients were assigned to each group. A χ(2) analysis and a mean differences test were performed according to variable types and survival curves per intention-to-treat., Results: Demographics were similar in both groups. The latency period was similar in both groups (26.7 vs. 25.6; p = 0.3). There were no differences in the results obtained. Nifedipine failed more frequently to obtain tocolysis when used as a first-line agent (80 vs. 90%, p = 0.0001). The group treated with fenoterol showed more drug adverse events (57.8 vs. 19.0%, p = 0.0001). The economic assessment did not evidence a significant difference in terms of cost savings between groups treated with either drug., Conclusion: The present study failed to demonstrate either clinical or economic superiority of any of the two drugs used in TPL management. The highest failure percentage of nifedipine when used as a first-line agent should encourage further research., (Copyright © 2012 S. Karger AG, Basel.)

The efficacy and safety of a novel fenoterol/ipratropium bromide metered-dose inhaler (MDI) formulated with a non-chlorinated propellant, HFA134a, has been compared with placebo and the conventional chlorofluorocarbon (CFC)-containing fenoterol/ipratropium bromide inhaler (Berodual) in asthmatic patients. Fifty-two patients were enrolled in two centres. The fenoterol/ ipratropium bromide treatment produced significantly (P < 0.0001) greater bronchodilatation than placebo. There were no significant differences between the mean peak and average forced expiratory volume in the first second (FEV1) for patients receiving 2 puffs of the fenoterol/ipratropium bromide HFA134a inhaler and the conventional CFC inhaler. In addition, time to onset and duration of efficacy were comparable for these two treatments. None of the patients showed a fall of > or = 15% in baseline FEV1 or needed rescue medication within 30 min after inhalation of the test drug. No paradoxical bronchoconstriction was observed as measured by sGaw. The two inhaler formulations were well tolerated. A taste-related complaint, lasting for a few minutes after inhalation, was reported by a higher proportion of patients who inhaled the HFA134a formulation, mainly by patients selected in one of the two centres. In conclusion, a dose of 100 micrograms fenoterol/40 micrograms ipratropium bromide inhaled from a MDI containing HFA134a propellant is safe and provides effective bronchodilatation of equivalent degree, onset and duration of action to the same dose from the conventional CFC formulation.

As an example of beta 2-agonists fenoterol was used in this study on 27 patients with chronic obstructive airways diseases (COAD). After refraining from any kind of bronchodilator during 12 h the patients were given the drug in a crossover design in three groups. Using aerosol inhalation, intravenous route and nasal instillation we measured the response of airway resistance, intrathoracic gas volume and fenoterol plasma concentrations. The plethysmographic measurement of airways resistance (Rt) and intrathoracic gas volume showed comparable results of bronchodilation (at different dosages) for each of the routes. Even the onset of action was nearly the same with all the different routes. The amount of bronchodilatation was in the range of 59% of the initial Rt values. The duration of bronchodilatation was much longer after metered dose inhalers (MDI) inhalation ( > 4 h) than after intravenous routes. The duration after nasal administration was in between. The infusion maintains its effect only as long as the infusion is given. The bronchodilation response induced by fenoterol reaches the same values with different routes of administration and depends on the amount of decrease of airway obstruction. The highest plasma concentrations were reached with the intravenous boluses. Immediately after injection the concentration decreased rapidly. The maximum plasma concentrations after MDI were around 20% of that after the intravenous route for the same bronchodilatation. The heart rate is a function of the plasma concentration. At low concentrations such as after aerosol inhalation of 200 micrograms the influence on the heart rate is not significant. After aerosol inhalation the effect at the receptor can be calculated to be > 7 times stronger than seen from any plasma concentration after intravenous administration. It is assumed that there are structures near the beta 2-bronchodilator receptor which are responsible for the long-lasting effect that is observed only after aerosol inhalation. These depot structures cannot be reached from the plasma in concentrations needed under in vivo conditions. Loss of these structures shortens the duration of the bronchodilator effect. In respect to effect/side effect relationship, more frequent administration of smaller doses may be the best method for administering beta 2-agonists as aerosols in patients with COAD. For many patients with severe forms of this disease, individual optimal dosage with MDI has to be defined following repeated measurements of the airway obstruction so as to achieve the best possible bronchodilatation.

A double-blind, randomized cross-over trial was carried out in 24 patients with chronic airflow obstruction. The patients were required to demonstrate a minimum 15% absolute increase in forced expiratory volume (FEV1) after a standard dose (0.4 mg) of fenoterol (F). On a separate occasion the effect of ipratropium bromide (IB; 0.04 mg) on FEV1 was tested also; according to the increase in FEV1 the patients were grouped into IB responders (delta FEV1 > 15%) and IB nonresponders (delta FEV1 < 15%). Two puffs of F/IB (0.1 mg/0.04 mg), salbutamol (S; 0.2 mg) and placebo (P) were given by metered-dose inhaler at the same time of the day on three different occasions. FEV1 and specific airway resistance (sRaw) were assessed before and at specific intervals following inhalation. The results showed that F/IB and S produced similar maximal increases in FEV1 (delta FEV1 32% for F/IB and 31% for S) and decreases in sRaw (delta sRaw 24% for F/IB and 21% for S). These effects were significantly different both from baseline values and from P. FEV1 was still significantly different 8 h after inhalation from P in the F/IB group, but not in the group that received S. The effect of IB on FEV1 in the pretest was compared with the subsequent response to F/IB. In IB responders F/IB seemed to produce slightly more effective bronchodilation. Side effects were minimal and clinically insignificant. In conclusion, F/IB, with its ability to effect sustained bronchodilation without adverse side effects, is a viable alternative to a monotherapy in chronic obstructive pulmonary disease.

