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Study objectives: Different b-agonists are compared with regard to their cardiodepressive side effects. Design: The metaphenolic bronchodilators reproterol, salbutamol, fenoterol, and terbutaline were introduced at a dosage of 0.0005 mmol to a maximum of 10 mmol per gram of heart tissue into the isolated working rat heart under hypoxic conditions, and the response was observed during subsequent reoxygenation. As an index of external heart work, aortic flow was measured. Heart rate, coronary flow, and developed pressure were recorded. At the end of heart perfusion, mitochondria were isolated and analyzed for adenosine triphosphatase activity, adenosine triphosphate (ATP) synthesis, and membrane fluidity. Moreover, intact mitochondria and lipid peroxidation were investigated using a model system. Measurements and results: Compared to controls, reproterol gave the most favorable results, with an increase of 25 to 30% of aortic flow during reoxygenation at a concentration of 10 mmol/g heart tissue. In contrast, both fenoterol and salbutamol at a concentration of 1 mmol/g heart tissue decreased aortic flow during reoxygenation, whereas terbutaline had a negative influence on aortic flow at 0.01 to 0.1 mmol/g heart tissue. Mitochondria of these hearts were isolated at the end of the experiment. Mitochondrial ATP synthesis was increased above controls at nearly all concentrations of reproterol. ATP synthesis was decreased at 1 mmol and 10 mmol fenoterol. As little as 0.0005 mmol terbutaline decreased ATP synthesis by 50%. In intact mitochondria, adenosine diphosphate (ADP) to oxygen ratios were found to be increased with terbutaline and fenoterol, indicating ADP consumption by myokinase activation. Lipid peroxidation was increased in a model system between concentrations of 0.002 mmol/mg and 0.04 mmol/mg phosphatidylcholine by fenoterol and terbutaline, whereas a decrease was noted with reproterol. Membrane fluidity was found increased after addition of reproterol, which supports the evidence of efficient ATP synthesis by this compound. Conclusions: Cardiodepressive side effects and greater toxicity of fenoterol and terbutaline were found under the conditions of our experiment. Salbutamol and, in particular, reproterol appear much better tolerated. In addition to partial b-adrenergic agonism, reproterol may exert an inhibitory influence on adenosine receptor sites and phosphodiesterase, which could result in membrane stabilization by saving cyclic adenosine monophosphate or ATP. (CHEST 2000; 117:519‐529)

Study objectives To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. Design Two randomized, three-way crossover studies. Setting Clinical research laboratory. Participants Healthy, nonsmoking volunteers. Interventions In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). Measurements and results Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV l , FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p Conclusion The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.

Background The effects of vasoactive drugs, including bronchodilators, on vascular and pulmonary dynamics are interrelated, complex and difficult to measure, but important because of potential deleterious effects on gas exchange. Methods To assess the effects of fenoterol at both high and low dose on pulmonary gas exchange in 24 hypoxemic patients with stable COPD: fenoterol, 5 mg; fenoterol, 1 mg and ipratropium bromide, 0.5 mg; ipratropium bromide, 0.5 mg; or matched placebo were nebulized in a double-blind, placebo-controlled fashion. Spirometry, ventilation, systemic hemodynamics, and respiratory and inert gases were measured before and 15, 60, and 120 min after each treatment. Results Compared with placebo, heart rate (p

Study objective To compare the maximal extrapulmonary effects of the β-agonists albuterol and fenoterol in eight healthy volunteers. Subjects and methods In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS 2 I]— a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuterol and fenoterol. In eight healthy volunteers, 400 µg of each drug was administered every 10 min until QS 2 I and plasma K+ had reached a plateau (±0.1 mmol/L for K+, and ±10 ms for QS 2 I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED 50F ) were calculated. Results The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs −1.03 mmol/L; p 2 I (-71.8 vs −57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p 50F was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS 2 I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052). Conclusions These findings suggest that albuterol behaves as a partial agonist at β-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.

Oxitropium bromide is a novel anticholinergic bronchodilator agent. The purpose of this study was to compare the bronchodilating and cardiovascular effects of oxitropium (0.2 mg), fenoterol (0.4 mg), combined oxitropium and fenoterol (0.2 mg and 0.4 mg, respectively) over a 10-h test period. Fourteen patients with chronic obstructive pulmonary disease (COPD) (FEV 1 , 0.95±0.38L) were studied in a randomized, double-blind, placebo-controlled trial. Combined oxitropium and fenoterol produced significantly greater improvements in FEV 1 over a time span of 15 min to 10 h and in the area under the time-FEV 1 curve (AUC) than either oxitropium or fenoterol alone. The effects of oxitropium on both FEV, and AUC values were similar to those of fenoterol. Oxitropium resulted in a greater increase in FEV, than the placebo even after 10 h. In contrast, fenoterol produced a significant improvement in the FEV, for only 15 min to 4 h. Oxitropium showed no adverse cardiovascular effects, whereas fenoterol was associated with an increased heart rate at 15 min and 1 h after the administration. We conclude that oxitropium bromide is an effective and safe bronchodilator for even elderly patients with COPD.

