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27-year-old woman was admitted to a large teaching hospital with a 3-day history of increasing breathlessness, wheeze, and nonproductive cough. She was known to have asthma, which was managed by her family physician with budesonide 200 m g formoterol 6 m g Turbuhaler (AstraZeneca, PLC; London, England) two inhalations twice daily and terbutaline 500 m g Turbuhaler as required . She admitted to poor compliance with her medication and had only started retaking her treatment in the week prior to admission. In the previous 5 years, she had two hospital admissions for mild exacerbations of asthma, both of which had settled within 2 days. She had received no further courses of corticosteroids. She was otherwise healthy with no history of diabetes mellitus or alcohol excess. She had a 3 pack-year smoking history, having stopped smoking 6 months prior to admission.

Study objective To compare the acute bronchodilatory effect of the long-acting β 2 -agonist formoterol against the short-acting β 2 -agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma. Design A randomized, double-blind, placebo-controlled, crossover study of the immediate effect of formoterol, 9 μg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction. Patients Twenty-four 7- to 15-year-old children with persistent asthma. Interventions The children performed standardized treadmill exercise tests, breathing dry air, with a submaximal workload. Study medication was administered 5 min after exercise if FEV 1 dropped ≥ 15% within 5 min after exercise. FEV 1 and forced expiratory flows were measured repeatedly until 60 min after dose. Results Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dose compared with placebo (p 1 5 min after dose (p = 0.15), with a mean increase from each predrug baseline of 62% of the maximum increase for both. Median times to recovery within 5% of baseline FEV 1 were 5.0 min and 7.4 min for formoterol and terbutaline, respectively (p = 0.33). Conclusion Single-dose formoterol, 9 μg, via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB in schoolchildren with persistent asthma. Formoterol is at least as effective as SABA and may be considered an alternative in the treatment of acute bronchoconstriction in school children.

Objective: The study was undertaken to investigate the influence of once-daily treatment with montelukast (Singulair; MSD; Glattbrugg, Switzerland) on levels of exhaled nitric oxide (eNO) and lung function in preschool children with asthma. Methods: A total of 30 children (19 girls), 2 to 5 years of age, in whom asthma had been newly diagnosed, who had a positive first-degree family history of asthma and a positive allergy test result, were allocated to undergo a 1-week run-in period of montelukast treatment. eNO and airway resistance were measured in all patients before (visit 1) and after the run-in period (visit 2), and after treatment with montelukast (4 mg once daily) for 4 weeks (visit 3). Results: There were no significant differences in all parameters before and after the run-in period. However, the mean (SD) levels of eNO and the mean (SD) levels of airway resistance after treatment at visit 3 were 11.6 parts per billion (ppb) [9.5 ppb] and 1.15 kPa/L/s (0.26 kPa/L/s), respectively, and were significantly lower compared to values of 33.1 ppb (12.0 ppb) and 1.28 kPa/L/s (0.23 kPa/L/s), respectively, before treatment (p < 0.001) and at visit 2 (p 0.01). There was no significant change in mean bronchodilator responsiveness between visit 3 (13.2%; SD, 6.8%) and visit 1/visit 2 (13.3%; SD, 7.0%; p 0.47). Conclusion: We have shown that montelukast has a positive effect on lung function and airway inflammation as measured by nitric oxide level in preschool children with allergic asthma. (CHEST 2005; 127:509–514)

Objective To determine the utility of inhaled hypertonic saline solution to treat ambulatory infants with viral bronchiolitis. Design Randomized, double-blind, controlled trial. Sixty-five ambulatory infants (mean ± SD age, 12.5 ± 6 months) with viral bronchiolitis received either of the following: inhalation of 0.5 mL (5 mg) terbutaline added to 2 mL of 0.9% saline solution as a wet nebulized aerosol (control; group 1; n = 32) or 0.5 mL (5 mg) terbutaline added to 2 mL of 3% saline solution administered in the same manner as above (treatment; group 2; n = 33). This therapy was repeated three times every day for 5 days. Results The clinical severity (CS) scores at baseline on the first day of treatment were 6.4 ± 1.8 in group 1 and 6.6 ± 1.5 in group 2 (not significant). After the first day, the CS score was significantly lower (better) in group 2 as compared to group 1 on each of the treatment days (p Fig 1 ). On the first day, the percentage decrease in the CS score after inhalation therapy was significantly better for group 2 (33%) than for group 1 (13%) [p Fig 1 ]. On the second day, the percentage improvement was better in the hypertonic saline solution-treated patients (group 2) as compared to the 0.9% saline solution-treated patients (group 1) [p = 0.01; Fig 1 ]. Conclusions We conclude that in nonasthmatic, nonseverely ill ambulatory infants with viral bronchiolitis, aerosolized 3% saline solution plus 5 mg terbutaline is effective in decreasing symptoms as compared to 0.9% saline solution plus 5 mg terbutaline.

Study objectives: To assess whether IVmethylprednisolone exerts a specific early effect on dyspnea inpatients with an exacerbation of asthma. Design: Randomized, placebo-controlled, double-blind crossover trial. Setting: Medium-sized university general hospital. Patients: Twenty-five asthma patients attending the chestclinic with spontaneous complaints of increases in dyspnea and with a, Borg scale dyspnea rating ≥ 1 at rest. Interventions: At 0 min, IV methylprednisolone (125 mg) vssaline solution; at 60 min, 5 × 500 μg terbutaline inhaled from aninhaler device. Measurements and results: Change indyspnea was assessed with bipolar visual analog scale (VAS) (much moreshort of breath, −100%; much less short of breath, + 100%),FEV1, and visual memory (using the Benton visual retentiontest). Eighteen subjects (mean age, 61 years) completed the study. At 5min and 60 min, shortness of breath improved with no statisticallysignificant difference between saline solution and methylprednisolone. The mean (SD) VAS rating at 60 min was 29% (39%) on the day thatsaline solution was administered and 36% (25%) on the day the steroidwas administered. FEV1 and Benton score did notsignificantly change from baseline on either study day. Shortness ofbreath and FEV1 improved following terbutalineadministration, with no significant difference between the days onwhich saline solution and the steroid were administered. In the sevensubjects who were randomized to receive methylprednisolone on the firstday, baseline dyspnea rated on the Borg scale was significantly loweron the second day (first day: median, 3; range, 3 to 4; second day: median, 2; range, 0.5 to 3; p=0.040). Conclusions: We conclude that in patients with an exacerbation of asthma, an IVbolus of methylprednisolone does not reduce dyspnea more than salinesolution after 5 min and 60 min.

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)

Purpose During the past 10 years, the acoustic analysis of breath sounds has been used as a diagnostic tool in patients suffering from obstructive respiratory diseases. Acoustic analysis might be able to monitor the response to bronchodilator therapy in a clinical setting. So far, few studies have been carried out in asthmatic patients. To assess the responses of a sampling of asthma patients to an inhaled bronchodilator (terbutaline) by means of spectral analysis of the tracheal sound performed during forced expiratory maneuvers. Material and methods Seventeen nonsmoking asthma patients (9 were male, 8 were female) who had been suffering from the disease for ≥ 15 years were included in the study, as were 15 normal subjects (7 were male, 8 were female). The average age (± SD) was 56.5 ± 15.2 years (FVC, 2.7 ± 0.9 L[63.4%]; FEV 1 , 1.5 ± 0.6 L [53.0%]). The tracheal sounds were collected during three forced expiratory maneuvers with a sampling frequency of 5,000 Hz and were analyzed by applying a 16-parameter autoregressive model. Results The centroid frequency decreased after the bronchodilator was given at different flow segments between 1.2 and 0.4 L/s, with significant changes between 0.6 and 0.4 L/s. Conclusions Patients with asthma showed changes in the spectral acoustic analysis frequencies after the administration of a bronchodilator drug (terbutaline) during forced expiratory maneuvers.