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.

The effect obtained using terbutaline and Duovent was studied in a group of 16 patients with chronic obstructive lung disease. The drugs were administered by aerosol in doses based on spirometric indices of flow and lung capacity. The results obtained confirm the efficacy of the two drugs in improving gas flow. This improvement persisted for 6-7 h after administration. Comparison of the two drugs has shown that as far as FVC is concerned, the improvement obtained with Duovent is longer-lasting than that with terbutaline. There were no side-effects.

Administration of fenoterol aerosol limited to the upper respiratory tract during intubation produced the same bronchodilatating effect as the usual administration to the whole respiratory tract by the metered-dose aerosols used clinically in patients with chronic obstructive airway disease. The site of action of the beta 2-sympathicomimetic drugs in this area of the respiratory tract appears to be in the sensory limb of the bronchoconstriction reflex.

Two double-blind studies were performed in allergic subjects with bronchial asthma to evaluate the bronchodilator effect and antiallergic protection of oxitropium bromide (OTB), a new antiallergic drug. Study 1, bronchodilator trial: 2 puffs of OTB or provocation tests in 12 subjects each. The bronchodilator effect of FEN was significantly better (between 0 and 30 min after drug administration). At the same time there was an improvement of PaO2 after FEN (before: 62.4 Torr; after: 70.1 Torr), but not after OTB. Study 2, antiallergic protection: OTB or FEN were administered 30 min before bronchial allergen provocation tests in 12 subjects each, complemented by open DSCG controls. All 3 drugs provided significant protection compared with nonmedicated control tests, but only inhibition of FEN was complete. In conclusion, beta 2-adrenergic drugs seem to be superior to anticholinergic drugs in allergic asthma, not only as bronchodilators, but also as prophylactic agents.

The cold-air isocapnic hyperventilation (CAIH) test is a challenge test for non-specific bronchitis which was recently incorporated into the study of bronchial hyperreactivity. As it is easy to perform and to reproduce, the CAIH test is regarded as a valuable examination in clinical pharmacology. We carried out a study using this test in 12 atopic asthmatics in intercritical phase. The patients were treated for a few days before, under double-blind conditions and random order, with Duovent (80 micrograms ipratropium bromide + 200 micrograms fenoterol), fenoterol (400 micrograms), salbutamol (200 micrograms), disodium cromoglycate (DSCG) (10 mg) and placebo. All the drugs were administered by aerosol 30 min before the test which was repeated at intervals of 120, 240 and 360 min after intake of the drug. Certain parameters of respiratory function were measured by dry spirometry (Vicatest 2 C) before administration of the drug as well as before and 0, 3, 5, 15, 30 and 60 min after each test. For the sake of brevity only the FEV1 values are shown in the figures since the other parameters all revealed a similar pattern. After placebo, all the patients reacted to the CAIH test with significant falls after each of the 4 tests, but there was no statistically significant difference between the 4 tests; there were no statistically significant differences between the pretreatment values in FEV1 recorded before each treatment (verum or placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

The hyperreactivity-modulating effect of SCH 1000 and fenoterol was tested in two groups of 10 patients. The drugs were administered at random, in simple blind fashion. Baseline pulmonary function was in the range of predicted values for all patients. One group received 80 micrograms of SCH 1000. When the drug was inhaled after carbachol challenge, pulmonary function returned to normal values in all patients. When the drug was inhaled before challenge, a shift to the right of the dose-effect curves was observed in all patients but 1. The other group received 800 micrograms of fenoterol. When the drug was administered after carbachol challenge, all 10 patients returned to baseline within 10 min. When it was given before carbachol challenge, a shift to the right of the dose-effect curves was observed in 9 patients out of 10. SCH 1000 and fenoterol induced an effective protection against carbachol, increasing the PD20 and shifting the dose-effect curves to the right in most of the asthmatics. In 2 patients, 80 micrograms of SCH 1000 or 800 micrograms of fenoterol seemed too low in order to achieve a complete protective effect.

The purpose of this study was to determine the level of protection afforded by fenoterol (200 microgram), administered by pressurized aerosol, in allergen-induced bronchospasm and to compare its effect with that of the same drug administered at the same dosage in powder form. It was a double-blind crossover study on 14 patients with atopic asthma. The administration of the drug took place at weekly intervals according to an appropriate randomized schedule. The sensitizing allergen was inhaled 30 min after the administration of the drug. Parameters of the respiratory function were controlled at fixed intervals over a 2-hour period. The study showed that both fenoterol formulations possess a protective effect in allergen-induced bronchospasm. No statistically significant difference between the two types of drug preparation (pressurized aerosol and powder form) was observed regarding the individual measuring times. In an overall evaluation, statistically significant differences between dry powder and pressurized aerosol have been observed.

