[Adrenergic beta 2-agonists are to be considered more as friends than enemies].
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Administration, Inhalation↗
Biomedical subjects
N Svedmyr
Publications and source records attributed to N Svedmyr.
Late asthmatic reaction decreased after pretreatment with salbutamol and formoterol, a new long-acting beta 2-agonist.
The inhibitory effect of salbutamol and formoterol, a new long-acting beta 2-agonist for inhalation, on the late asthmatic reaction (LAR), was studied in 12 patients with allergic asthma. After a single-blind, placebo-treatment control, equipotent bronchodilating doses of inhaled salbutamol (500 micrograms) and formoterol (30 micrograms) were administered 30 minutes before bronchial allergen challenge in a double-blind randomized design. The early asthmatic reaction was completely inhibited by both drugs (p less than 0.01) but not by placebo. The LAR was also significantly inhibited by both drugs (p less than 0.01); formoterol was only slightly, but significantly, more effective than salbutamol (p = 0.04). In contrast to some earlier studies, the present study indicates an inhibitory effect of beta 2-agonists on the LAR.
Adrenergic beta-Agonists↗
Twelve months, treatment with inhaled salmeterol in asthmatic patients. Effects on beta 2-receptor function and inflammatory cells.
Salmeterol is a new beta 2-receptor agonist with a prolonged duration of action after inhalation, exceeding 12 h in most patients. We have performed a 12-month open follow-up study on 11 patients with reversible asthma. All patients were given salmeterol inhalations (50 micrograms twice daily). Additional asthma treatment included inhaled corticosteroids in all patients, and oral slow-release theophylline or beta 2-receptor agonists in a minority of patients (3 and 1, respectively). Before salmeterol treatment was initiated and after 3, 6, 9 and 12 months of salmeterol treatment, a cumulative dose-response curve to inhaled salbutamol (100, 300 and 900 micrograms) was performed, and FEV1 measured. We also evaluated the effect of each salbutamol dose on finger tremor, systemic blood pressure and heart rate. Blood tests, including white blood count and electrolytes, were taken at each visit. After salmeterol treatment was initiated, morning FEV1, measured before the morning asthma medication, was significantly improved (p < 0.05). The responsiveness to inhaled salbutamol was not decreased during salmeterol treatment, except in one patient with asthma worsening over the study year. Baseline finger tremor measured before salbutamol dose-response curves, was significantly lower at the 12-month visit than before treatment was initiated (p < 0.05). Effects of salbutamol on systemic blood pressure, heart rate or finger tremor was not significantly changed during salmeterol treatment. We found a successive and significant decrease in blood eosinophils (p < 0.05) during the 12 months of salmeterol treatment, when the patient with asthma worsening was excluded in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Bronchodilator intake and plasma levels on admission for severe acute asthma.
We have measured the plasma levels of salbutamol, terbutaline and theophylline in 140 patients (70 men, mean age 57 yrs) arriving for emergency treatment with severe acute asthma. The aim of the study was to investigate how the measured plasma levels correlated with the reported bronchodilator intake and whether the pretreatment beta 2-agonist levels influenced the effect of emergency salbutamol treatment. We found a highly significant correlation between the reported 24 h dose and the measured plasma concentrations for all three drugs. A plasma concentration less than 40 mumol.l-1 was found in 63 of the 107 patients who had taken theophylline, while no patient had a plasma concentration greater than 110 mumol.l-1. A plasma concentration above the suggested therapeutic range was found in 23 of the 95 patients who had taken terbutaline (greater than 30 nmol.l-1) and in 12 of the 98 patients who had taken salbutamol (greater than 60 nmol.l-1). A significant negative correlation was found between the initial plasma beta 2-agonist levels and the bronchodilation after i.v. salbutamol treatment (5 micrograms.kg-1), while there was no clear indication that high plasma beta 2-agonist levels reduced the bronchodilator effect of a high dose of inhaled salbutamol (0.15 mg.kg-1 x 2). We conclude that some patients arriving with acute asthma have high blood concentrations of beta 2-agonists, which possibly limit the response to i.v. beta 2-agonist treatment, while the effect of high-dose inhaled beta 2-agonists appears to be related to a lesser degree to the drug concentration on arrival. In this study overtreatment with theophylline appears to be uncommon.
Acute Disease↗
Tetrodotoxin does not block the epithelium-dependent release of prostaglandin E2 induced by electrical field stimulation in isolated ferret trachea.