An open, randomized, parallel-group study was conducted to investigate whether asthmatic patients, considered adequately treated with a corticosteroid and/or short-acting beta 2-agonist via pressurized metered-dose inhaler (pMDI), could be transferred to a corresponding nominal dose of budesonide and/or terbutaline via Turbuhaler, an inspiratory flow-driven multidose dry powder inhaler (Astra Draco; Lund, Sweden), without a decrease in the effect of treatment. One thousand four patients (555 women; mean age, 44 years; mean peak expiratory flow [PEF], 102% predicted normal value) were randomized and treated with either pMDI (current therapy) or Turbuhaler for 52 weeks. The variables studied were asthma-related events, morning PEF, and inhaler-induced clinical symptoms. Asthma-related events were defined in two ways: (1) sum of health-care contacts plus doublings or additions of steroids, and (2) number of 2 consecutive days with PEF less than 80% of baseline. Baseline was obtained from a 2-week run-in period while receiving previous therapy. No statistically significant difference was found in asthma-related events according to definition 1. According to definition 2, there was a statistically significant difference between the groups in favor of Turbuhaler (p = 0.008). The mean number of events was 1.7 with Turbuhaler and 2.2 with pMDI. The mean number of weeks per patient with a PEF less than 90% of baseline was 4.5 with Turbuhaler compared with 6.0 with pMDI (p = 0.002). The sum of inhaler-induced symptoms after 1 year of use was statistically significantly lower with Turbuhaler (0.40) than with pMDI (0.75) (p = 0.0001). In conclusion, budesonide and terbutaline in Turbuhaler offered a superior alternative to corticosteroids and bronchodilators delivered by pMDIs in the maintenance treatment of asthma.

Background: The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. Phase 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta(2)-agonist plus inhaled corticosteroid (BA+CS) was more effective in improving the FEV(1) and the provocative concentration of histamine causing a 20% reduction in FEV(1) (PC20) than treatment with a beta(2)-agonist plus anticholinergic (BA+AC) or placebo (BA+PL). Phase 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 mu g beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA+/-AC) could also improve FEV(1) and PC20 to the same degree, A distinction was made between patients with predominantly asthma (high baseline reversibility, Delta FEV(1) greater than or equal to 9% of predicted), and predominantly COPD (low baseline reversibility, Delta FEV(1) Results: Improvement of FEV(1) percent predicted by inhaled CS was comparable both in the asthmatics between phase 1 (13.8% predicted) and phase 2 (8.5% predicted; p=0.13) as well as in the patients with COPD (2.5% and 1.5% predicted, respectively), PC20, however, increased significantly more in the asthmatics in phase 1 (1.77 doubling concentration [DC]) than in phase 2 (0.79 DC; p=0.03). Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 (0.74 DC) than in phase 2 (0.00 DC; p=0.19). Conclusions: Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV(1), improvements in PC20 are significantly less. These findings in patients with longer-existing asthma concur with other findings in newly detected asthma. We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility.

Once-daily morning (7 AM) vs evening (10 PM) administration of the terbutaline prodrug bambuterol (20-mg tablet dose) was investigated in a double-blind, cross-over, randomized, and placebo-controlled study involving 29 diurnally active patients with asthma. Terbutaline plasma concentration, spirometry, and drug tolerance were assessed during 39-h inpatient studies. A 7-day washout period separated each treatment. Mean 24-h plasma concentration was comparable for morning and evening bambuterol (13.2 vs 14.0 nmol/L). The Cmax for evening vs morning dosing was 17.2 vs 15.5 nmol/L (p < 0.02). The 24-h mean FEV1 was greater (p < 0.001) for bambuterol (morning: 3.2 L; evening: 3.4 L) vs placebo (2.9 L) as it was for FVC, FEF25-75%, and peak expiratory flow rate (PEFR), with the maximum effect at 4 AM independent of medication time. Evening dosing, however, resulted in greatest 7 AM (awakening) FEV1, FEV25-75, and PEFR (p < 0.03). With reference to corresponding-in-time placebo values, improvement in FEV1 at the end of the 24-h dosing intervals amounted to 0.34 L (13.5%) (p < 0.0004) and 0.35 L (15.9%) (p < 0.0012) with evening and morning bambuterol dosing, respectively. Side effects were greater for bambuterol than placebo, but not significantly so. Once-daily bambuterol therapy proved to be an effective treatment for asthma, whether administered in the evening or morning. Evening dosing seems best for nocturnal asthma since airway patency overnight and on awakening at 7 AM is most improved.

beta-Adrenergic agonists are useful for the emergency treatment of asthma. Recently, magnesium sulfate (MgSO4) has also been shown to be efficacious in this situation. beta-Agonists have unwanted cardiovascular and metabolic actions: increased systolic blood pressure, corrected QT interval (QTc), serum glucose and insulin, and decreased RR interval, diastolic blood pressure, serum potassium, phosphate, and calcium. As beta-agonists and MgSO4 quite possibly will be used in combination, we sought to determine how MgSO4 would affect these actions. Healthy young male adults were administered two doses of terbutaline sulfate, 0.25 mg subcutaneously, 30 min apart on two separate occasions, in a randomized, double-blind fashion. On one occasion, 4 g of MgSO4 was administered intravenously over the same 30-min period. On the other, normal saline solution was given as a placebo. Cardiovascular and metabolic variables were measured sequentially for 2 h. Data at 60 min with p values given for a summation of all time points are as follows: MgSO4 increased terbutaline's effects on the RR interval by 0.09 s, p0.0001; QTc interval by 0.01 s, p0.0007; diastolic blood pressure by 8 mm Hg, p = 0.0001; serum calcium by 0.13 mg/dl, p = 0.01; and glucose by 9 mg/dl, p0.0001. MgSO4 also mitigated the systolic blood pressure elevating the effect of terbutaline by 5 mm Hg (p = 0.007). The magnitude of the response potentiations was modest. We conclude that combining terbutaline and MgSO4 is unlikely to result in serious short-term adverse events, if used acutely in patients with relatively normal cardiac and metabolic function. MgSO4 may act by potentiating the effect of beta-agonists on magnesium requiring enzymes such as adenyl cyclase.

Introduction Positive expiratory airway pressure seems to dilate narrowed or collapsed airways, but this may be accompanied by a maintained and harmful increase in resting lung volume in obstructive pulmonary disease. Purpose To evaluate the influence of inhaled terbutaline and positive expiratory pressure (PEP) on airway resistance (Raw) and functional residual capacity (FRC) in bronchial asthma. Design Randomized crossover design, single blind with regard to inhaled medication, open with regard to PEP (PEP can be felt). Material and Methods Ten patients with bronchial asthma inhaled placebo and terbutaline in doses of 0.125 mg, 0.5 mg, and 1.5 mg by cone spacer combined with a facemask giving 0, 10, or 15 cm H 2 O PEP on separate days. FRC and Raw were measured by body plethysmography before and after inhalations. Data were analyzed by analysis of variance with terbutaline dose and PEP as factor levels. Results The effect of terbutaline: Raw decreased significantly (p 2 O, mean 0.6 (95 percent CI: —1.1, — 0.2) and 0.9 (95 percent CI: —1.3, — 0.4) cm H 2 O/L/s. The FRC did not change significantly with the PEP level. Conclusion PEP only had influence on Raw when insufficient doses of terbutaline were inhaled, whereas once an efficient dose of terbutaline was administered, significant bronchodilation was achieved with or without PEP. Positive expiratory pressure did not increase FRC.