Histamine inhalation provocation tests were performed in 18 asymptomatic asthmatic patients with progressively increasing doses of a pressurized aerosol of histamine phosphate. Forced expiratory volume in 1 s (FEV1), total neuromuscular output, assessed by mouth occlusion pressure (P0.1), mean inspiratory flow (VT/Ti), and the P0.1/(VT/Ti) ratio, which represents an index of effective inspiratory impedance of the respiratory system, were measured. With histamine, compared to control, FEV1 decreased and P0.1/(VT/Ti) increased (p less than 0.01 for both). After bronchoconstriction was reversed by administration of a beta 2-agonist bronchodilator (fenoterol), a significant decrease in P0.1/(VT/Ti) (p less than 0.001) and a significant increase in FEV1 (p less than 0.01) were noted as compared to histamine. With histamine, change in P0.1/(VT/Ti) was found to be related to its pre-histamine value (p less than 0.01). Furthermore, with histamine and fenoterol, changes in P0.1/(VT/Ti) and concurrent changes in FEV1 were found to be significantly related (p less than 0.001). From these data we calculated that the P0.1/(VT/Ti) ratio provides a useful tool in the clinical assessment of histamine-induced bronchospasm.

A group of patients suffering from chronic obstructive lung disease, selected according to clinical criteria and respiratory function, were treated daily for at least 84 days using a metered aerosol containing a combination of a beta 2-agonist (fenoterol) and an atropine-like drug (ipratropium bromide). Every 14 days, respiratory and cardiovascular function was measured and analysed statistically. Information was compiled daily by the patients themselves on dyspnoea, cough, peak flow, any increase in dosage over the recommended dose and any side-effects that might have developed. The results obtained demonstrated that the combination of fenoterol and ipratropium bromide produced clear improvements in respiratory function and symptomatology throughout the observation period. The drug was well tolerated by the majority of patients.

Plasma cAMP was determined using the method of Tovey et al. in normal pregnant women with a mean concentration of 18.9 +/- 0.8 pmol/ml (x- +/- SEM). Between weeks 9-12 and 33-36 of gestation, there were two peaks, with a mean cAMP of 22.5 +/- 2.4 which were significantly increased in comparison to the other weeks of pregnancy. Significantly decreased values were found in patients with threatened abortion (weeks 12-28) which terminated in abortion (11.6 +/- 2.4; p < 0.01). In premature labor no differences were found. During therapy with fenoterol there were highly significantly increased plasma cAMP levels (48.2 +/- 2.8; p < 0.0005). During thyroid hormone therapy in euthyroid goiter, cAMP was significantly decreased (14.0 +/- 1.4; p < 0.05). 1 week after cessation of therapy a highly significant increase of cAMP was observed (38.2 +/- 6.9; p < 0.0005). There was a negative linear regression between T3 and cAMP (2p < 0.01). In pregnancy with hypertension cAMP was significantly elevated (30.5 +/- 3.8 p < 0.0005), but nearly normal under antihypertensive therapy. In pregnancy with edema only, no difference was found. Induction of labor with PGE2 alpha was followed by a decrease of plasma cAMP.

To assess the dose of oral fenoterol, a beta 2-receptor stimulant, which provided optimal bronchodilation with minimal side effects, we studied 12 children using a double-blind crossover comparison of three dose levels, 2.5, 5 and 7.5 mg, and a placebo. ventilatory function, pulse rate, blood pressure and clinical examination were compared over a 3-hour period. Administration of fenoterol resulted in bronchodilation; a maximal effect was seen at 60--90 min lasting over the period of the study. 7.5 mg of fenoterol produced the maximal bronchodilation, but it was not significantly different from 5 mg. Side effects were minimal and no significant drug-response relationship was noted for blood pressure and pulse rate. 5 mg of fenoterol provided optimal bronchodilation with minimal side effects.

100 patients with premature contractions were treated with the beta-adrenergic agent fenoterol for up to 9 weeks. To rule out a detrimental effect on the myocardium, the creatine kinase isoenzyme MB, which is specific to the myocardium, was determined regularly in addition to electrocardiographic monitoring. No pathological enzyme activity was detected even in long-term tocolytic therapy with the maximum dose.

The bronchodilating effect of Duovent (0.2 mg fenoterol +0.8 mg ipratropium bromide) was compared with that of each of its components at the same doses. Twenty patients were included in the trial. Maximum expiratory flow-volume curves with air and helium-oxygen, intrathoracic gas volume and airway conductance were used for assessing the bronchomotor tone before and 15, 30, 60, 240 and 360 min after drug administration. All the drugs showed a significant bronchodilating effect. No differences between Duovent and fenoterol or ipratropium bromide were observed except a slight but statistically significant greater decrease of ITGV with Duovent. When expressing the data as percentage variation of the initial values, Duovent induced a better effect than the other drugs. The evaluation of density dependence was highly disappointing, and no conclusion can be drawn.