Electrical field stimulation (EFS) has previously been shown to induce the release of prostaglandin (PG) E2 from ferret tracheal epithelium. We have now conducted a study to see whether this effect of EFS is due to the activation of nerves or whether it is a non-neural effect. The release of PGE2 and 6-keto-PGF1 alpha into the bath fluid was assayed in isolated ferret tracheas with (E+) or without (E-) epithelium, stimulated by either EFS or direct vagal nerve stimulation (DNS) repeatedly for 120 min. EFS-stimulated E+ preparations showed a gradual decline in the contractile responses (30 +/- 1% of baseline) and an increase in PGE2 to 296 +/- 38 pg/ml. In EFS-stimulated, epithelium-denuded (E-) preparations, the decline was significantly lower (11 +/- 5%), as well as the final concentration of PGE2 (107 +/- 21 pg/ml). In DNS-stimulated E+ preparations, the contraction decline was 8 +/- 1% and the final concentration of PGE2 was less than 6 pg/ml. Although tetrodotoxin (TTX) abolished the contractile response in EFS-stimulated E+ preparations, it did not significantly reduce the release of PGE2 (260 +/- 6 pg/ml), whereas atropine partly counteracted the release. The bath concentration of 6-keto-PGF1 alpha increased, independently of the electrical stimulation, contractile response, or presence of the epithelium. We conclude that EFS activates the epithelium-dependent release of PGE2 by a TTX-resistant mechanism. This may be due to an activation of TTX-resistant nerves, or possibly to a non-neural effect, such as a direct effect on the epithelial cells. The results indicate that the airway epithelium has the ability to respond to certain stimuli with a pronounced release of PGE2, thereby counteracting bronchoconstriction.
6-Ketoprostaglandin F1 alpha↗
Beta-agonists--friends or foes?
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Adrenergic beta-Agonists↗
Inhaled formoterol during one year in asthma: a comparison with salbutamol.
Eighteen patients, who had previously taken part in a 2 wk cross-over comparison between formoterol and salbutamol, now took part in a one year double-blind study comparing salbutamol 200 micrograms b.i.d. with formoterol 12 micrograms b.i.d. Additional doses were taken when needed and were recorded. Ten patients were started on formoterol and eight on salbutamol. After one month, the patients were allowed to shift to the alternative drug. Two patients withdrew from the study. At the end of the study, 13 of 16 patients were on formoterol, thus showing a long-lasting preference for this drug. Forced expiratory volume in one second (FEV1) dose-response curves for inhaled salbutamol were repeatedly recorded during the study, and no tachyphylaxis was found. One patient stopped taking inhaled steroids but continued taking formoterol and theophylline. He deteriorated with a decreased response to salbutamol. After re-introduction of inhaled steroids his condition improved. This case indicates that effective bronchodilator therapy may mask the deterioration of asthma.
Administration, Inhalation↗
The current place of beta 2-agonists in the management of asthma.
Inhaled beta 2-stimulants are the most effective drugs for acute asthma attacks. This is probably due to the functional antagonism against a large variety of possible asthma mediators. A slight rebound increase of bronchial hyperreactivity 12 to 23 h after stopping regular treatment has been proposed. This finding is not well documented and must be further studied. There is no convincing evidence that tachyphylaxis of clinical importance to the bronchodilating effect occurs in asthmatics receiving normal doses of beta 2-receptor stimulants but cannot be totally excluded. Candidates for regular inhaled beta 2-agonist treatment always have inflammation in their airways and should be given inhaled steroids. Steroids not only seem to reduce airway inflammation and hyperreactivity but they also reverse beta 2-receptor subsensitivity in experimental studies. Patients on purely prophylactic antiasthmatic drugs should be instructed always to carry their beta 2-stimulants inhalers.
Administration, Inhalation↗
Epithelium-derived PGE2 inhibits the contractile response to cholinergic stimulation in isolated ferret trachea.