A new long-acting bronchodilator prodrug, bambuterol hydrochloride, was tested in a randomized, crossover, and double-blind study in elderly asthmatic patients (aged 64 to 82 years). They received placebo and 5-mg, 10-mg, and 20-mg tablets once daily for a week at each dose. The plasma concentration of the active metabolite, terbutaline, increased linearly with the dose of drug (p0.001). Peak expiratory flow rate increased with dose in the morning (p0.001 for 10-mg and 20-mg doses) and afternoon (p0.05 for 10 mg; p0.001 for 20 mg) and was different from placebo for the 10-mg/d and 20-mg/d regimens. The use of supplemental inhaled beta 2-adrenergic agonist therapy was reduced during the night for the 10-mg (p0.05) and 20-mg (p0.01) doses in comparison to placebo. No significant effects of treatment on blood pressure and pulse were demonstrated. Tremor and palpitations were mild and related to the dose. These data suggest that treatment once daily with bambuterol hydrochloride in a dose of 10 or 20 mg improves pulmonary function and is well tolerated as bronchodilator therapy in elderly patients with asthma.

To investigate whether enalapril (E) 10 mg and spironolactone (S) 100 mg attenuate the hypokalemic effect of inhaled terbutaline (T).Randomized single-blind crossover. Subjects received the following treatment combinations: (a) placebo (P), (b) T alone, (c) T + E, or (d) T + S.University Department of Clinical Pharmacology.Twenty healthy volunteers (ten male, ten female) of mean age 22.8 +/- 3.1 years.Serum potassium, magnesium, ECG changes (R-R interval, T wave, and QTc interval) for 4 h after terbutaline inhalation.Baseline serum potassium levels were higher following prior treatment with E and S; P, 3.78 mmol/L (3.67 to 3.88); T + E, 3.93 mmol-1 (3.82 to 4.03); and T + S, 4.03 mmol/L (3.93 to 4.14) (p less than 0.05). Mean potassium concentrations over 4 h were also higher following prior treatment with E and S; T, 3.58 mmol/L (3.54 to 3.63); T + E, 3.68 mmol/L (3.64 to 3.72) (p less than 0.05); and T + S, 3.73 mmol/L (3.68 to 3.78) (p less than 0.01).Enalapril and spironolactone protect against the fall in serum potassium over 4 h by elevating baseline potassium concentration. These potassium-sparing drugs, however, should not be used to prevent the hypokalemic and electrocardiographic sequelae of inhaled beta 2-agonists.

In order to investigate whether treatment with terbutaline (1 mg subcutaneously) in patients with bronchial obstruction is accompanied by changes in the densities of receptors of the autonomic nervous system, β-adrenergic receptors or m-cholinergic receptors were measured in membrance preparations of human peripheral lung tissue from patients undergoing lung resection for bronchial carcinoma. The density of β-adrenergic receptors and mononuclear leukocytes (MNLs) of treated and untreated patients and β-adrenergic receptors and m-cholinergic receptors in lung strips from the same patients exposed to terbutaline in vitro were studied for comparison. In patients, treatment with terbutaline did not have any effect on human lung β-adrenergic receptors and m-cholinergic receptors, whereas a 57 percent decline was measured in the number of β-receptors on MNLs of the very same patients. In contrast, in vitro exposure of human peripheral lung strips to terbutaline (100 μmol/L for 36 hours) evoked a time-dependent and concentration-dependent decline of 46 percent in β-adrenergic receptors. Again, there was no change in the number of m-cholinergic receptors. The antagonist affinities, as judged from the K D values, did not differ under either condition. We concluded that lung β-adrenergic receptors are subject to down-regulation when exposed to agonists in vitro. This down-regulation in the human lung is not accompanied by alterations in m-cholinergic receptors. Down-regulation of β-adrenergic receptors or upregulation of m-cholinergic receptors appears not to play a role in the proposed tolerance to β-adrenergic receptor agonist treatment in clinical situations. The reduction of β-adrenergic receptors in MNLs provides evidence that treatment with terbutaline was sufficient to affect β-adrenergic receptors in vivo in certain cell types but also shows that alterations in blood cells do not necessarily reflect the situation in the lung.

The influence of positive expiratory pressure (PEP) applied during inhalation of a beta 2-agonist in treatment of bronchial asthma was investigated in a randomized crossover study with two-week treatment periods. In one period, two puffs (0.5 mg) of terbutaline was given from a metered dose inhaler and inhaled through a device consisting of a conespacer connected to a facemask giving PEP (10 to 15 cm H2O). In a second period, terbutaline 0.5 mg was inhaled similarly but without PEP, and in a third period placebo spray was inhaled with PEP. Treatments were given three times daily. Peak expiratory flow (PEF) was measured before and after each inhalation and symptom scores for dyspnea, cough, and mucus production were noted in a diary. All treatments increased PEF significantly (p less than 0.0001). The mean increase was 32 L/min during treatment with terbutaline and PEP. This was greater than the increase of 25 L/min during terbutaline treatment (p = 0.005). The increase in PEF during terbutaline treatment was significantly higher than the achieved 18 L/min during PEP (p = 0.026). The study showed improved bronchodilation when PEP was combined with inhalation of beta 2-agonist compared with beta 2-agonist alone.

Beta 2-adrenoceptor agonists act against bronchoconstriction by stimulating beta 2-adrenoceptors in bronchial smooth muscle. However, tachyphylaxis has been argued to occur because of beta 2-adrenoceptor down-regulation following therapy with beta 2-adrenergic agents. To investigate receptor alterations, human peripheral mononuclear leukocytes are frequently used, since human lung tissue is not easily available. In order to study whether beta 2-adrenoceptors in MNL reliably reflect the conditions in the human lung tissue, we compared MNL and human lung tissue of 18 patients who had to undergo lung resection. Ten patients were untreated, and eight had bronchodilator therapy prior to therapy with terbutaline because of bronchoconstriction. Both in human lung and MNL, the beta 2-adrenoceptor subpopulation was characterized by competition experiments with the beta 1-selective antagonist CGP 207.12 A and the beta 2-selective antagonist ICI 118.551. In MNL, a significant decrease in the density of beta 2-adrenoceptors was found in treated but not in untreated patients, while the antagonist affinity of the beta 2-adrenoceptors remained unchanged. However, in lung parenchyma, which was obtained at the very same time from the same patients, no down-regulation of the total amount of beta 2-adrenoceptors could be measured. It is concluded that MNLs are a reliable model for studying properties of beta 2-adrenoceptor regulation. However, the hereby obtained results show that MNLs do not reflect the conditions of beta 2-adrenoceptors in human lung tissue. Human lung tissue is found to be less susceptible than human MNL for beta 2-adrenoceptor down-regulation by terbutaline treatment at therapeutic doses.(ABSTRACT TRUNCATED AT 250 WORDS)