Twelve patients, aged over 60 years and suffering from chronic obstructive lung disease, were treated for 12 weeks with Duovent (fenoterol + ipratropium bromide). The clinical check-ups and indices of bronchial obstruction (FEV1, VC, RV, sGaw) were performed every 14 days. Improvement in symptoms corresponded to a significant improvement in the functional parameters. No negative cardiovascular effects, significant side-effects, or tolerance were seen after drug administration.

Fenoterol (Berotec) was administered by inhalation, using a Bennett nebulizer, to symptom-free asthmatic children aged 6-13 years. It was demonstrated in a double-blind, crossover trial in 6 children that the improvement in the forced expiratory volume produced by inhalation of a nebulised fenoterol solution was not a placebo effect. Fenoterol (0.1 mg) produced effective bronchodilatation but there was a significant logarithmic dose-response relationship over the dose range tested (0.1-0.8 mg cumulative). There was no effect of the drug on heart rate even with the 0.8 mg dose.

The bronchodilator effect of Duovent (a combination of a beta-2-agonist, fenoterol, and an anticholinergic, ipratropium bromide) was compared with that of Reproterol (a pharmacological hybrid which presents both resorcinol and theophylline portions) in 16 patients suffering from chronic reversible airway obstruction. Each of the 16 patients (14 males and 2 females, mean age 65.8 years) had a baseline FEV1 ranging from 30 to 70% of their predicted values (CECA values) (mean value +/- SE of the group: 1,238 +/- 78 ml), which increased at least 15% after the inhalation of two puffs of 400 micrograms fenoterol (percent increase of the group: 26.5 +/- 2%, mean +/- SE). This single-blind study was carried out on 3 different days, between 8:30 a.m. and 4:30 p.m. After measurement of the baseline functional parameters [FVC (forced vital capacity), FEV1 (1-second forced expiratory volume), and FEF25-75 (forced expiratory flow between 25 and 75% of vital capacity)], each patient was given two puffs of placebo the 2nd day, and either of Duovent (200 micrograms of fenoterol and 80 micrograms of ipratropium bromide) or of Reproterol (1 mg) the 1st or the 3rd day, at random. The measurements of functional parameters were repeated after 30, 120, 240, 360 and 480 min. Blood pressure, heart rate and possible side effects were recorded at the same time. Both Duovent and Reproterol, at all times, produced a statistically significant increase in FEV1 and FEF25-75.(ABSTRACT TRUNCATED AT 250 WORDS)

A blind randomized cross-over comparative study of salbutamol and the combination fenoterol/ipratropium was carried out in 20 patients with mild to moderate bronchial asthma; clinical and functional serial parameters were evaluated. The combination was more effective than salbutamol in preventing crisis and incidence of cough and wheezing, and in the spirometric results. There were no significant differences in expectoration and the functional parameters improved not only in flow but also in volume. Pathogenesis is discussed.

Fourteen patients with chronic obstructive lung disease (COLD) were studied. All were in a relatively stable clinico-functional state, and bronchospasm was reversible with fenoterol. The study was carried out over 3 days. Duovent and Carbuterol were given at random on the 1st or 3rd day to each patient; the placebo was always given on the 2nd day. Each drug was administered with 2 puffs of a metered-dose aerosol, corresponding to 200 micrograms fenoterol + 80 micrograms ipratropium bromide for Duovent and 200 micrograms of active substance for Carbuterol. The patients were studied for 7 h after administration of the 3 preparations. Ventilatory and cardiocirculatory parameters as well as local and systemic tolerance of the drugs were evaluated. The data show that Douvent has a more rapid and powerful bronchodilator action compared to Carbuterol. The action of Duovent is more constant and prolonged compared to the other drug and acts on both proximal and distal airways. Local and systemic tolerance is excellent for both drugs studied. In conclusion, Duovent is a rational and effective combination in the treatment of bronchospasm.

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.

The effect of the combination fenoterol-ipratropium bromide (Duovent) as a bronchodilator drug versus salbutamol and placebo was investigated in 20 patients with chronic obstructive lung disease in a random cross-over trial. Our study was performed not only to evaluate the bronchodilator response, but especially to quantify the possibly more prolonged action of Duovent versus salbutamol, based on registration of prevention of asthma attacks, time effects and protective activity, management and tolerance. Each patient received therapy for 3 weeks; in each week only one of the preparations: salbutamol, Duovent or placebo was used. Respiratory function tests were determined every week on the 3rd, 5th and 7th days at the same time exactly at 30 and 60 min after drug inhalation. Additionally we registered, for each patient, daily symptomatology (e.g., asthma attacks, cough, additional daily puff use, adverse reactions) by using a personal clinical diary. The results and analysis of the pulmonary tests (especially FEV1 and peak expiratory flow) confirmed the bronchodilator effect of both drugs, higher for Duovent but not sufficient to reach statistical significance. Clinical condition, regarding number, severity of asthma crises and additional puff use, showed a significant statistical variation for each symptom either as regards advantage of Duovent and salbutamol versus placebo, or advantage of Duovent versus salbutamol. Therefore, the results of this trial reveal an excellent bronchodilator effect of both drugs and confirm a higher clinical efficacy of Duovent if used in long-term treatment, with good tolerability.