The aim of this study was to investigate whether the administration of prednisone potentiates any of the acute biochemical and cardiovascular effects of high-dose inhaled beta-agonist drugs. These agents are known to cause dose-related changes in plasma potassium and glucose, as well as ECG changes in heart rate, corrected QT interval (QTc), T wave, and U wave. On theoretical grounds, the concomitant use of systemic corticosteroids might enhance these actions. Twenty-four healthy subjects were randomized to receive one of three treatments: salbutamol 5 mg or fenoterol 5 mg or normal saline solution. Each drug was administered twice, 30 min apart by nebulizer, and the procedure was repeated after each subject had received prednisone 30 mg daily for one week. Plasma potassium and glucose levels were measured, and ECGs were obtained after each treatment, together with 12-h Holter monitoring for arrhythmias. Changes in plasma potassium and glucose following nebulized beta-agonist were significantly greater after treatment with prednisone. Baseline potassium level fell from 3.75 mmol/L (95 percent CI 3.61, 3.89) to 3.50 mmol/L (95 percent CI 3.36, 3.64), and thereafter all values were significantly lower at each time point (p = 0.003). The lowest mean plasma potassium was obtained 90 min after fenoterol administration with prednisone pretreatment: 2.78 mmol/L (95 percent CI 2.44, 3.13). Increases in heart rate and QTc interval following both beta-agonist drugs were significant, but T-wave amplitude reductions did not reach significance. Prednisone treatment did not significantly alter the cardiovascular responses. Supraventricular and ventricular ectopic activity was related to beta-agonist use, but no potentiating effect was noted following steroid treatment. We conclude that the acute biochemical effects of beta-agonist administration are augmented by prior treatment with prednisone, but this is not the case for ECG effects. However, the degree of hypokalemia noted as a result of this drug interaction may be of clinical significance in the hypoxic conditions of acute airways obstruction.

The effects of three different regimens of inhaled bronchodilators on spirometry and respiratory impedance as measured with the technique of forced oscillations were compared in a double-blind crossover study in 22 patients with stable chronic obstructive pulmonary disease (FEV1 less than 70 percent predicted). On three trial days, patients inhaled, in random order, 40 micrograms ipratropium bromide, 200 micrograms fenoterol hydrobromide, or a combination of 40 micrograms ipratropium and 100 micrograms fenoterol from a powder inhaler, followed by a second dose of the same drug after 60 min. The effects were measured at baseline and 20, 40, 60, and 120 min after the first inhalation. No significant decrease in total respiratory resistance at 8 Hz (Rrs [8]) was observed after ipratropium, whereas Rrs (8) decreased significantly 20 min after fenoterol and 40 min after the combination regimen (p less than 0.05). All three studied drugs resulted in a significant increase in the reactance (p less than 0.01) and decrease in resonant frequency. Both fenoterol (delta FEV1 34 percent, p less than 0.0001) and the combination regimen (delta FEV1 38 percent, p less than 0.0001) resulted in a significantly larger increase in FEV1 than ipratropium alone (delta FEV1 17 percent, p less than 0.0001). A second dose of fenoterol and of the combination regimen resulted in a further significant increase in FEV1 after 120 min (p less than 0.05). A second dose of ipratropium did not result in a further significant increase in FEV1. The changes in respiratory impedance were qualitatively similar for all three drug regimens, but larger in absolute terms after fenoterol and the combination regimen than after ipratropium. The similar effect of these drugs on the reactance can be explained by an increase in the capacitance of the respiratory system, and in combination with a decrease in frequency dependence of resistance, by assuming a decrease in peripheral airway resistance.

Two recent epidemiologic case-control studies suggested that fenoterol, a selective beta-adrenergic agonist, was associated with an increase in the risk of asthma death. The results of these studies were criticized because of methodologic problems in the choice and selection of control subjects; the different methods used to gather exposure data in cases and control subjects; and because of inadequate classification and adjustment for asthma severity. In response to this controversy, a new study is underway, the Saskatchewan Asthma Epidemiology Project. The SAEP includes two complementary studies, an historic cohort and a case-control analysis, that employ the computerized databases of the Saskatchewan Health Department. A unique aspect of the SAEP is the attempt to incorporate knowledge of asthma physiology and management into the design of the studies. Specifically, the study design recognized the role of antiinflammatory drugs in asthma treatment; the distinction between asthma death and near-fatal asthma; the severity of asthma; patterns of drug use; and the distinction between inadequate clinical care and disease severity. The strategies we employed in the SAEP may prove helpful to investigators whenever clinical and biologic processes create sources of potential bias requiring special procedures for the design and analysis of epidemiologic studies.

