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Biochimica Et Biophysica Acta Nov 2016This study investigated the effect of the β receptor agonist terbutaline on the single channel activity of BK channel. The effects of racemate and two isomers of...
This study investigated the effect of the β receptor agonist terbutaline on the single channel activity of BK channel. The effects of racemate and two isomers of terbutaline were all assessed. β adrenoceptors were stably overexpressed on HEK293 cells by lentiviral transduction method and chicken BK channels were transiently expressed on normal HEK293 cell line or HEK293 cells overexpressing β receptors. Data showed that terbutaline significantly increased the single channel open probability of BK channel within 10min. The channel activating effects of terbutaline are stereoselective and mainly stay with the R-enantiomers. The opening probability of BK channel at 10min after drug application normalized to that just before drug application (Po10/Po0s) for R- and S-terbutaline were 7.85±3.20 and 1.06±0.45 respectively at 1μM concentration, corresponding to 28.37±9.96 and 2.68±1.09 at the higher concentration of 10μM. ICI 118551 blocked the effect of R- but not S-terbutaline (10μM), whereas atropine blocked the channel activating effects of S-terbutaline of higher concentration. In addition, the muscarinic receptor agonist carbachol increased the BK channel activity in an atropine-sensitive manner as an positive control experiment, which indicate the involvement of M receptor in the channel activating effect of S-terbutaline.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Atropine; Carbachol; Chickens; Gene Expression; Genetic Vectors; HEK293 Cells; Humans; Ion Channel Gating; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Lentivirus; Membrane Potentials; Muscarinic Agonists; Muscarinic Antagonists; Propanolamines; Receptors, Adrenergic, beta-2; Receptors, Muscarinic; Stereoisomerism; Terbutaline; Transgenes
PubMed: 27480802
DOI: 10.1016/j.bbamem.2016.07.016 -
The Cochrane Database of Systematic... Apr 2012Epidemiological evidence has suggested a link between beta(2)-agonists and increases in asthma mortality. There has been much debate about possible causal links for this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Epidemiological evidence has suggested a link between beta(2)-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe.
OBJECTIVES
The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists.
SEARCH METHODS
We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol. The date of the most recent search was January 2012.
SELECTION CRITERIA
We included controlled, parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular formoterol and were of at least 12 weeks' duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.
DATA COLLECTION AND ANALYSIS
Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second author checked them. We sought unpublished data on mortality and serious adverse events.
MAIN RESULTS
The review includes 22 studies (8032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease-specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Peto odds ratio (OR) 1.57; 95% CI 1.06 to 2.31). One extra serious adverse event occurred over 16 weeks for every 149 people treated with regular formoterol (95% CI 66 to 1407 people). The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicate that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline.
AUTHORS' CONCLUSIONS
In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all severities of adverse events or limited to those events that are thought by the investigator to be drug-related.
Topics: Adrenergic beta-Agonists; Adult; Age Factors; Albuterol; Asthma; Bronchodilator Agents; Child; Chronic Disease; Ethanolamines; Formoterol Fumarate; Humans; Terbutaline
PubMed: 22513944
DOI: 10.1002/14651858.CD006923.pub3 -
Frontiers in Immunology 2021Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link...
OBJECTIVE
Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β-adrenergic drugs affect joint destruction in adjuvant-induced arthritis.
METHODS
Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization.
RESULTS
On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint.
CONCLUSION AND SIGNIFICANCE
Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.
Topics: Adrenergic alpha-Antagonists; Adrenergic beta-2 Receptor Agonists; Animals; Arthritis, Experimental; Drug Combinations; Freund's Adjuvant; Joints; Male; Phentolamine; Rats, Inbred Lew; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta-2; Signal Transduction; Terbutaline; Rats
PubMed: 34220796
DOI: 10.3389/fimmu.2021.628065 -
Respiratory Medicine Aug 2001Formoterol and salmeterol are both long-acting bronchodilators that are effective in the treatment of asthma. However, some differences exist in their pharmacology that... (Review)
Review
Formoterol and salmeterol are both long-acting bronchodilators that are effective in the treatment of asthma. However, some differences exist in their pharmacology that are reflected in their clinical profiles. Formoterol has a rapid onset of action, whereas salmeterol causes bronchodilation in a somewhat slower manner. However, both ofthese drugs are long-acting. After single doses clear effects are maintained for 12 h after inhalation, and with high doses effects are observed even at 24 h. Differences between the maximal effects of both drugs are also a consequence of their pharmacological properties. Thus, formoterol has higher intrinsic activity than salmeterol, which means that it is a full agonist, whereas salmeterol is a partial agonist on the beta2-receptor. Physicochemical properties of the drugs may explain the differences in onset and duration of action. Adequate water solubility and moderate lipophilicity of formoterol ensures rapid diffusion to the beta2-receptor on the smooth muscle and rapid bronchodilating activity. Salmeterol, on the other hand, may diffuse more slowly to the beta2-receptor because of its high lipophilicity explaining the slower onset of action. Unlike salbutamol, which is hydrophilic and has a rapid onset and short duration of action, both formoterol and salmeterol possess adequate lipophilic properties to remain in the airway tissues as a depot in close vicinity to the beta2-receptor, explaining their long duration of effect. The long duration of salmeterol has also been suggested to depend on an anchored binding within the beta2-receptor. The pharmacological evidence for a rapid onset of action of formoterol, but long duration of effect, is supported by several clinical studies. The fast onset of bronchodilation and high intrinsic activity of formoterol therefore suggest that it can be used for relief treatment in patients with asthma if they are concomitantly treated with inhaled glucocorticoids.