A fixed combination of long-acting beta(2)-agonists (LABA) plus inhaled corticosteroids (ICS) has never been proven to reduce asthma exacerbations vs ICS alone in children. This 12-month, double-blind, randomized study in 341 children (age range, 4 to 11 years) with asthma uncontrolled on ICS investigated whether a novel regimen using budesonide/formoterol for maintenance and reliever therapy (Symbicort maintenance and relief therapy [SMART]) [Symbicort; AstraZeneca RD, Lund, Sweden] could reduce exacerbations.Patients received SMART (budesonide/formoterol 80/4.5 microg qd maintenance plus additional inhalations for symptom relief), budesonide/formoterol 80/4.5 microg qd for maintenance (fixed combination), or higher-dose budesonide 320 microg qd (fixed-dose budesonide). Blinded as-needed medication (terbutaline 0.4 microg) was provided in both fixed-dose groups.SMART prolonged the time to first exacerbation vs fixed-dose budesonide (p = 0.02) and fixed-dose combination (p0.001). Rates of exacerbation requiring medical intervention were reduced by 70 to 79% with SMART vs fixed-dose budesonide and fixed-dose combination (0.08/patient vs 0.28/patient and 0.40/patient, respectively; both p0.001). Mild exacerbation days and awakenings were significantly lower with SMART; yearly growth improved by 1.0 cm vs fixed-dose budesonide (p0.01).The SMART regimen using budesonide/formoterol for both maintenance and as-needed symptom relief reduces the exacerbation rate compared with both fixed-dose combination and higher fixed-dose ICS alone in children with asthma.

To compare a novel asthma management strategy--budesonide/formoterol in a single inhaler for both maintenance therapy and symptom relief--with a higher dose of budesonide plus as-needed terbutaline.This was a 6-month, randomized, double-blind, parallel-group study in patients with mild-to-moderate asthma (n = 697; mean age, 38 years [range, 11 to 79 years]; mean baseline FEV1, 75% of predicted; mean inhaled corticosteroid [ICS] dosage, 348 microg/d). Following a 2-week run-in period, all patients received two blinded, dry powder inhalers, one containing maintenance medication and one containing medication to be used as needed for the relief of symptoms. Patients were randomized to receive either budesonide/formoterol (80 microg/4.5 microg, two inhalations qd) for maintenance plus additional inhalations as needed for symptom relief, or budesonide (160 microg, two inhalations qd) for maintenance medication plus terbutaline (0.4 mg) as needed. The primary efficacy variable was morning peak expiratory flow (PEF).Patients receiving budesonide/formoterol showed greater improvements in morning PEF than patients receiving budesonide (increases of 34.5 L/min vs 9.5 L/min, respectively; p0.001). The risk of having a severe exacerbation (hospitalization/emergency department [ED] treatment, oral steroids for asthma, or aor = 30% decrease from baseline in morning PEF on 2 consecutive days) was 54% lower with budesonide/formoterol vs budesonide (p = 0.0011). Budesonide/formoterol patients experienced 90% fewer hospitalizations/ED treatments due to asthma than budesonide patients (1 vs 10, respectively; p = 0.026). The increased efficacy with budesonide/formoterol was achieved with less ICS than was used in the budesonide group (mean dose, 240 microg/d vs 320 microg/d, respectively) and with 77% fewer oral steroid treatment days vs budesonide (114 days vs 498 days, respectively). Both treatments were well tolerated.Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline.

Study objectives: Wheezing is a common clinical finding in patients with asthma and COPD during episodes of severe airway obstruction, and can also be heard in normal subjects during forced expiratory maneuvers; however, the properties of wheezing are difficult to perceive and quantify during auscultation. We therefore developed and evaluated a new technique for recording and analyzing wheezing during forced expiratory maneuvers in a group of patients with obstructed airways (asthma, COPD) and a control group of healthy subjects. Material and methods: Sixteen patients with asthma (9 men and 7 women), 6 patients with COPD (6 men), and 15 healthy subjects (7 men and 8 women) were enrolled. The patients had moderate-to-severe obstruction (FEV1 of 40 to 53% predicted). A contact sensor on the trachea was used to record sound during forced expiratory maneuvers. Wheeze detection was carried out by a modified algorithm in a frequency-time space after applying the fast Fourier transform. Results: More wheezes were recorded in patients with obstructed airways than in control subjects: asthma patients, 8.4 6.4 wheezes; COPD patients, 10.4 6.1 wheezes; and control subjects, 2.9 2.0 wheezes (mean SD). The mean frequency of all detected wheezes was higher in control subjects than in patients with obstructed airways (asthma patients, 560.9 140.8 Hz; COPD patients, 669.4 250.1 Hz; and control subjects, 750.7 175.7 Hz). The total number of wheezes after terbutaline inhalation changed more in patients with obstructed airways than in control subjects. Conclusions: The new method that we describe for studying airway behavior during forced expiratory maneuvers is able to identify and analyze wheeze segments generated in patients with obstructed airways, as evidenced by the greater number of wheezes detected in the patient group, the main finding of this study. This method clearly and objectively identifies the presence of obstructive disease. (CHEST 2002; 122:186 –191)

Objectives Treatment with inhaled corticosteroids reduces bronchial hyperresponsiveness and relieves airways obstruction in patients with asthma. Up to now, it is unknown whether initial improvements are maintained over a long period of time. Therefore, we assessed whether initial improvements in FEV 1 , provocative concentration of histamine causing a 20% fall in FEV 1 (PC 20 ), and peak expiratory flow (PEF) persist with a constant dose of inhaled corticosteroids. Furthermore, we investigated whether FEV 1 , PC 20 , PEF indexes, and symptom scores improve after increasing the dose of inhaled corticosteroids in patients who did not respond sufficiently to treatment with beclomethasone dipropionate (BDP), 800 μg/d. Methods Sixty-eight patients with bronchial hyperresponsiveness and airways obstruction completed a previous study on 3 years of treatment with terbutaline, 500 μg qid, and BDP, 200 μg qid. Fifty-eight of these patients participated in the current extension of another 2.5 years of follow-up. Every 6 months, FEV 1 and PC 20 were measured. Five patients dropped out of the study, one for pulmonary reasons. Forty-four patients continued treatment with BDP, 800 μg/d (BDP-800 group), and 9 patients received a higher dose of BDP (500 μg tid; BDP-1,500 group) after the first 3 years because of a rapid decline in FEV 1 (> 50 mL/yr) despite BDP treatment during the previous study period. Results After the initial improvement, the mean slope of individual regression lines for FEV 1 , PC 20 , and morning PEF were − 28 mL/yr,− 0.01 doubling concentrations per year, and 0.6 L/min/yr, respectively, in the BDP-800 group. In the BDP-1,500 group, there were no statistically significant improvements in FEV 1 , PC 20 , PEF indexes, and symptom scores after increasing the dose of BDP. Conclusions We conclude that initial improvements in FEV 1 , PC 20 , and PEF are well preserved over 5 years in patients with obstructive airways diseases who are treated with terbutaline and BDP. In the patients who responded sufficiently to 800 μg/d of BDP, there was no accelerated decline in FEV 1 compared with the general population. Increasing the dose of BDP in a small group of patients with an accelerated fall in FEV 1 (initially treated with a moderate dose of BDP) resulted in no significant improvement in FEV 1 , PC 20 , PEF indexes, and symptom scores.

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.