Different beta-agonists are compared with regard to their cardiodepressive side effects.The metaphenolic bronchodilators reproterol, salbutamol, fenoterol, and terbutaline were introduced at a dosage of 0.0005 micromol to a maximum of 10 micromol per gram of heart tissue into the isolated working rat heart under hypoxic conditions, and the response was observed during subsequent reoxygenation. As an index of external heart work, aortic flow was measured. Heart rate, coronary flow, and developed pressure were recorded. At the end of heart perfusion, mitochondria were isolated and analyzed for adenosine triphosphatase activity, adenosine triphosphate (ATP) synthesis, and membrane fluidity. Moreover, intact mitochondria and lipid peroxidation were investigated using a model system.Compared to controls, reproterol gave the most favorable results, with an increase of 25 to 30% of aortic flow during reoxygenation at a concentration of 10 micromol/g heart tissue. In contrast, both fenoterol and salbutamol at a concentration of 1 micromol/g heart tissue decreased aortic flow during reoxygenation, whereas terbutaline had a negative influence on aortic flow at 0.01 to 0.1 micromol/g heart tissue. Mitochondria of these hearts were isolated at the end of the experiment. Mitochondrial ATP synthesis was increased above controls at nearly all concentrations of reproterol. ATP synthesis was decreased at 1 micromol and 10 micromol fenoterol. As little as 0.0005 micromol terbutaline decreased ATP synthesis by 50%. In intact mitochondria, adenosine diphosphate (ADP) to oxygen ratios were found to be increased with terbutaline and fenoterol, indicating ADP consumption by myokinase activation. Lipid peroxidation was increased in a model system between concentrations of 0.002 micromol/mg and 0.04 micromol/mg phosphatidylcholine by fenoterol and terbutaline, whereas a decrease was noted with reproterol. Membrane fluidity was found increased after addition of reproterol, which supports the evidence of efficient ATP synthesis by this compound.Cardiodepressive side effects and greater toxicity of fenoterol and terbutaline were found under the conditions of our experiment. Salbutamol and, in particular, reproterol appear much better tolerated. In addition to partial beta-adrenergic agonism, reproterol may exert an inhibitory influence on adenosine receptor sites and phosphodiesterase, which could result in membrane stabilization by saving cyclic adenosine monophosphate or ATP.

Introduction Inhaled anticholinergic drugs are often recommended for use as a first-line therapy for patients with COPD because they provide similar or more effective bronchodilating actions, as well as fewer side effects. It is not known, however, which class of bronchodilators is more advantageous for pulmonary hemodynamics, particularly during exercise. Objectives To compare the effects of oxitropium and fenoterol on pulmonary hemodynamics in patients with COPD at rest and during exercise. Patients The study participants consisted of 20 consecutive male patients with stable COPD, a mean (± SD) age of 68 ± 8 years old, and an FEV 1 /FVC ratio of 47.5 ± 10.0%. Methods Eleven patients inhaled two puffs of oxitropium, and nine patients inhaled two puffs of fenoterol. Seven members of each group performed incremental exercise using a cycle ergometer. The hemodynamic measurements with right heart catheterization were performed by taking the average of three consecutive respiratory cycles before and after the administration of inhaled bronchodilators at rest and during exercise. Results At rest, despite a similar improvement of spirometric data with the two drugs, fenoterol, not oxitropium, caused significant increases in heart rate and cardiac output, a decrease in pulmonary vascular resistance, and a deteriorated Pa o 2 . During exercise, however, both drugs similarly attenuated elevations in the mean pulmonary arterial pressure (40 ± 12 to 38 ± 10 mm Hg by oxitropium, and 41 ± 9 to 36 ± 9 mm Hg by fenoterol), the mean pulmonary capillary wedge pressure, and the mean right atrial pressure. Conclusion Our findings indicate that both classes of bronchodilators are equally beneficial in the attenuation of right heart afterload during exercise in patients with COPD.

To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers.Two randomized, three-way crossover studies.Clinical research laboratory.Healthy, nonsmoking volunteers.In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany).Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p0.01).The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.

Background It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma. Methods Asthmatic patients presenting to the ED with acute severe asthma (FEV 1 less than 50% of predicted) were enrolled in a multi-center, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 µg per puff, or albuterol, 100 µg per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled β 2 -agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV 1 plateau ( ie , >10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV 1 were assessed after each dose. Results 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV 1 160 mL more than albuterol. The mean (SEM) FEV 1 increase from baseline was 0.75±0.06 L in the fenoterol group and 0.59±0.06 L in the albuterol group (p>0.03). Both β2-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23±0.04 mmol/L) than in the salbutamol (0.06±0.03 mmol/L) group (p=0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011±0.003 s compared with 0.003±0.003 s in the albuterol group (p>0.05). Differences in hypokalemia and Q-Tc prolongation associated with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group. Conclusions In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 µg per puff by MDI valved holding chamber and mask, to a total dose of 3,200 µg and salbutamol (100 µg per puff) to a total dose of 1,600 µg over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV 1 significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia. (CHEST 1996; 110:595-603)

To compare the maximal extrapulmonary effects of the beta-agonists albuterol and fenoterol in eight healthy volunteers.In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS2I]--a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuternol and fenoterol. In eight healthy volunteers, 400 microg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (+/- 0.1 mmo l/L for K+, and +/- 10 ms for QS2I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED50F) were calculated.The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p0.002), QS2I (-71.8 vs 57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p0.002). The dose required to produce the ED50f was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS2I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052).These findings suggest that albuterol behaves as a partial agonist at beta-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.

Question What is the relative per microgram potency and side effect profile of the β -agonists salbutamol and fenoterol? Method The relative bronchodilator (ΔFEV 1 , V ˙ 25, V50) potency and side effect profile (Δtremor, heart rate, breathlessness, BP) of nebulized salbutamol and fenoterol were evaluated by means of a randomized, double-blind, crossover, cumulative (50 to 2,500 µ g) dose-response study. Both β -agonists were administered to 12 patients with stable asthma over age 18 years with baseline FEV 1 between 35 to 70 percent predicted. Results (1) Salbutamol and fenoterol both provided significant bronchodilatation compared with baseline. (2) There was no dose-effect difference between the two β -agonists with respect to bronchodilator response. (3) Overall there was no significant difference between the side effect profiles of the two β -agonists, although at the highest dose of fenoterol, there was marginally greater tremor when measured by accelerometry. (4) There was no difference in the vital signs or subjective patient evaluations of tremor, palpitations, or breathlessness as estimated by a visual analogue scale. (5) No significant adverse reactions occurred. Summary and conclusion Equivalent bronchodilatation and similar side effect profiles were measured in a group of patients with stable asthma after treatment with nebulized salbutamol or fenoterol in the dose range 50 to 1,250 µ g (cumulative, 2,500 µ g). This indicates that both β -agonists have similar per microgram potency and side effect profiles. Observed clinical differences in response or side effects associated with fenoterol metered-dose inhaler administration may be a result of its higher dose per puff metered-dose inhaler formulation.