We have previously reported that epithelium-dependent inhibitory factors, both prostanoids and non-prostanoids, can be activated by electrical field stimulation (EFS) and direct nerve stimulation (DNS) in an in vitro nerve-muscle preparation of ferret trachea. In this study we set out to compare the release of the inhibitory prostanoids, PGE2 and PGI2, in preparations with intact and with removed epithelium. Ferret tracheae were mounted in organ baths and phasic contractions were induced by EFS and DNS. The bath concentrations of PGE2 and the PGI2-metabolite 6-keto-PGF1 alpha were measured using radioimmuno assays. The gradual decrease in contractile response to DNS, 2 Hz for 120 min, was 95 +/- 2% of baseline (mean +/- SEM) in preparations with intact epithelium compared with 29 +/- 8% in epithelium-denuded preparations (p less than 0.001). The bath-levels of PGE2 showed a slight but significant (p less than 0.01) increase in denuded preparations with a final bath-concentration at 120 min of 13 +/- 3 pg/ml. The release of PGE2 was more pronounced in preparations with intact epithelium which resulted in a final bath-concentrations of PGE2 of 84 +/- 38 pg/ml which was significantly higher compared with epithelium-denuded preparations and also compared with time-matched controls with the same pattern of contraction induced by DNS alone. The concentrations of 6-keto-PGF1 alpha showed a slight increase which was of comparable magnitude (ns) in intact and denuded preparations. In conclusion this study demonstrates that the cyclooxygenase-dependent component of the epithelium-dependent inhibition of the contractile response to cholinergic nerve stimulation in ferret trachea is mediated by PGE2 but not by PGI2.
6-Ketoprostaglandin F1 alpha↗
Nerve stimulation releases mucosa-derived inhibitory factors, both prostanoids and nonprostanoids, in isolated ferret trachea.
The influence of an intact mucosa layer in isolated ferret trachea on the contractile responses to repeated, short-lasting (20 s, every 2 min) nerve stimulations was studied in a nerve-muscle preparation stimulated to cholinergic-evoked contractions by either direct vagal nerve stimulation (DNS) or transmural electrical field stimulation (EFS). The contractile responses were monitored by three strain gauges connected to the proximal, middle, and distal segments of the trachea. The mucosa was either left intact (M+) or removed from the membranous part by dissection (M-). The successive decrease in contractile responses was studied for 60 min using repeated DNS and for a further 60 min using alternating EFS and DNS. During the first period, in which DNS alone was used, there was a significantly more pronounced decrease in the M+ preparation compared with the M-. This effect was most prominent in the proximal part of the trachea and was not blocked by indomethacin. During the subsequent stimulation period in which alternating EFS and DNS were used, the rate of decrease was significantly greater in all segments. In this phase, however, the inhibitory mucosa-dependent effect was significantly attenuated by indomethacin treatment. In conclusion, this study demonstrates that the mucosa-dependent inhibition or relaxation in ferret trachea is mediated by both a prostanoid and a nonprostanoid factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis.
Salmeterol (SM) is a new beta 2-adrenoceptor agonist for inhaled use that has been shown to produce long-lasting bronchodilation in asthmatic patients. In the present study, evaluating efficacy and possible development of tachyphylaxis after SM, 12 patients with stable asthma were included after the demonstration of reversibility in FEV1 of at least 15% to 200 micrograms salbutamol (SB) or 20% to 500 micrograms SB. At inclusion all patients were receiving treatment with inhaled beta 2-agonists, and 11 of the 12 patients were also receiving inhaled corticosteroids. The patients were treated for two 2-wk periods with either inhaled SM 50 micrograms twice a day or SB 200 micrograms four times a day, following a double-blind, double-dummy, randomized design. The treatment periods were separated by a washout period of 1 wk. Dose-response curves to inhaled SB were obtained the day before and the day after each treatment period. On each of these days, basal FEV1, tremor, heart rate, and blood pressure were recorded and were then followed after the inhalation of 100 + 300 + 900 micrograms SB to obtain a cumulative dose-response curve. During the treatment periods, as well as during the washout week after each treatment, the patients recorded their morning and evening peak expiratory flow (PEF) each day before the inhalation of the study drug. Subjective asthma symptoms were monitored by a visual analog scale after each treatment period. The dose-response curves to SB revealed no signs of a reduced response to SB after any of the treatments, but significant increases in basal FEV1 and FVC were seen after the SM period (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Action of corticosteroids on beta-adrenergic receptors. Clinical aspects.