During the past 10 years, the acoustic analysis of breath sounds has been used as a diagnostic tool in patients suffering from obstructive respiratory diseases. Acoustic analysis might be able to monitor the response to bronchodilator therapy in a clinical setting. So far, few studies have been carried out in asthmatic patients. To assess the responses of a sampling of asthma patients to an inhaled bronchodilator (terbutaline) by means of spectral analysis of the tracheal sound performed during forced expiratory maneuvers.Seventeen nonsmoking asthma patients (9 were male, 8 were female) who had been suffering from the disease foror = 15 years were included in the study, as were 15 normal subjects (7 were male, 8 were female). The average age (+/- SD) was 56.5 +/- 15.2 years (FVC, 2.7 +/- 0.9 L [63.4%]; FEV1, 1.5 +/- 0.6 L [53.0%]). The tracheal sounds were collected during three forced expiratory maneuvers with a sampling frequency of 5,000 Hz and were analyzed by applying a 16-parameter autoregressive model.The centroid frequency decreased after the bronchodilator was given at different flow segments between 1.2 and 0.4 L/s, with significant changes between 0.6 and 0.4 L/s.Patients with asthma showed changes in the spectral acoustic analysis frequencies after the administration of a bronchodilator drug (terbutaline) during forced expiratory maneuvers.

Aerosolized beta2-agonists have been associated with increased morbidity in asthmatics. These drugs cause transient increases in heart rate and decreases in serum potassium levels after these drugs are first utilized. This study is designed to elucidate whether beta-adrenergic tolerance to the hemodynamic, cardiac, and electrolyte effects of inhaled terbutaline occurs during 14 days of maintenance therapy.Eight patients with stable asthma weaned off beta2-agonist therapy were studied in a randomized, double-blinded, placebo-controlled study utilizing aerosolized terbutaline, 400 microg q6h. Hemodynamic measurements and M-mode echocardiography were performed before and 15 and 30 min after the initial dose of terbutaline or placebo and after a dose of aerosolized terbutaline after 14 days of aerosolized terbutaline maintenance therapy. Holter monitors were worn on the first day of placebo or terbutaline therapy and on day 14 of terbutaline therapy. Plasma potassium, bicarbonate, and glucose levels, pH, renin activity, and serum insulin and aldosterone levels were measured before and after 24 and 48 h after terbutaline or placebo therapy and after 14 days of aerosolized terbutaline maintenance therapy.Terbutaline increased cardiac index and decreased systemic vascular resistance greater after 14 days of therapy compared with the first dose (5.2+/-0.5 vs 4.4+/-0.6 L/min/m2; p0.05; and 760+/-62 vs 1,016+/-118 dyne x s x cm(-5), p0.01). After 14 days of terbutaline therapy, the mean maximum heart rate and number of episodes of heart rate100 beats/min were higher compared with the other study day (p0.05). Plasma potassium level decreased from 4.29+/-0.09 to 3.65+/-0.16 mmol/L after 24 h of terbutaline and to 3.90+/-0.11 mmol/L after 48 h. Plasma potassium level returned to baseline after 14 d of terbutaline therapy. Plasma glucose and serum insulin levels rose significantly 24 h and 48 h after terbutaline and returned to baseline after 14 d of terbutaline therapy. Serum aldosterone level decreased significantly as serum potassium level decreased in the first 48 h of terbutaline therapy but returned to baseline levels after 14 d of terbutaline.Cardiovascular beta2-receptors in patients with stable asthma do not develop tolerance to the effects of low-dose aerosolized terbutaline after 14 days of maintenance therapy. In contrast, the homeostatic mechanisms regulating serum potassium develop tolerance to low-dose terbutaline maintenance therapy. Lack of cardiovascular tolerance to maintenance doses of aerosolized beta2-agonists may be important in increased morbidity if excessive amounts of these drugs are administered during asthma exacerbations.

The capacity of the alveolar epithelial barrier to remove excess alveolar fluid from the airspaces of the lung was studied in an experimental model of moderate hyperoxic lung injury. Rats were exposed to 100% oxygen for 40 h in an exposure chamber and compared with control animals exposed to room air. Extravascular lung water was calculated gravimetrically. Alveolar and lung liquid clearance were studied over 1 h by instillation of a 5% albumin solution with 1.5 microCi of 125I-labeled albumin (6 mL/kg into both lungs). The concentration of both the unlabeled and labeled albumin was used to calculate alveolar liquid clearance. Hyperoxic rats developed pulmonary edema, with a 33% increase in extravascular lung water to 5.3 +/- 0.1 g of water per gram of dry lung, compared with 4.0 +/- 0.2 g of water per gram of dry lung in control rats (p0.05). This degree of edema was associated with a significant increase in the alveolar-arterial oxygen difference (241 +/- 61 vs 124 +/- 14 mm Hg in control animals exposed to room air, p0.05). Despite this moderate degree of lung injury, alveolar fluid clearance was normal (30 +/- 3%) compared with control rats (33 +/- 6%). Furthermore, the hyperoxic injured rats responded normally to an exogenous beta-adrenergic agonist (terbutaline, 10(-4) mol/L) with a 67% increase in the rate of alveolar liquid clearance (50 +/- 5%). Thus, in the setting of moderate hyperoxic lung injury, the alveolar epithelial barrier is still capable of removing fluid at a normal rate and responding to beta-adrenergic agonist treatment. These experimental results have potential clinical implications for patients with acute lung injury.

In patients with COPD, a relationship between breathlessness and respiratory effort, assessed in terms of mouth occlusion pressure (P0.1), has been described. To evaluate the short-term effects of inhaled terbutaline on breathlessness, breathing pattern, and P0.1 in patients with nonreversible COPD, we designed a randomized, double-blind, parallel, placebo-controlled study. Twenty-five patients with stable nonreversible COPD, mean age 64 +/- 11 years, were enrolled in the study. Patients received 500 micrograms inhaled terbutaline or placebo. Breathlessness, using the Borg scale, breathing pattern, and P0.1 were measured at baseline and 30 min after inhalation. Terbutaline resulted in a significant decrease in Borg scale, while no differences were observed after placebo. No significant changes in breathing pattern were found. Nevertheless, a decrease in P0.1 (0.31 +/- 0.07 vs 0.21 +/- 0.05 kPa; p0.001) after terbutaline inhalation was observed. Borg score was correlated with P0.1 in all patients. Moreover, changes in Borg score after medication were directly proportional to P0.1 changes (r = 0.85; p0.01). We conclude that terbutaline decreases central inspiratory drive and improves breathlessness in patients with nonreversible COPD.

The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. PHASE 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid (BA + CS) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20% reduction in FEV1 (PC20) than treatment with a beta 2-agonist plus anticholinergic (BA + AC) or placebo (BA + PL). PHASE 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 micrograms beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA +/- AC) could also improve FEV1 and PC20 to the same degree. A distinction was made between patients with predominantly asthma (high baseline reversibility, delta FEV1or = 9% of predicted), and predominantly COPD (low baseline reversibility, delta FEV19% of predicted).Improvement of FEV1 percent predicted by inhaled CS was comparable both in the asthmatics between phase 1 (13.8% predicted) and phase 2 (8.5% predicted; p = 0.31) as well as in the patients with COPD (2.5% and 1.5% predicted, respectively). PC20, however, increased significantly more in the asthmatics in phase 1 (1.77 doubling concentration [DC]) than in phase 2 (0.79 DC; p = 0.03). Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 (0.74 DC) than in phase 2 (0.00 DC; p = 0.19).Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV1, improvements in PC20 are significantly less. These findings in patients with longer-existing asthma concur with other findings in newly detected asthma. We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility.