To compare aerosol delivery to the lungs in ventilated patients from two devices with holding chamber and two devices without holding chamber.A controlled clinical trial with randomization to one of four delivery devices.An academic university-affiliated Canadian ICU.Forty-eight patients undergoing mechanically assisted ventilation for a variety of clinical reasons and each judged to require inhaled bronchodilator therapy by the attending physician.Patients received 4 puffs of fenoterol labeled with technetium 99m pertechnetate delivered by metered-dose inhaler via 1 of the following: A, a 167-ml chamber device; B, a 700-ml chamber device; C, a nonchamber device (A, B, and C, all in the ventilator inspiratory line); and D, a nonchamber device on the end of the endotracheal tube.One-minute images of the thorax were made by a portable gamma camera at the bedside. Deposition of radioactivity in the lungs (uncorrected for tissue absorption and calculated as a percentage of the radioactivity delivered from 4 puffs) was 5.53 +/- 0.72 (mean +/- 1 SEM), 6.33 +/- 1.16, 1.67 +/- 0.43, and 3.89 +/- 0.52 percent for devices A, B, C, and D, respectively (p = 0.004). Subgroup analysis showed a statistically significant difference in delivery between devices A and C and between devices B and C only.There were statistically significant differences between delivery from both chamber devices and the inline nonchamber device, but not between delivery from other devices. Further work will be necessary to determine the effect of device position in the ventilator circuit on aerosol delivery.

Slow inspiratory vital capacity (IVC) and forced expiratory volume in 1 s (FEV1) before and after an inhaled beta-agonist are widely used to detect reversible airflow limitation in patients with chronic obstructive lung disease. The measurement of airways resistance (Raw) during quiet breathing with the body plethysmograph is less frequently used. It may well be of importance in clinical emphysema where measurement of FEV, is confounded by the collapse of the bronchi, which does not occur when measuring Raw during quiet breathing. We assessed whether Rrs, in addition to IVC and FEV1, can be used to gain a better insight into the reversibility with 400 mug of fenoterol in patients with clinical emphysema. We studied a group of 51 patients (9 women and 42 men; mean [+/- SD] age, 64.7 [7.7] years) who had a clinical diagnosis of emphysema. Significant reversibility was identified by spirometry (IVC, FEV1) and body plethysmography (Raw) in 20 patients (39 percent). Inspiratory vital capacity alone identified reversibility of airflow limitation in 11 patients (22 percent). In 5 patients (10 percent), the postbronchodilator improvement was seen exclusively in the Raw measurement. In the remaining patients, absence of improvement in spirometric and plethysmographic parameters was found. Subjective improvement occurred to the same extent in patients whose Raw and IVC improved. We concluded that Raw gives important information about the reversibility of airways obstruction in patients with clinical emphysema. Therefore, we suggest that tests during quiet breathing should be part of the routine examination of airways obstruction in patients with ''irreversible'' obstruction by conventional spirometry.

Undertreatment of chronic asthma may reflect uncertainty as to how it may be best controlled. We compared the effects of increased inhaled corticosteroid vs regular inhaled bronchodilator in 32 adult asthmatics. During three 16-week treatment periods, comprising baseline inhaled corticosteroid (mean 505 micrograms daily) and on-demand beta-agonist, baseline inhaled corticosteroid and increased (regularly scheduled four times daily) beta-agonist, and increased inhaled corticosteroid (mean 1478 micrograms daily) and on-demand beta-agonist, subjects recorded symptoms, morning and evening peak flow, and additional medication. Of 25 subjects whose control differed significantly between treatments with baseline vs increased corticosteroid, 22 (88 percent) favored the increased dosage (p0.001). Of 28 subjects whose control differed between treatments with regular beta-agonist vs increased corticosteroid, 24 (86 percent) were better controlled with increased inhaled corticosteroid and were worse with regular beta-agonist (p0.001). Only one quarter the number of exacerbations were experienced during treatment with increased inhaled corticosteroid. Upper airway adverse effects were minor and easily controlled. Hence, asthma with persistent symptoms was better controlled by increased inhaled corticosteroid therapy than by increased use of inhaled beta-agonist.

Two recent epidemiologic case-control studies suggested that fenoterol, a selective beta-adrenergic agonist, was associated with an increase in the risk of asthma death. The results of these studies were criticized because of methodologic problems in the choice and selection of control subjects; the different methods used to gather exposure data in cases and control subjects; and because of inadequate classification and adjustment for asthma severity. In response to this controversy, a new study is underway, the Saskatchewan Asthma Epidemiology Project. The SAEP includes two complementary studies, an historic cohort and a case-control analysis, that employ the computerized databases of the Saskatchewan Health Department. A unique aspect of the SAEP is the attempt to incorporate knowledge of asthma physiology and management into the design of the studies. Specifically, the study design recognized the role of antiinflammatory drugs in asthma treatment; the distinction between asthma death and near-fatal asthma; the severity of asthma; patterns of drug use; and the distinction between inadequate clinical care and disease severity. The strategies we employed in the SAEP may prove helpful to investigators whenever clinical and biologic processes create sources of potential bias requiring special procedures for the design and analysis of epidemiologic studies.