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).

Exercise-induced asthma (EIA) is a frequent symptom in asthmatic patients. The study of drugs which inhibit EIA is very important because EIA seriously limits the life of the patients. In addition, this study could allow further insights to be gained into the pathogenesis of the phenomenon. The aim of the present study is to evaluate the duration of the protective effect of fenoterol alone or in combination with ipratropium bromide administered 5 h before exercise. For this purpose we studied 12 asthmatic patients (7 males and 5 females, mean age 23, range 7-41 years) with EIA, in clinical and functional stable state. Respiratory function parameters were measured before and 5 h after the administration of fenoterol 400 or 200 micrograms, or fenoterol 200 micrograms plus ipratropium bromide 80 micrograms (Duovent), or placebo in randomized order. Then, such parameters were measured at 5, 15, 30, and 60 min after exercise, which consisted of free running up and down the stairs. The results show that, at 5 h after the administration of each drug, the protective action against EIA is only partial. However, the intense bronchodilation afforded by the 'active' drugs, and particularly by 400 micrograms of fenoterol, keeps post-exertional respiratory parameters above the baseline values.

Duovent-Berodual was compared with salbutamol from metered aerosols, in subjects with asthma, in a double-blind, randomised, placebo-controlled cross-over study. 10 stable asthmatics, 9 females and 1 male, all on regular inhaled bronchodilators and steroid treatment, were studied following prior assessment of reversibility. This was confirmed by at least a 15% improvement in forced expiratory volume in 1s (FEV1) following 200 micrograms of inhaled salbutamol. Inhaled bronchodilator therapy and oral theophyllines (4 subjects) were withheld for 8 and 48 h prior to investigation. Baseline FEV1 for each study day varied by less than 15%. Duovent-Berodual produced a greater improvement in mean FEV1 and mean peak expiratory flow rate (PEFR) compared with salbutamol at all time points. This was significant (p less than 0.05) for FEV1 at 120, 180, 210 and 240 min post-treatment. For PEFR a significant difference in response (p less than 0.05) was achieved at 90, 120, 150 and 210 min post-treatment. No significant difference was demonstrated for forced vital capacity (FVC) between the two active treatments at any time point. Ipratropium has been shown to improve FVC disproportionately to FEV1 and this has been attributed to dilatation of small airways. Seven subjects in this study described their asthma as lifelong. The failure to demonstrate significant differences in FVC response may reflect damage to small airways that render them unresponsive to ipratropium. This study demonstrates that Duovent-Berodual provides a significant improvement in bronchodilatation extending through to 4 h when compared with salbutamol.

In a double-blind crossover study, the effects of fenoterol powder inhaled from capsules (0.2 mg) and the powder inhaler with salbutamol capsules (0.4 mg) were compared. A single dose of each was administered on 2 subsequent days in random order. The effects on lung function test results were followed from 15 to 360 min after administration. Apart from the overall comparison, special attention was paid to the beginning and the end of the test periods. Statistically significant differences were found only in a few parameters and showed a trend for fenoterol to have a somewhat longer effect and for salbutamol to have a faster onset of effect. The differences between the effects of the two drugs were clinically not relevant. Blood pressure and heart rate were unaffected by either treatment.

Fourteen out-patients with chronic bronchitis (n = 5) or chronic bronchial asthma (n = 9) entered a trial devised to evaluate the effect of the combined inhalation by pressurized aerosol of fenoterol 200 micrograms + ipratropium bromide 80 micrograms three times daily in a 12-week period of treatment. On the basis of the ventilatory and clinical findings, effective bronchodilatation with clinical improvement after drug inhalation was noticed throughout the whole observation time. In detail, the behaviour either of the FEV1 values at the control days or of the daily self-monitored peak expiratory flow (PEF) data showed a constant, statistically significant increase in the post-bronchodilator values with a prompt, long-lasting and persistent effect over the 3-month period; self-monitored PEF rates were particularly consistent with this result. No side-effects were seen in any cases, including the 5 patients who needed extra use of inhalers. The findings of the trial suggest that the combined inhalation of fenoterol and ipratropium bromide may play an important role in long-term therapy of many patients with chronic bronchitis or chronic bronchial asthma.

Berotec (0.4 mg fenoterol hydrobromide, regimen B), Atrovent (0.08 mg ipratropium bromide, regimen A) and Duovent (0.2 mg fenoterol hydrobromide and 0.08 mg ipratropium bromide, regimen D) were administered by metered dose inhalers (MDI) to 12 patients with asthma (regimens D and B only) and 12 patients with chronic airflow obstruction (CAO). The increase in FEV1 was similar after all regimens, but greater in the patients with asthma than those with CAO. In the patients with asthma, the increase in FVC was greater after Berotec than Duovent but the difference may not be clinically important. In the patients with CAO, the increase in FVC was greater after Duovent than after the other regimens. Subjective side effects were commoner after Berotec than the other regimens, hence in the doses used Duovent may offer some clinical advantage as compared with Berotec and Atrovent used alone.