Once-daily morning (7 AM) vs evening (10 PM) administration of the terbutaline prodrug bambuterol (20-mg tablet dose) was investigated in a double-blind, cross-over, randomized, and placebo-controlled study involving 29 diurnally active patients with asthma. Terbutaline plasma concentration, spirometry, and drug tolerance were assessed during 39-h inpatient studies. A 7-day washout period separated each treatment. Mean 24-h plasma concentration was comparable for morning and evening bambuterol (13.2 vs 14.0 nmol/L). The Cmax for evening vs morning dosing was 17.2 vs 15.5 nmol/L (p0.02). The 24-h mean FEV1 was greater (p0.001) for bambuterol (morning: 3.2 L; evening: 3.4 L) vs placebo (2.9 L) as it was for FVC, FEF25-75%, and peak expiratory flow rate (PEFR), with the maximum effect at 4 AM independent of medication time. Evening dosing, however, resulted in greatest 7 AM (awakening) FEV1, FEV25-75, and PEFR (p0.03). With reference to corresponding-in-time placebo values, improvement in FEV1 at the end of the 24-h dosing intervals amounted to 0.34 L (13.5%) (p0.0004) and 0.35 L (15.9%) (p0.0012) with evening and morning bambuterol dosing, respectively. Side effects were greater for bambuterol than placebo, but not significantly so. Once-daily bambuterol therapy proved to be an effective treatment for asthma, whether administered in the evening or morning. Evening dosing seems best for nocturnal asthma since airway patency overnight and on awakening at 7 AM is most improved.

To study the effect of intravenous (i.v.) terbutaline on potassium (K) and magnesium (Mg) distribution, ECG changes, and prevalence of ventricular ectopic beats in healthy subjects.Randomized double-blind, placebo-controlled crossover. Subjects received either placebo or terbutaline (bolus, 0.25 mg; maintenance dose, 5 micrograms/min).University Department of Clinical Chemistry.Ten healthy male volunteers. Mean age was 24.1 (range, 20 to 31) years.Serum potassium and magnesium muscle potassium and magnesium, and muscle sodium-potassium pump number. Urinary excretion of potassium and magnesium. ECG changes (T-wave and QTC interval) and the number of ventricular ectopic beats.Terbutaline produced an immediate decrease in serum potassium level from 4.17 (4.04 to 4.30) mmol/L to a nadir of 3.32 (3.06 to 3.58) mmol/L (p0.001). The urinary excretion of potassium decreased from 0.077 mmol/min (0.052 to 0.102) to 0.038 mmol/min (0.025 to 0.051) (p0.01). There was an increase in the number of sodium potassium pumps from 1,104.1 nmol/kg dry weight (1,030.6 to 1,177.5) to 1,273.3 nmol/kg dry weight (1,193.5 to 1,353.2) (p0.01), but no measurable change in muscle potassium. The QTC interval increased from 395 (385 to 405)ms to 449 (432 to 466) ms (p0.003). There was no change in the number of ventricular ectopic beats.Short-term i.v. administration of terbutaline produced hypokalemia partly due to an increase in the number of sodium-potassium pumps. Furthermore, terbutaline induced changes in ECG with a highly significant lengthening of the QTc interval but with an unchanged number of ventricular ectopic beats in healthy subjects.

The bronchodilating effect of terbutaline dry powder inhaled via Turbuhaler was compared with terbutaline inhaled via a conventional, chlorofluorocarbon (CFC) inhaler and Nebuhaler (750 ml spacer) in 68 consecutive patients attending the emergency department with acute severe bronchial obstruction. The study was of an open, randomized, parallel group design with one study day. Patients were treated with 2.5 mg of terbutaline 15 min apart, either as dry powder via Turbuhaler or with a CFC inhaler in conjunction with Nebuhaler. Data from 62 patients were analyzed. The mean baseline FEV 1 values were 0.81 L (SD, 0.64; range, 0.14 to 2.74 L) in the Turbuhaler group (n = 33), and 0.90 L (SD, 0.90; range, 0.27 to 2.60 L) in the Nebuhaler group (n = 29). The mean increases in FEV 1 from baseline were 0.40 L (SD, 0.40; range, 0.06 to 2.36 L) and 0.21 L (SD, 0.25; range, −0.05 to 0.95 L) 10 min after the last inhalation via Turbuhaler and Nebuhaler, respectively. The difference between mean values of the increase in FEV 1 after terbutaline treatment with Turbuhaler and the CFC inhaler and Nebuhaler was statistically significant (p = 0.0004, ANOVA). This study showed that inhalation of terbutaline via Turbuhaler produced a significantly greater increase in FEV 1 compared with the same dose of terbutaline administered via the CFC inhaler and Nebuhaler in patients attending the emergency department with acute severe bronchial obstruction.

Selective beta 2-agonist aerosols may produce significant cardiovascular effects. In the present study we used Holter monitoring to compare the arrhythmogenic effects of inhaled terbutaline (TE), a beta 2-agonist, with that of ipratropium bromide (IB), a nonabsorbable cholinergic drug. Fourteen patients with concomitant obstructive lung disease, ischemic heart disease, and complaints of postinhalation palpitations were studied in a random, double-blind, cross-over fashion. Both drugs significantly improved vital capacity and FEV1. Heart rate and the frequency of premature beats were not significantly affected by the bronchodilators. We conclude that no clear connection between inhaled bronchodilators and arrhythmias could be demonstrated.

Positive expiratory airway pressure seems to dilate narrowed or collapsed airways, but this may be accompanied by a maintained and harmful increase in resting lung volume in obstructive pulmonary disease.To evaluate the influence of inhaled terbutaline and positive expiratory pressure (PEP) on airway resistance (Raw) and functional residual capacity (FRC) in bronchial asthma.Randomized crossover design, single blind with regard to inhaled medication, open with regard to PEP (PEP can be felt).Ten patients with bronchial asthma inhaled placebo and terbutaline in doses of 0.125 mg, 0.5 mg, and 1.5 mg by cone spacer combined with a facemask giving 0, 10, or 15 cm H2O PEP on separate days. FRC and Raw were measured by body plethysmography before and after inhalations. Data were analyzed by analysis of variance with terbutaline dose and PEP as factor levels.The effect of terbutaline: Raw decreased significantly (p0.0001) after 0.125 mg and 1.5 mg. The FRC did not change significantly. The effect of PEP: Raw decreased, but significantly only when the dose of 1.5 mg terbutaline was excluded from the analysis. Raw decreased with PEP 10 and 15 cm H2O, mean 0.6 (95 percent CI: -1.1, -0.2) and 0.9 (95 percent CI: -1.3, -0.4) cm H2O/L/s. The FRC did not change significantly with the PEP level.PEP only had influence on Raw when insufficient doses of terbutaline were inhaled, whereas once an efficient dose of terbutaline was administered, significant bronchodilation was achieved with or without PEP. Positive expiratory pressure did not increase FRC.