Impedance measurement of the respiratory system by forced oscillations is a sensitive and accurate method to detect mechanical parameters, especially in normal subjects. The effects of inhalation of 0.2 mg of fenoterol and 0.02 mg of ipratropium bromide on the impedance of the respiratory system was studied in 20 healthy subjects in a frequency spectrum between 4 and 52 Hz. Both agents caused a statistically significant decrease in resistance ( R rs). Inhalation of fenoterol and ipratropium bromide caused a significant increase in reactance (Xrs). The decrease in R rs was greater after inhalation of fenoterol than after ipratropium bromide. Fenoterol and ipratropium bromide caused qualitatively similar changes in R rs and X rs of the respiratory system. The changes in Ars can be explained by dilation of the central airways. The changes in X rs are supposed to be the result of an increase in the capacitance of the lungs.

Metered-dose aerosol treatment with fenoterol for three consecutive days, in eight patients suffering from allergic asthma, caused the disappearance of FEV1 and MEF50 circadian rhythm. We attribute such behavior to the suppression of the bronchomotor tone induced by fenoterol. The administration on different days of a single dose of fenoterol aerosol in another group of eight patients pointed out the variability of the effects of the drug at different hours of the day. We believe the results obtained are important for a better dosage and time distribution of the therapy with beta2 agonists.

The efficacy and side effects of oxitropium bromide, a new anticholinergic bronchodilator drug, were tested in a double-blind placebo-control study. Twenty-four men, aged 58 to 72 years, with chronic partially reversible obstruction of the airways were used as subjects. Three doses of oxitropium were tested (100µg, 200µg, and 300µg) to determine the optimum dose by metered-dose inhaler. A comparison was also made between oxitropium, fenoterol (400µg), and a combination of oxitropium (200µg) and fenoterol (400µg). Fenoterol produced a greater degree of maximal bronchodilatation than each of the three doses of oxitropium, and its effect was more rapid in onset (30 vs 120 minutes to peak effect); however, the duration of action of oxitropium was greater than that of fenoterol (ie, the forced expiratory volume in one second [FEV 1 ] remained within 5 percent of peak FEV 1 for three hours, compared to one hour). Oxitropium in the 100μg dose was inferior to 200µg and 30µg in subjective efficacy scores, peak percent change in FEV„ forced vital capacity, (FVC), mean forced expiratory flow over the middle half of the FVC, and duration of action; there was no difference between 200µg and 300µg. The oxitropium-fenoterol combination had a rapid onset of action, and a greater peak effect was achieved than for oxitropium alone. The main unwanted effect was a mildly unpleasant taste. Anticholinergic effects were not seen in this group of elderly men. Oxitropium bromide therefore is an effective bronchodilator with slow onset but prolonged activity and few side effects when used in patients with moderately severe obstruction of the airways. An appropriate dose appears to be 20µg. Addition of oxitropium to fenoterol appears to offer even greater efficacy.

Aerosolized fenoterol in a dosage of 400 microgram was compared to isoproterenol 150 microgram in 31 asthmatic subjects during the course of a double-blind parallel 90-day study. Bronchodilator activities of the two drugs were evaluated for up to 6 hours on days 1, 45 and 90. Analysis of the data revealed that fenoterol consistently produced a significantly greater increase in FEV1, FEF25-75% and Gaw/VL. Specific airway conductance increased on each test day 25 percent or more above baseline for over three hours after use of fenoterol and for only one hour after use of isoproterenol. Fenoterol has less effect upon the cardiovascular and central nervous systems, but produced a greater incidence of shaking compared to isoproterenol. Patients used fenoterol less frequently than isoproterenol which can be attributed to the former having a greater peak effect and time course of bronchodilation. The therapeutic efficacy of fenoterol was sustained throughout this three-month study, and suggests that this relatively selective beta2 adrenergic drug will provide a well tolerated, alternative aerosol for chronic use in asthma.

The effects of inhaling 0.4 mg of fenoterol hydrobromide (Berotec), 0.2 mg of albuterol (salbutamol), or placebo were compared in a doable-blind three-way crossover study in a group of 12 asthmatic patients. After inhalation of fenoterol, the maximum increase in the forced expiratory volume in the first second (FEV 1 ) was 0.76 L (48 percent) and in the peak expiratory flow (PEF) was 100 L/min (47 percent). The corresponding figures after inhalation of albuterol were 0.68 L (46 percent) and 98 L/min (48 percent), respectively. In comparison with administration of placebo, the FEV 1 was significantly increased until six hours after inhalation of either drug. From three to six hours after inhalation, the effect of administration of fenoterol (as measured by FEV 1 or PEF) significantly exceeded that of albuterol. Administration of either drug resulted in approximately equal bronchodilation (as measured by the increase in FEV 1 or PEF), the effect of inhalation of fenoterol being of longer duration.