Twenty-four elderly male patients with moderate-to-severe chronic airway obstruction took part in a double-blind, placebo-controlled, randomized dose-response and response-duration comparison of a new inhaled anticholinergic bronchodilator oxitropium bromide and the inhaled beta-agonist bronchodilator fenoterol hydrobromide. On 6 separate days lung function changes and side effects were monitored for 8 h after either placebo, oxitropium 100, 200 and 300 micrograms, fenoterol 400 micrograms, or oxitropium 200 micrograms plus fenoterol 400 micrograms. Fenoterol alone and in combination with oxitropium produced a rapid peak effect (mean delta FEV1 = 41.6 and 39.5%, respectively at 30 min). Oxitropium alone had a slow onset of action (peak delta FEV1 seen at 120 min: 100 micrograms = 22.7%, 200 micrograms = 29.9%, 300 micrograms = 28.2%). However, mean FEV1 remained within 5% of peak for 60 min after fenoterol, but for 180 min after each dose of oxitropium and after fenoterol plus oxitropium. No differences between oxitropium 200 and 300 micrograms were seen; however, these doses produced more prolonged bronchodilatation than did oxitropium 100 micrograms. The fenoterol-plus-oxitropium combination produced even more prolonged bronchodilatation. The only side effect, seen with each inhaler was a mildly unpleasant taste. No anticholinergic effects were seen. We conclude that oxitropium is an effective bronchodilator with slow onset but prolonged duration of action. In combination with fenoterol it produced both rapid and prolonged bronchodilatation in patients with chronic airflow obstruction.

Twenty-one stable asthmatic patients were randomly allocated to be treated with either Duovent (ipratropium bromide 40 micrograms and fenoterol 100 micrograms) and Berodual (ipratropium bromide 20 micrograms and fenoterol 50 micrograms) in a cross-over double-blind design over a 12-week period, each treatment period lasting for 6 weeks. During the study, patients used the test medicine 2 puffs 4 times daily. At the day of inclusion, 6 and 12 weeks after start, a dose-response curve was obtained after inhalation of the test medicine used during the previous 6-week period. Asthma symptoms were recorded in a diary card and morning and evening peak flow was measured. Berodual and Duovent showed a significant bronchodilating effect, the effect of Duovent comparatively more pronounced, but the absolute lung function values after Berodual equalized the effect of Duovent. No difference between peak flow values measured in the morning and evening could be demonstrated. We conclude that no preference between either Duovent or Berodual could be established in the treatment of asthma.

Haemodynamic investigations, partly using invasive monitoring, concerning interactions between the beta-mimetic effect of fenoterol and the alpha-sympathetic blockade of spinal or epidural anaesthesia were made in a total of 49 patients during pregnancy, during caesarean section and in non-pregnant women. Haemodynamic effects of fenoterol during regional anaesthesia were compared with those during general anaesthesia (n = 17). Epidural or spinal anaesthesia enhance vascular beta-mimetic reactions at the start of tocolysis, leading to a profound but short-lasting decrease in blood pressure. This initial hypotension is more pronounced after regional than after general anaesthesia.

Combinations of beta-stimulant and anticholinergic drugs have been advocated as a potentially useful tool in the treatment of reversible airway obstruction. We investigated the effectiveness and safety of a metered aerosol preparation delivering fenoterol 100 micrograms and ipratropium bromide 40 micrograms per puff: two dosages (2 puffs and 4 puffs) were used in 16 asthmatic patients, and their acute effects (up to 420 min) were investigated in a double-blind randomized trial. The results point out a reasonably good response to both dosages, with no notable difference between them as far as vital capacity, FEV 1, MMEF and Vmax75 are concerned. This finding indicates the possibility of achieving a satisfactory bronchodilation at beta-stimulant dosages far lower than the standard ones commonly used and therefore minimizing the risk of untoward cardiovascular effects.

Oxitropium bromide (Ba 253) is a new inhaled bronchodilating agent with anticholinergic properties. The effect of this compound (100 micrograms) was compared to that of ipratropium bromide (40 micrograms), the beta 2-receptor stimulant fenoterol (400 micrograms) and placebo in 8 patients with exercise-induced asthma. The drugs were administered by metered dose inhalers, after which exercise test were performed on ergometer cycles at the times of the drugs' maximal effects. Forced expiratory volume during 1 S and vital capacity were recorded basally, repeatedly during 20 min after exercise and following the inhalation of isoprenaline (160 micrograms) which was given 20 min after exercise. Fenoterol possessed a very good protective effect against exercise-induced bronchoconstriction in all patients, whereas the other drugs differed very little from placebo. Thus, only 4 patients did benefit from ipratropium bromide, 1 patient from oxitropium bromide and 2 patients from placebo. No side effect occurred. In the doses used the two anticholinergic agents ipratropium bromide and oxitropium bromide were less effective than a beta 2-adrenoreceptor stimulant like fenoterol in protecting against exercise-induced 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.