Study objective It has been suggested that the defective cyclic AMP-dependent Cl – secretion and the increased Na + absorption from airway epithelia in cystic fibrosis (CF) may lead to dehydrated secretions and impaired mucociliary clearance. Beta 2 -adrenergic agonists are unable to stimulate the Cl – transport in the airways in CF while being able to do so in normal airways. Thus, we questioned whether the β 2 -adrenergic agonist, terbutaline, would improve mucociliary clearance in patients with CF as it does in healthy subjects. Design A double-blind, randomized cross-over trial. Setting Whole lung and regional mucociliary clearance of a radioaerosol was measured for 3 h by gamma camera. One minute of cough clearance was measured at 3 h. Pulmonary function was measured before and after the gamma camera study. Patients Ten young patients with CF were studied; three were heterozygous for deletion of the phenylalanine at position 508 (ΔF508), and seven were ΔF508 homozygous. Interventions Inhalation of 1 mg of terbutaline (4 puffs) and placebo via a metered-dose inhaler by spacer. Measurements and results The largest differences in tracheobronchial retention (percent) in the whole lung and regional lung zones were generally observed within 1 h after terbutaline and placebo treatment: whole lung (mean ± SD), 60 ± 22 percent and 63 ± 20 percent; central zone, 41 ± 19 percent and 50 ± 25 percent; midzones, 65 ± 27 percent and 63 ± 19 percent; and peripheral zones, 77 ± 28 percent and 72 ± 28 percent, respectively [p>0.1]. Whereas none of these differences was statistically significant, subanalyses suggested an improvement in mucociliary clearance by terbutaline in the three ΔF508 heterozygous patients but not in the seven ΔF508 homozygous patients. One minute of voluntary coughing resulted in clearance of less than 8 percent of the initial radioactivity, with a trend of more peripheral zone clearance after terbutaline compared with placebo. A small significant decrease in airway resistance was detected 3 h after terbutaline. Conclusions We conclude that 1 mg of terbutaline did not improve mucociliary clearance significantly in the patients with CF. Also, the effect of terbutaline was much less than demonstrated earlier in healthy subjects. This is consistent with earlier findings of a lack of β-adrenergic modulation of Cl – transport in CF. Thus, no rehydration of the dry mucus in CF is expected, and a possible β 2 -agonist-induced increase in ciliary beating would have only a minor effect on overall mucociliary clearance.

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.

Twelve patients with stable asthma (mean age, 39 years; asthma duration, 11 years; mean forced expiratory volume in 1 s, 65 percent of predicted; and reversibility, 31 percent) were studied in a double-blind crossover trial. The patients were studied during three test days. Airway resistance and specific airway conductance (Raw and SGaw) were measured using a body plethysmograph and pulse rate, blood pressure, tremor, and subjective effects were recorded before and 1, 3, 5, 10, 15, 30, 60, and 120 min after the test doses. A baseline Raw variability of +/- 20 percent was allowed between the test days. Formoterol 12 micrograms, 24 micrograms, and terbutaline 500 micrograms were given in a spacer (Nebulator) in a randomized double-blind crossover manner as two puffs with a 30-s interval in between. The effect of formoterol 12 micrograms on Raw was significantly better than terbutaline after 3, 5, 10, 60, and 120 min. Formoterol 24 micrograms was significantly better than terbutaline as soon as 3 min after inhalation and at every point in time after that. Formoterol 24 micrograms tended to be better than formoterol 12 micrograms but the differences were not significant at any point in time. All three treatments were well-tolerated. No differences were observed for pulse rate, blood pressure, tremor, or palpitations. The overall onset of bronchodilatation after formoterol 12 and 24 micrograms was faster than after terbutaline 500 micrograms. The tolerability of formoterol was good.

Nine asthmatic patients with an allergy to birch or timothy underwent bronchial allergen provocations on three different trial days, with intervals of 2 to 5 wk. Two weeks prior to one of the provocations, no medication was allowed. Before the other two provocations the patients had been on continuous treatment with oral terbutaline (7.5-mg slow-release pill bid) for 2 wk, which was discontinued 12 or 48 h before the allergen provocation. After allergen challenges, terbutaline was inhaled in increasing doses (0.5 mg, 1.0 mg, and 2.0 mg), and pulmonary function was measured after each dose. Before each allergen provocation, blood samples were drawn for measurements of catecholamine and terbutaline concentrations and for in vitro measurements of beta-adrenergic receptor function on lymphocytes (isoproterenol-induced accumulation of cyclic AMP). Beta-adrenergic receptor function on blood lymphocytes was impaired after the two treatment periods, compared with the drug-free period, and was significantly more depressed at 12 h than 48 h after dosing. The bronchial responsiveness to allergen, defined as PC20PEF (median values), was 1,700 biologic units (BU) after the period of no treatment and 220 BU and 445 BU at 12 and 48 h after discontinuation of the terbutaline treatment (p less than 0.1 after 48 h). Five of the nine patients exhibited increased bronchial responsiveness 48 h after treatment, compared to results without treatment. The responsiveness was similar on all occasions in three patients. The bronchodilator response to inhaled terbutaline after allergen-induced bronchoconstriction was attenuated (p less than 0.01) at both 12 and 48 h after terbutaline, compared to results without treatment, indicating desensitization also of the bronchial beta-adrenergic receptors. We conclude that the early bronchial responsiveness to allergen is increased following a period of continuous treatment with a beta-adrenergic receptor agonist in some asthmatic patients and that the capability of a beta-agonist to reverse allergen-induced bronchoconstriction is attenuated after beta-agonist treatment.

The purpose of the study was to investigate whether a constant submaximal exercise challenge affected the plasma pharmacokinetics of an inhaled beta 2-adrenoceptor agonist, terbutaline sulfate. Eight healthy nonsmokers participated in a study comprising measurements of plasma concentrations of terbutaline on two separate study days. Plasma samples were frequently collected at rest during study day 1, and on the second study day, during and after a 30-min exercise challenge, which was performed immediately after inhalation of the drug. The rate of increase of plasma concentrations and the maximal plasma concentrations were higher during exercise than during rest (p less than 0.01 and p less than 0.05, respectively). The plasma concentration fell rapidly after cessation of the exercise and approached those obtained at rest. We suggest that increased pulmonary and/or bronchial blood flow and altered surface tension of the liquid lining of the air space may contribute to the enhancement of absorption of this hydrophilic compound during exercise. Based on the levels of the maximal plasma concentrations reached during exercise in this study, the results would be to increase the frequency of administration of the drug, rather than to increase the administered doses, if the aim is to prevent or ameliorate exercise-induced asthma and potential systemic side effects.

In order to investigate whether treatment with terbutaline (1 mg subcutaneously) in patients with bronchial obstruction is accompanied by changes in the densities of receptors of the autonomic nervous system, beta-adrenergic receptors or m-cholinergic receptors were measured in membrance preparations of human peripheral lung tissue from patients undergoing lung resection for bronchial carcinoma. The density of beta-adrenergic receptors and mononuclear leukocytes (MNLs) of treated and untreated patients and beta-adrenergic receptors and m-cholinergic receptors in lung strips from the same patients exposed to terbutaline in vitro were studied for comparison. In patients, treatment with terbutaline did not have any effect on human lung beta-adrenergic receptors and m-cholinergic receptors, whereas a 57 percent decline was measured in the number of beta-receptors on MNLs of the very same patients. In contrast, in vitro exposure of human peripheral lung strips to terbutaline (100 mumol/L for 36 hours) evoked a time-dependent and concentration-dependent decline of 46 percent in beta-adrenergic receptors. Again, there was no change in the number of m-cholinergic receptors. The antagonist affinities, as judged from the KD values, did not differ under either condition. We concluded that lung beta-adrenergic receptors are subject to down-regulation when exposed to agonists in vitro. This down-regulation in the human lung is not accompanied by alterations in m-cholinergic receptors. Down-regulation of beta-adrenergic receptors or up-regulation of m-cholinergic receptors appears not to play a role in the proposed tolerance to beta-adrenergic receptor agonist treatment in clinical situations. The reduction of beta-adrenergic receptors in MNLs provides evidence that treatment with terbutaline was sufficient to affect beta-adrenergic receptors in vivo in certain cell types but also shows that alterations in blood cells do not necessarily reflect the situation in the lung.