The bronchoconstriction of asthma displays a circadian rhythm with exacerbations often occurring in the early morning hours. Gas exchange abnormalities during sleep in patients with severe asthma have been documented; however, the influence of sleep on gas exchange in the asthmatic with few or no daytime or nocturnal symptoms is poorly understood. To determine if abnormalities in oxygenation might occur during sleep, we studied 12 stable adult asthmatic patients with reversible airflow obstruction during sleep on three consecutive nights, with night 1 being for acclimatization. On test nights 2 and 3, the subjects received, in random double-blind fashion, either inhaled fenoterol or its placebo. Spirometry was performed before and after bronchodilator treatment and on the next morning. The mean FEV1 was 63 percent predicted before treatment. There was significant (p

In two groups of patients, 15 with asthma and 15 with chronic bronchitis, the bronchodillator effects of ipratropium bromide, of fenoterol plus theophylline, and of the combination of the three drugs, were compared using a double-blind, single-dose, placebo-controlled format Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis (ΔFEV 1 = .29 L in one hour in asthmatic patients, .18 L in patients with bronchitis). In contrast, fenoterol plus theophylline induced a considerably greater effect in asthmatic patients (ΔFEV 1 = .41 L in one hour) than in those with bronchitis (ΔFEV 1 = .07 in one hour). The use of the three drugs in combination compared with ipratropium bromide alone, or fenoterol plus theophylline alone, resuited in a significant additional bronchodilatation in asthmatic patients. In the patients with bronchitis, the triple combination was dearly superior to fenoterol plus theophylline. A similar trend was present in comparing the triple combination to ipratropium bromide, but the difference did not reach statistical significance. There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive. Asthmatic patients and the physician were able to distinguish the triple combination from placebo. No such ability was demonstrated with respect to those with bronchitis. AD three drugs were weD tolerated. Side effects were mostly mild, and none was related to the use of ipratropium.

Fenoterol hydrobromide (Berotec; formerly Th 1165a) is a sympathomimetic bronchodilator drug. Twenty subjects with mild to moderate reversible bronchospasm completed a double-blind multiple crossover study of single doses of 5 mg, 7.5 mg, and 10 mg of fenoterol hydrobromide, 24 mg of ephedrine, and placebo. Spirometric and body-plethysmographic measurements were performed sequentially prior to administration of drug or placebo and each hour up to eight hours afterwards. No significant drug-response relationship was noted for pulse rate or blood pressures, and side effects (eg, shakiness, nervousness) were minimal. Administration of fenoterol resulted in bronchodilation; a peak effect was noted at two to three hours after administration, and the duration of action was up to eight hours. A statistically significant dose-response relationship was observed; therapy with 5 mg of fenoterol hydrobromide was superior to placebo and equal to ephedrine, and doses of 7.5 mg and 10 mg of fenoterol hydrobromide were significantly better than placebo or ephedrine.

We have compared the short-term effects of buccal administration of a solution containing 500μg of fenoterol and of aerosol administration of 200μg and 400μg of fenoterol from a metered-dose inhaler with administration of a placebo in ten asthmatic subjects. The study was performed in double-blind fashion, with randomized administration of drugs or placebo, to determine if the systemic absorption of β2-adrenergic agonists from the buccal mucosa affected airways or if there were buccal β2-adrenergic receptors mediating the responses of the airways. The bronchodilatation after each treatment, assessed by the mean area (± SE) under the curve of the forced expiratory volume in one second, was as follows: placebo, 0.34 ± 0.30 L/hr; buccal administration of 500μg of fenoterol, 0.64 ± 0.20 L/hr (P > 0.05); inhalation of 200μg of fenoterol, 2.05 ± 0.36 L/hr (P

To compare the acute bronchodilator effect of increasing doses of intravenous theophylline and inhaled beta adrenergic agonists, we administered intravenous theophylline dissolved in ethylenediamine or proxyphylline and diprophylline or placebo in a double blind fashion to nine asthmatics on three different days. At each session, 100 mg theophylline or placebo were given during each of five subsequent periods of 30 minutes' duration and followed by inhalation of 0.4 mg fenoterol. In contrast to placebo, 500 mg theophylline in ethylenediamine or proxyphylline and diprophylline significantly decreased mean specific airway resistance (SRaw in cmH 2 O•s) from 31.2 to 23.6 or 34.2 to 23.5 at theophylline serum concentrations of 14.4 or 16.6 mg/L, respectively. Fenoterol lowered SRaw to about 40 percent of the respective baseline values independent of theophylline or placebo pretreatment. We conclude that the acute bronchodilator effect of theophylline is weak in comparison to inhaled beta agonists. Furthermore, proxyphylline and diprophylline cause a weak but not significant bronchodilation when compared to ethylenediamine.