Duovent activity was compared with placebo in a double-blind study carried out in 20 children, aged between 5 and 14 years, suffering from bronchial asthma. The experiment lasted 2 weeks. The patients were divided into two groups. In the 1st week, group I was treated with Duovent and group II with placebo, in the 2nd week vice versa. There was no reduction in cough or dyspnea in subjects treated with placebo, and only a slight increase (not significant) in peak expiratory flow (PEF). In the subjects treated with Duovent, there was a clear reduction in cough and dyspnea and a significant increase in PEF. The effect of the drug was still evident after 8 h, and it was well tolerated without side effects. The high number of additional sprays required during the placebo period was further evidence of the therapeutic efficacy of Duovent, which in almost all cases met the daily therapeutic requirements of the small patients. Duovent appears to be an effective drug in the treatment of bronchial asthma in children, both clinically and functionally.

The protective effect on bronchospasm, induced by carbachol, of 2 puffs of fenoterol (200 micrograms), ipratropium bromide (80 micrograms) and Duovent (200 micrograms fenoterol + 80 micrograms ipratropium bromide) was compared in a group of 12 asthmatic patients. The double-blind study was always performed at the same time of day, 2 and 5 h after premedication, on 4 consecutive days. After the 1st day, when placebo was given, the drugs were administered randomly. As regards PD20 FEV1 (dose of carbachol necessary to determine a 20% decrease in FEV1), Duovent was found to be the most active drug. A very clear difference was seen 2 h later, not only compared to fenoterol (PD20 placebo, means +/- SD: 90.8 +/- 93.2 micrograms; PD20 Duovent: 1,876.5 +/- 1,103.5 micrograms; PD20 fenoterol: 324.3 +/- 220.7 micrograms) but also with ipratropium bromide (PD20: 1,215.8 +/- 950 micrograms). After 5 h, the three treatments maintained a significant action, but the efficacy of Duovent, while significantly greater than that of fenoterol, was very similar to that of ipratropium (PD20 placebo: 78.4 +/- 92.6 micrograms; PD20 fenoterol: 134.6 +/- 138.2 micrograms; PD20 ipratropium bromide: 295.4 +/- 337 micrograms; PD20 Duovent: 286.7 +/- 181.2 micrograms).

Fenoterol with ipratropium bromide (Duovent) is a recently used combination between an anticholinergic and a beta-adrenergic drug useful in obtaining a more effective bronchodilatation and/or reducing the single drug doses. It has been suggested that, as in the case of beta-agonists, its clinical efficacy may be limited by the development of tolerance. We studied the effects of inhaled Duovent in 15 asthmatic patients for 3 months, using a rigidly controlled protocol. Appropriate serial physiological measurements were made at regular intervals during the 90-day study. In all instances the day-one bronchodilator response was significant, prompt and sustained: at 1, 4, 8 and 12 weeks the response was statistically the same as on day 1. It is concluded that, when the important variables are properly controlled, no evidence of tolerance to long-term therapy with Duovent is demonstrable.

Seventeen asthmatic, non-atopic patients (aged 15-48 years) were studied at different hours of the day. On 3 different days, they were submitted to a fog-test at 03:00 p.m. and at 03:00 a.m. On 2 different days, they were given fenoterol (200 micrograms) or Duovent (fenoterol 200 micrograms plus ipratropium bromide 80 micrograms). We were able to demonstrate significant inter-hour differences of the basal values of all parameters, except FVC, in all patients at 03:00 p.m. and at 03:00 a.m. We did not observe any inter-hour difference after the fog-test. Both fenoterol and Duovent improved challenge-induced bronchoconstriction. After the fog-test, both drugs showed an inter-hour variability of ventilatory parameters, which was not significant without drugs because it was masked by the magnitude of the obstructive response to challenge.

The efficacies of inhaled doses of fenoterol 200 micrograms, ipratropium bromide 40 micrograms and their combination (200 + 40 micrograms) were compared in a double-blind, placebo-controlled cross-over study in 24 adult patients with stable asthma bronchiale. The tests were performed during 4 consecutive days. The change in bronchial obstruction was assessed by means of spirometry [forced expiratory volume in 1 s (FEV 1.0), forced vital capacity (FVC), peak expiratory flow (PEF)] and body plethysmography [thoracic gas volume (TGV), airway resistance (Raw)] measurements. The values of FEV% and specific airway conductance (SGaw) were calculated. The frequency of side-effects was recorded. During the treatment with the combination of ipratropium bromide and fenoterol the change in the mean SGaw differed highly significantly (p less than 0.001) from placebo in the initial bronchodilator response and at 3, 4 and 5 h. With fenoterol, compared to placebo, a highly significant difference in bronchodilator effect lasted for 4 h, with ipratropium bromide for 3 h. Similarly, a highly significant difference measured with FEV 1.0 during the medication with the combination of ipratropium bromide and fenoterol lasted for 4 h, with fenoterol alone for 2 h, and with ipratropium alone for 1 h. The most harmful side-effect in this group of asthmatics proved to be muscular tremor, caused most often by the combination of ipratropium bromide and fenoterol. The findings of this study suggest that the combination of ipratropium bromide and fenoterol gives a stronger bronchodilatation and a more prolonged effect in asthmatics than ipratropium bromide or fenoterol alone.(ABSTRACT TRUNCATED AT 250 WORDS)

In 10 patients with airway obstruction, spirographic indices and maximal expiratory flow rates were measured before inhalation of fenoterol and at different time intervals, for 5 h, following the inhalation of 200 mug of this substance. 10 min after inhalation of fenoterol, there was a statistically significant increase in all lung function indices. A further increase was observed later. 3 h after inhalation of fenoterol, all indices were still significantly higher than control values. No side effects were observed. At all time intervals, the increase of the forced expiratory volume in 1 sec (FEV1.0), peak expiratory flow rate (PEFR) and maximal expiratory flow rate at 50 and 75% of the vital capacity reached a similar level of statistical significance. It is concluded that for the trial of the bronchodilator drugs, any of these indices may be used, and for practical purposes FEV1.0 and PEFR are best suited.