Inhaled beta 2-stimulants are the most effective drugs for acute asthma attacks. This is probably due to functional antagonism against a large variety of possible asthma mediators. A defect in beta-receptor function is not the cause of asthma but treatment with beta 2-stimulants induces a down-regulation of beta-receptors and beta-receptor function outside the lung. There is, however, no convincing evidence that tachyphylaxis of clinical importance to the bronchodilating effect occurs in asthmatics receiving normal doses of beta 2-receptor stimulants. A slight rebound increase of bronchial hyperreactivity has, however, been demonstrated 12 to 23 h after stopping regular treatment. This may be due to slight tachyphylaxis not visible in normal lung function tests. Inhaled steroids should be given to all asthmatics needing regular inhaled beta 2-agonist treatment, at least to adults. Steroids not only seem to reduce bronchial inflammation and hyperreactivity, and thereby the distribution of inhaled drugs, but also attend to reverse beta 2-receptor subsensitivity.
Adrenergic beta-Agonists↗
Effects of dilevalol, a beta-adrenoceptor antagonist with intrinsic sympathetic activity in asthmatic patients.
The effects on baseline ventilation as well as beta 2-receptor stimulant-induced bronchodilation and tremor of atenolol and dilevalol, a beta-blocking agent with non-selective beta-antagonistic properties and intrinsic activity on the beta 2-receptor were evaluated in 8 patients with stable asthma. Both atenolol and dilevalol were found to significantly decrease both forced expiratory volume during 1 s (FEV1) and forced vital capacity (FVC). This decrease was significantly more pronounced after atenolol. Both agents decreased systolic and diastolic blood pressure as well as heart rate to a similar degree. Increased activation of beta 2-adrenoceptors by terbutaline infusion resulted in increased FEV1 and FVC as well as beta 2-adrenoceptor mediated reflex tachycardia and skeletal muscle tremor. The dose response curves for all these parameters were significantly shifted to the right and a decrease of the maximum relative response was seen after atenolol pretreatment. This effect was more pronounced after treatment with dilevalol with a further shift to the right of the response curve and a decrease of the maximum relative response. The haemodynamic and ventilatory effects of dilevalol are consistent with a non-selective beta-adrenoceptor blockade combined with intrinsic activity on the beta 2-receptors.
Adrenergic beta-Antagonists↗
Beta 2-adrenoceptor stimulation inhibits ganglionic transmission in ferret trachea.
To study the effect of beta-adrenoceptor stimulation on the transmission through airway parasympathetic ganglia, we used an in vitro nerve-muscle preparation of ferret trachea. Isometric muscle contractions were induced for 20 s every 2 min alternating with postganglionic activation by electrical field stimulation (EFS) or with preganglionic activation by direct nerve stimulation (DNS). The pulse frequency was always 12 Hz. A possible modulation of ganglionic transmission was assessed by comparing contractions induced by DNS to contractions induced by EFS. In 9 experiments isoprenaline initially reduced the response to EFS and DNS to the same extent, indicating an effect on postganglionic structures. After 20-30 min exposure the response to preganglionic activation by DNS was further reduced indicating an inhibition of ganglionic transmission. The concentration/response relationship for the ganglionic effect of isoprenaline was shifted about ten times to the right by 0.1 microM propranolol (n = 5) and by a beta 2-adrenoceptor-antagonist (0.1 microM ICI 118.551) (n = 8), whereas a beta 1-adrenoceptor-antagonist (10 microM practolol) had no, or only slight, effect. In two experiments pretreatment by 0.1 microM phenoxybenzamine for 20 min did not prevent ganglionic inhibition by 0.3 microM isoprenaline. We conclude that parasympathetic ganglia in ferret trachea have beta-adrenoceptors mediating inhibition of ganglionic transmission, and that these probably are of the beta 2 type. Tentatively these receptors could be operated upon by circulating catecholamines.
Adrenergic beta-Agonists↗
Classification of beta-adrenoceptors in ferret tracheal smooth muscle by pharmacological responses.
Beta-adrenoceptors in ferret tracheal smooth muscle were classified into beta 1 or beta 2 by determination of (i) the potency rank order for isoprenaline, noradrenaline and adrenaline, and (ii) apparent pA2-values for a specific beta 1-antagonist (practolol) and a specific beta 2-antagonist (ICI 118.551) and (iii) concentration-inhibition curves for procaterol, a beta-agonist showing a biphasic concentration-response curve in organs with a mixed beta 1 and beta 2 adrenoceptor population. We used in vitro tracheal rings and assessed the responses to beta-adrenoceptor agonists as inhibition of phasic contractions elicited by electrical field stimulation (2 Hz for 20 s) or relaxation of tonic contractions elicited by acetylcholine (0.5 microM). The potency rank order for the agonists was isoprenaline greater than noradrenaline approximately adrenaline indicating action through beta 1-receptors. Apparent pA2-values for the antagonists were for 1, 3 and 10 microM practolol 6.0 (SE 0.27), 6.1 (SE 0.21) and 6.3 (SE 0.03), respectively. Apparent pA2 for 0.1, 1 and 10 microM ICI 118.551 were 6.8 (SE 0.25), 6.7 (SE 0.12) and 6.1 (SE 0.14), respectively. These values agree well with published pA2-values for the action of these drugs on beta 1-adrenoceptors. However, the Schild plot for ICI 118.551 was alinear indicating a possible heterogeneity of the beta-adrenoceptors in ferret trachea. The concentration-response curve for procaterol showed the biphasic form typical for organs with a mixed beta 1 and beta 2 population. However, the lower part of the curve, reflecting stimulation of beta 2-adrenoceptors reached only 17.5% (SE 1.4) of the maximally achieved inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Formoterol fumarate, a new beta 2-adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration.