1978;73;936-943 Chest Michael T. Newhouse and Richard E. Ruffin Deposition and Fate of Aerosolized Drugs http://chestjournal.chestpubs.org/content/73/6_Supplement/936.citation can be found online on the World Wide Web at: The online version of this article, along with updated information and services ) ISSN:0012-3692 http://chestjournal.chestpubs.org/site/misc/reprints.xhtml ( without the prior written permission of the copyright holder. reserved. No part of this article or PDF may be reproduced or distributed Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights of been published monthly since 1935. Copyright1978by the American College is the official journal of the American College of Chest Physicians. It has Chest

In an attempt to find the optimal single therapeutic dose of fenoterol inhalant solution administered by compressor-powered nebulization, bronchodilator and side effects of five different doses of fenoterol (0.5, 1.0, 1.5, 2.0, and 2.5 mg) and of placebo were compared with those of the recommended therapeutic dose delivered from a metered dose canister in 16 patients with reversible airway obstruction. The fenoterol (except for the metered dose) and the placebo were given in a double-blind, cross-over manner. In comparison with placebo, all doses of fenoterol produced a significant increase in average values of FEV 1 , FEF 25-75% , FVC, and SG aw and decrease in FRC for five to eight hours. There was a trend for the bronchodilator action to become greater and more prolonged with increasing doses of fenoterol. Compared with 0.4 mg given from a metered dose canister, 0.5 mg of fenoterol delivered by compressor powered nebulization was equally effective in bronchodilator potency. Dose-by-dose comparison with isoproterenol indicates that fenoterol is a more potent and longer lasting bronchodilator and has no significant effect on heart rate and blood pressures. The most common side effects were shakiness or tremor of hands, which appeared to be dose-related in terms of incidence and intensity. The results of the present study suggest that 0.5 to 1.0 mg of fenoterol is a suitable single therapeutic dose when administered by compressor-powered nebulization.

The effects of oral doses of theophylline and a s -adrenergic agonist, fenoterol, were examined in 18 asthmatic young adults. Significant bronchodilation was seen with high-dose theophylline (FEV 1 increased 14 percent) and with full 10-mg doses of fenoterol (FEV 1 increased 10 percent). Low-dose theophylline alone (130 mg) increased FEV 1 by 5 percent, but when combined with 5 mg of fenoterol, a 14 percent improvement was seen, demonstrating significant (P=.003) additive effects. The ability of the two drugs to prevent the asthmatic response to exercise was not additive. The mean fall in FEV 1 was not statistically different when subjects exercised after receiving a placebo (32 percent) 130 mg of theophylline (27 percent), or 130 mg of theophylline with 5 mg of fenoterol (18 percent). Furthermore, side effects associated with the two drags, such as tachycardia, tremor, or CNS stimulation, were significantly increased when the two drugs were given simultaneously. Thus, little therapeutic benefit was gained from simultaneous therapy. Both bronchodilation and toxicity were equivalent to that seen with larger therapeutic doses of either drug given alone, and protection from the effects of a frequently encountered stress was not significantly enhanced.

The bronchodilator response to inhaled fenoterol (400 micrograms) was examined in the morning and in the afternoon before and during oral sustained-release aminophylline treatment in eight patients with chronic reversible airway obstruction. Bronchodilatation was evaluated by measuring serial peak expiratory flow rates (PEFR) for eight hours after inhaled fenoterol and calculating the area under the time-response curves and the percentage increment from the baseline values. The patients showed an enhancement of the bronchodilatation achieved with fenoterol in the morning during aminophylline treatment. In the afternoon, instead, the effect of the fenoterol was not improved by oral aminophylline. This different effect of oral aminophylline might depend on the variable degree of potential reversibility present or diurnal variation in the bronchial response.

Comparative evaluation of the bronchodilator and cardiovascular effects of cumulative dose of fenoterol and salbutamol (albuterol) aerosols was carried out in an open crossover study on 15 patients with chronic stable reversible airways obstruction. On a weight for weight basis, there was no significant difference in the bronchodilator efficacy of fenoterol and salbutamol; though the heart rates after fenoterol were significantly higher than after salbutamol. Ventricular dysrhythmias requiring premature cessation of the study in four patients were seen with fenoterol; whereas no significant ventricular dysrhythmias were observed with salbutamol. It is concluded that salbutamol has lesser cardiostimulatory effects than fenoterol.

The effectiveness of inhaled fenoterol doses of 0.4 mg and 0.8 mg in preventing exercise-induced asthma was investigated in 12 patients. Exercise-induced asthma was prevented by both doses for two hours after administration, but the effect of neither dose was significantly different from that of placebo four hours after. There was no statistically significant difference between the effects of the two fenoterol doses; and only a few patients were protected for more than two hours by the higher dose.

The bronchoconstriction of asthma displays a circadian rhythm with exacerbations often occurring in the early morning hours. Gas exchange abnormalities during sleep in patients with severe asthma have been documented; however, the influence of sleep on gas exchange in the asthmatic with few or no daytime or nocturnal symptoms is poorly understood. To determine if abnormalities in oxygenation might occur during sleep, we studied 12 stable adult asthmatic patients with reversible airflow obstruction during sleep on three consecutive nights, with night 1 being for acclimatization. On test nights 2 and 3, the subjects received, in random double-blind fashion, either inhaled fenoterol or its placebo. Spirometry was performed before and after bronchodilator treatment and on the next morning. The mean FEV1 was 63 percent predicted before treatment. There was significant (p less than 0.05) improvement in FEV1 on fenoterol night after treatment which was also present the next morning. Mean prefenoterol FEV1 was 2.04 +/- .15 (SEM) and increased to 2.61 +/- .17 after the bronchodilator. The mean morning FEV1 was 2.27 +/- .20. Mean preplacebo FEV1 was 2.07 +/- .12 and did not change significantly with placebo bronchodilator. Sleep analysis demonstrated no significant differences in total sleep time or duration of oxyhemoglobin desaturation between nights. The incidence of sleep disordered breathing was very low (0.14 apneas/hour). The frequency of apneas and hypopneas did not change significantly with treatment. Two of the 12 subjects experienced an asthma attack on placebo night which did not recur following active bronchodilator administration. We conclude that stable asthmatic patients with few nocturnal complaints have a low frequency of disordered breathing and desaturation events during sleep.