Until now very few studies have been performed on the prevention of exercise-induced asthma (EIA) in children with ipratropium bromide + fenoterol. This is why we decided to study 30 children aged between 6 and 15 years, whose EIA was confirmed by a test including a 6-min free race on day 1 of the study. The criterion was a decrease of more than 20% of the basal values of forced expiratory volume in 1 s (FEV1) or FMF. Children whose FEV1 or FMF baseline values were under 60% of those expected according to Polgard tables were excluded. Three tests were performed, the first to determine EIA, the second was performed 72 h later after inhalation of placebo. 72 h after day 2 the patients returned in order to repeat the test, but this time, aerosol therapy with the combination ipratropium + fenoterol was applied prior to the race. The dosage of the combination was 1 puff of aerosol per 10 kg body weight, up to a maximum of 4 puffs. Each puff of the combination contains 0.02 mg of ipratropium bromide and 0.05 mg fenoterol. Functional assessment of children was carried out by means of forced spirometry. There were no significant differences between the placebo group and the group which received no medication, but there was a significant difference between the treated group and the other two, not only in the FEV1 and FMF values but also in forced vital capacity TEST.(ABSTRACT TRUNCATED AT 250 WORDS)

The lecithin content of 157 amniotic fluid samples taken from 60 patients who had been treated with Fenoterol over a long period of time (longer than 30 mg/daily per os for 14 days; intravenous infusion for longer than 7 days) was calculated thin-layer chromatographically according to Kynast and Saling. These lecithin levels were statistically compared with the levels in a control (Wilcoxon test). It emerged that the lecithin levels in the long-term beta-mimetic therapy group were significantly lower, i.e., from 33/0 to 39/6 (33/0-34/6, p less than 0.05; 35/0-39/6, p less than 0.01). The answer to the question how often levels occur in the long-term group which are below the as critical described level of 3 mg Lec/100 ml amniotic fluid appears to be clinically important. It is shown that values below the critical level from 33/0 to 39/6 are much more frequent in the long-term beta-mimetics therapy group than in the control group. There is no known explanation for this. It was concluded that the application of beta-mimetics in cases of long-term tocolysis should only be discontinued when the lecithin content of the amniotic fluid lies above the critical limit of 3 mg Lec/100 ml.

Beta 2-adrenergic and anticholinergic drugs have shown an action in modulating bronchial hyperreactivity to various stimuli (chemical, physical, immunological, pharmacological). The aim of our study was to compare the efficacy of a combination of ipratropium bromide and fenoterol (Duovent) with the activity of single drugs in the prevention of histamine-induced bronchospasm. Twenty-six atopic asthmatic subjects were examined in a double-blind trial, during an asymptomatic period, with a FEV1 value not lower than 20% of the predicted normal value. During 4 consecutive days all patients received 2 puffs, respectively, of Duovent (200 micrograms fenoterol + 40 micrograms ipratropium bromide), fenoterol (400 micrograms), ipratropium bromide (80 micrograms) and placebo in a randomized order. PD20 values were evaluated after each drug administration: after 2 h in 16 patients and after 5 h in the other 10 patients. The data were modified to log values, and statistical analysis was performed by two-way analysis of variance. This study showed that Duovent and fenoterol have a protective effect against histamine-induced bronchospasm with a significant increase in the PD20 values 2 h (p less than 0.01) and 5 h (p less than 0.05) after treatment when compared to placebo. Duovent inhalation determined a more protective effect than other drugs but not significantly when compared to fenoterol. Some advantages in the modulation of bronchial reactivity could be seen from using Duovent because with the lower dose of the beta 2-adrenergic drug the same results could be obtained without side-effects.

Uterine hyperactivity can be treated with uterine relaxants. In order to establish the most satisfactory dosage for Fenoterol, several doses were administered intravenously to pregnant women during birth and the actions on uterine relaxation and on side effects were examined. Saline was injected in a group of patients as control. With doses of 20 and 40 micrograms Fenoterol, submaximal uterine relaxation times of 7.3 and 7.9 min were obtained. Subjective side effects were observed, such as palpitations and restlessness; maternal blood pressure was unchanged. The pulse rate increased significantly only after 40 micrograms. 10 micrograms Fenoterol induced a uterine relaxation time of 5.6 min, was without side effects and was therefore regarded as the most satisfactory dosage. With 5 micrograms Fenoterol a relaxation time of only 3.2 min was observed. In the control group, administration of saline was without any observable effect.