Four double-blind, double-dummy, randomized, crossover studies were performed in nine asthmatic patients to evaluate beta 2-adrenoceptor selectivity and the duration of effect of formoterol. One study with cumulatively increasing doses of formoterol and salbutamol showed that with the inhaled route, formoterol was 5-15 times more potent than salbutamol with respect to bronchodilation. In a second study, 6 micrograms formoterol and 0.1 mg salbutamol were given for comparison of effect duration. Five hours after salbutamol inhalation the FEV1 values were back to basal. Eight hours after formoterol inhalation about 75% of the maximum bronchodilation remained and the FEV1 was significantly higher than after salbutamol inhalation. By oral route, a study with cumulatively increasing doses showed that as a bronchodilator formoterol was about 50 times more potent than salbutamol. The same potency difference was seen for increase of heart rate and decrease of diastolic blood pressure, indicating that the clinical selectivity for beta 2-adrenoceptors is equal for the two drugs. In a fourth study comparable doses by oral route did not show any difference in the duration of bronchodilation. We conclude that inhaled formoterol is 5-15 times more potent than salbutamol. Inhaled formoterol produces longer duration of bronchodilation, with clinically relevant bronchodilation for at least 8 h. The prolonged duration of formoterol was not seen with oral treatment.
Administration, Inhalation↗
Broxaterol, a new beta 2-adrenoceptor agonist compared to salbutamol in asthmatics, oral and inhalation treatment.
Two double-blind, double-dummy, randomized, crossover studies were performed in 8 asthmatic patients to evaluate beta 2-adrenoceptor selectivity and potency of broxaterol compared to salbutamol. By oral route, a study with cumulatively increasing doses (total dose broxaterol 1.675 mg and salbutamol 26 mg) showed that as a bronchodilator broxaterol was 12-16 times more potent than salbutamol. The same potency difference was seen for an increase of heart rate and decrease of diastolic blood pressure, indicating that the clinical selectivity for beta 2-adrenoceptors is equal for the two drugs. One study with cumulatively increasing doses of broxaterol and salbutamol (total dose 1.5 mg for both) showed that with the inhaled route, broxaterol was somewhat less potent than salbutamol with respect to bronchodilation. Side effects, increase of heart rate and tremor were considerably less pronounced by the inhaled route as compared to the same bronchodilatory effect given by the oral route.
Administration, Inhalation↗
Formoterol, a new long-acting bronchodilator for inhalation.
The aim of this study was to evaluate if treatment with inhaled formoterol is appreciated by asthmatics and whether it causes tachyphylaxis. Twenty stable asthmatics were included in a randomized, double-blind, crossover study. They were treated for two weeks either with formoterol or salbutamol, with one week washout inbetween. They were given 12 micrograms formoterol or 200 micrograms salbutamol twice daily and instructed to use additional spray doses on demand. On a diary card they recorded the number of doses, asthma symptoms and peak expiratory flow rate (PEFR) before every dose. Forced expiratory volume in one second (FEV1) dose-response curves for salbutamol (total dose 1.3 mg) were performed before and after each treatment period to evaluate development of tachyphylaxis. There was a significant difference in favour of formoterol concerning symptoms, PEFR recordings, spray consumption, and preference. Fifteen patients preferred formoterol and two salbutamol. The dose-response curves before formoterol and before, as well as after salbutamol were almost identical. After formoterol the curve had changed; both basal and maximum values were higher than before. Thus, no evidence of tachyphylaxis was found, compared to the ordinary beta-stimulant treatment.
Administration, Inhalation↗