The thoracocardiograph (TCG) displays cardiac oscillations transmitted to the external surface of the thorax through inductive plethysmographic transducers placed transversely around the thorax near or about the xiphoid process. Such signals, with the appearance of ventricular volume curves, were used to compute changes of stroke volume (SV) and cardiac output (CO) in normal subjects. Their values were compared with changes of SV and CO measured with the impedance cardiograph (IC). Increases of SV and CO were produced with subcutaneous terbutaline and there was excellent agreement between TCG and IC values, best from TCG transducers placed at the xiphoid process and 3 cm caudal to it, although TCG locations 6 cm caudad and 3 cm cephalad to the xiphoid were also satisfactory. Since the site 3 cm caudad to the xiphoid process is known to anatomically transect solely a segment of the left ventricle, it was designated the TCG-Reference location. Both TCG and IC derived SV were not altered during postural shifts about a horizontal axis. Neither TCG nor IC showed the expected large decreases of SV from supine posture to head-up tilt. With baseline TCG and IC measurements in 60 degrees head-up tilt. MAST suit application increased CO measured with TCG but not with IC. Neither TCG nor IC revealed alteration of CO with nasal CPAP up to 10 cm H2O despite a rise in functional residual capacity (FRC) level of 870 ml. This investigation indicates that TCG has promise as a near continuous, noninvasive monitor of SV and CO in normal subjects if postural axis is fixed and does not require highly trained personnel or labor-intensiveness for its operation.

For subjects with EIA participating in physical activities throughout the day, prolonged duration of protection is desirable. The purpose of this study was to determine whether in EIA a combination of the recommended aerosol doses of the beta 2-adrenergic receptor agonist, terbutaline sulfate (0.5 mg), and cromolyn sodium (disodium cromoglycate; 2 mg) provides longer protection against EIA than either drug alone. On four separate days, following the administration of either placebo, terbutaline alone, cromolyn sodium alone or terbutaline and cromolyn sodium together, 12 subjects (seven men and five women; aged 18 to 28 years) with EIA performed four identical eight minute treadmill runs, each separated by two-hour intervals. Drug treatments were given double-blind, with the order counterbalanced using a Latin-square design. Pulmonary function was recorded before the drug, immediately before and after exercise, and at 3, 4, 5, 6, 7, 10, 15, and 30 minutes after exercise. Inspired ventilation, heart rate, and environmental conditions were monitored during exercise. A two-way analysis of variance was performed to investigate the main effects of time and drug treatment. Results indicated that in comparison with placebo, EIA was significantly reduced by either cromolyn sodium or terbutaline administered up to two hours (p less than 0.01) and by the combination (cromolyn sodium and terbutaline) up to four hours after inhalation (p less than 0.05). No significant differences were found between the combination and terbutaline during the initial two hours (p less than 0.5). We conclude that a combination of beta 2-adrenergic receptor agonist and cromolyn sodium is the treatment of choice for prolonged effective protection from EIA.

PURPOSE: Clinical and basic studies have suggested that interleukin 2 (IL-2) plays an important role for the development of pulmonary edema. However, its precise mechanism is still undetermined. For the resolution of pulmonary edema, alveolar fluid clearance is essential, and this clearance is known to be dependent of ion transport ability of alveolar epithelial cells. In this study, we determined the effects of IL-2 on alveolar fluid clearance. METHODS: Isotonic 5% albumin solutions with pharmacological treatments were instilled into the distal airways in the isolated rat lungs. The lungs were inflated with 100% oxygen at 8cm H2O and placed in a humid incubator at 37°C. Alveolar fluid clearance was estimated by the progressive increase in the albumin concentration over 1h. RESULTS: Seven male S-D rats were used in each group. IL-2 stimulation caused dose-dependent increase in alveolar fluid clearance (Control, IL-2 (50U/ml), IL-2 (5000U/ml), vs. IL-2 (10000U/ml): 15.8 1.8%, 15.3 1.5%, 21.8 1.0%, vs. 24.6 1.7: P 0.05). Terbutaline ( adrenergic receptor agonist) caused significant increase in alveolar fluid clearance (27.8 1.1%), and this increase was inhibited by propranolol ( adrenergic receptor blocker). In contrast, propronolol did not inhibit the IL-2 stimulation. CONCLUSION: This study indicates that IL-2 increases alveolar fluid clearance in the isolated rat lungs. Because the stimulatory effect by IL-2 is not inhibited by propranolol, IL-2 may increase alveolar fluid clearance via nonadrenergic receptor mediated pathway. CLINICAL IMPLICATIONS: Intravenous administration of IL-2 has been shown to cause pulmonary edema. However, our results suggest that IL-2 stimulates transalveolar fluid transport for clearance of excess edema fluid. This study was supported by Grant for Promoted Research from Kanazawa Medical University (S2003-8). DISCLOSURE: Makoto Sugita, None.

Forty-eight children with known asthma (ranging in age from 2 to 16 years) were studied during an acute attack. Each received either terbutaline or epinephrine subcutaneously in a random double-blind fashion. Measurement of heart rate, respiratory rate, and systemic arterial systolic and diastolic blood pressures and careful clinical assessment of obstruction of the airway were made before and at 15, 30, and 60 minutes after the administration of the drugs. Appreciable and significant clinica] improvement was noted in 19 of the 24 patients in both groups and was of comparable magnitude. A small, but significant, increase in heart rate was noted in those patients requiring only one injection of terbutaline, suggesting that the drug's selectivity for the lung is relative, not absolute. The present study demonstrates that terbutaline is an effective bronchodilator drug in acute childhood asthma.

To examine the additive properties and the sites of action of inhaled atropine sulfate (0.05 mg/kg of body weight) and terbutaline sulfate (0.005 mg/kg) in patients with chronic airflow obstruction, we tested these aerosols separately and together in a double-blind random sequence. Twelve patients with chronic bronchitis and perennial obstruction of airflow were studied by measuring three indices of efficacy (specific airway conductance [Gsw/Vl], the forced expiratory volume in one second [FEV1] and the forced vital capacity [FVC]) and three indices of the site of action within the airway (Δ[(Gaw/Vl)/FEV1], the difference between the change in forced expiratory flow at 75 percent of vital capacity and the change in forced expiratory flow at 25 percent of vital capacity, and the change in density dependence of maximal airflow at 50 percent of vital capacity). Both atropine and the combination of atropine and terbutaline improved all indices of efficacy significantly more than did terbutaline. With individual exceptions, the addition of terbutaline to atropine improved Gaw/Vl but not forced airflow. All measures of site of action suggested an advantage for atropine in relatively proximal airways. These results indicate that combined therapy with β-adrenergic and anticholinergic bronchodilator drugs fa marginally more effective than therapy with atropine alone in these patients and suggest that anticholinergic aerosols dilate larger airways more effectively than the β-agonists.

The bronchodilator and cardiovascular effects of orally administered tablets containing 2.5 mg of terbutaline and 25 mg of ephedrine were compared in a double-blind parallel manner in children (ages, 7 to 14 years) weighing 25 to 50 kg (44 to 110 lb). Both drugs produced bronchodilation within one-half hour, and this effect was maintained up to six hours, with a peak between two and three hours. Small increases in the pulse rate were measured within an hour following administration of both drugs. No significant variation was noted in blood pressure. No adverse effects (including tachyphylaxis and tremor) were observed for either drug during a three-month period. Both bronchodilator agents were shown to be equally effective in the dosages used. Terbutaline is a safe bronchodilator drug when administered orally in 2.5-mg doses for children with chronic asthma in this range of ages and weights, with minimal cardiovascular side effects and effective bronchodilation.