The effectiveness of inhaled fenoterol doses of 0.4 mg and 0.8 mg in preventing exercise-induced asthma was investigated in 12 patients. Exercise-induced asthma was prevented by both doses for two hours after administration, but the effect of neither dose was significantly different from that of placebo four hours after. There was no statistically significant difference between the effects of the two fenoterol doses; and only a few patients were protected for more than two hours by the higher dose.

Bronchodilator and side effects of fenoterol hydrobromide (Th1165a; hydroxyphenylorciprenaline; Berotec) and isoproterenol given by inhalation were compared in a double-blind crossover study involving 20 volunteer subjects with reversible obstructive disease of the airways. Subjects inhaled medications from aerosol canisters containing fenoterol hydrobromide (0.1 mg, 0.2 mg, or 0.4 mg) or isoproterenol (0.15 mg) or an inert placebo propellant in a random sequence of five testing days. All active drugs substantially increased the forced expiratory volume in one second, the mean forced expiratory flow during the middle half of the forced vital capacity, and the specific conductance. The onset of bronchodilation after both fenoterol and isoproterenol was rapid, but the effect from fenoterol lasted much longer, up to eight hours. None of the medications caused significant tachycardia or hypertension. After inhalation of 0.1 mg of fenoterol hydrobromide, none of the subjects reported nervousness, headache, tremor, or nausea, in contrast with results reported for isoproterenol, higher aerosol doses of fenoterol, or oral administration of fenoterol. No additional therapeutic benefit was found in the administration of higher doses of fenoterol.

It has been stated that body plethysmography is the most sensitive test for evaluating bronchodilators, and that from spirometry, the FEF25–75% is the most sensitive of the indices. To test these statements, the FEV 1 , FCV, FEV 1 /FVC%, FEF25–75%, Gaw/V L and Raw were evaluated for their ability to separate different drug regimens. Twenty patients with reversible airway disease were randomly given fenoterol 400, 200, or 100 µ g; isoproterenol 150 µ g; and placebo in a double blind crossover study. Pulmonary function tests were obtained serially at predetermined time intervals. When the time-weighted mean percentage improvements were compared, it was found that the Gaw/V L improved the most, followed by the FEF25–75%, FEV 1, Raw and FVC. However, with analysis of variance, the following F values for the differences between drugs were found: FEV 1 , 10.14; Raw, 8.56; FVC, 7.82; Gaw/V L , 6.09; FEF25–75%, 5.17 suggesting that the FEV 1 was the best test Moreover, when comparisons between drugs were made, the FEV 1 yielded more statistically significant differences (seven) than did the Gaw/V L (five), FEF25–75% (five), and Raw (six). In no drug comparison did plethysmography or the FEF25–75% allow more or different conclusions than did the FEV 1 . Analysis of variance separately at each time yielded similar results. It is concluded that the FEV 1 is the best test for evaluating the response to bronchodilators in patients and that use of body plethysmography and the FEF25–75% do not allow any more conclusions than can be made with the FEV 1 and FVC alone.

In an attempt to find the optimal single therapeutic dose of fenoterol inhalant solution administered by compressor-powered nebulization, bronchodilator and side effects of five different doses of fenoterol (0.5, 1.0, 1.5, 2.0, and 2.5 mg) and of placebo were compared with those of the recommended therapeutic dose delivered from a metered dose canister in 16 patients with reversible airway obstruction. The fenoterol (except for the metered dose) and the placebo were given in a double-blind, cross-over manner. In comparison with placebo, all doses of fenoterol produced a significant increase in average values of FEV1, FEF25-75%, FVC, and SGaw and decrease in FRC for five to eight hours. There was a trend for the bronchodilator action to become greater and more prolonged with increasing doses of fenoterol. Compared with 0.4 mg given from a metered dose canister, 0.5 mg of fenoterol delivered by compressor powered nebulization was equally effective in bronchodilator potency. Dose-by-dose comparison with isoproterenol indicates that fenoterol is a more potent and longer lasting bronchodilator and has no significant effect on heart rate and blood pressures. The most common side effects were shakiness or tremor of hands which appeared to be dose-related in terms of incidence and intensity. The results of the present study suggest that 0.5 to 1.0 mg of fenoterol is a suitable single therapeutic dose when administered by compressor-powered nebulization.

Three doses of fenoterol were administered by metered-dose inhaler to 20 adult subjects with asthma in order to determine the optimal dose for routine administration. Inhaled doses of 100 micrograms, 200 micrograms, and 400 micrograms of fenoterol with isoproterenol and placebo controls were administered in a randomized double-blind crossover regimen. We found that 200 micrograms of fenoterol by metered-dose inhaler produced a longer duration of action, greater peak response, and greater overall time-weighted responses in the forced expiratory volume in one second, in the mean forced expiratory flow during the middle half of the forced vital capacity, and in airway resistance than did the other drug regimens. The 400 micrograms dose of fenoterol produced no increase in response over that seen after the 200 micrograms dose. Side effects were minimal and no greater than with isoproterenol.