Topics: Adrenergic beta-Agonists; Albuterol; Animals; Asthma; Blood Glucose; Blood Pressure; Bronchodilator Agents; Dose-Response Relationship, Drug; Ethanolamines; Formoterol Fumarate; Heart Rate; Humans; Potassium; Randomized Controlled Trials as Topic; Receptors, Adrenergic, beta-2; Salmeterol Xinafoate; Terbutaline; Time Factors
PubMed: 11534896
DOI: 10.1053/rmed.2001.1139 -
The American Journal of Cardiology Aug 2007Terbutaline is used to treat fetal bradycardia in the setting of complete heart block (CHB); however, little is known of its effects on atrial and ventricular beat rates...
Terbutaline is used to treat fetal bradycardia in the setting of complete heart block (CHB); however, little is known of its effects on atrial and ventricular beat rates or patterns of heart rate (HR) acceleration. Fetal atrial and ventricular beat rates were compared before and after transplacental terbutaline treatment (10 to 30 mg/day) by fetal echocardiography in 17 fetuses with CHB caused by immune-mediated damage to a normal conduction system (isoimmune, n = 8) or a congenitally malformed conduction system associated with left atrial isomerism (LAI, n = 9). While receiving terbutaline, 9 of the 17 fetuses underwent fetal magnetocardiography (fMCG) to assess maternal HR and rhythm, patterns of fetal HR acceleration, and correlation between fetal atrial and ventricular accelerations (i.e., AV correlation). Maternal HR and fetal atrial and ventricular beat rates increased with terbutaline. However, terbutaline's effects were greater on the atrial pacemaker(s) in fetuses with isoimmune CHB and greater on the ventricular pacemaker(s) in those with LAI-associated CHB. Patterns of fetal HR acceleration also differed between isoimmune and LAI CHB. Finally, despite increasing HR, terbutaline did not restore the normal coordinated response between atrial and ventricular accelerations in isoimmune or LAI CHB. In conclusion, the pathophysiologic heterogeneity of CHB is reflected in the differing effect of terbutaline on the atrial and ventricular pacemaker(s) and varying patterns of HR acceleration. However, regardless of the cause of CHB, terbutaline augments HR but not AV correlation, suggesting that its effects are determined by the conduction system defect rather than the autonomic control of the developing heart.
Topics: Adrenergic beta-Agonists; Adult; Echocardiography, Doppler; Female; Fetal Diseases; Follow-Up Studies; Heart Atria; Heart Block; Heart Rate; Heart Ventricles; Humans; Magnetocardiography; Maternal-Fetal Exchange; Pregnancy; Retrospective Studies; Terbutaline; Treatment Outcome; Ultrasonography, Prenatal
PubMed: 17697825
DOI: 10.1016/j.amjcard.2007.03.081 -
The Cochrane Database of Systematic... Apr 2009Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Traditionally inhaled treatment for asthma has been considered as preventer and reliever therapy. The combination of formoterol and budesonide in a single inhaler introduces the possibility of using a single inhaler for both prevention and relief of symptoms (single inhaler therapy).
OBJECTIVES
The aim of this review is to compare formoterol and corticosteroid in single inhaler for maintenance and relief of symptoms with inhaled corticosteroids for maintenance and a separate reliever inhaler.
SEARCH STRATEGY
We last searched the Cochrane Airways Group trials register in September 2008.
SELECTION CRITERIA
Randomised controlled trials in adults and children with chronic asthma.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion and extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes.
MAIN RESULTS
Five studies on 5,378 adults compared single inhaler therapy with current best practice, and did not show a significant reduction in participants with exacerbations causing hospitalisation (Peto OR 0.59; 95% CI 0.24 to 1.45) or treated with oral steroids (OR 0.83; 95% CI 0.66 to 1.03). Three of these studies on 4281 adults did not show a significant reduction in time to first severe exacerbation needing medical intervention (HR 0.96; 95% CI 0.85 to 1.07). These trials demonstrated a reduction in the mean total daily dose of inhaled corticosteroids with single inhaler therapy (mean reduction ranged from 107 to 267 micrograms/day, but the trial results were not combined due to heterogeneity). The full results from four further studies on 4,600 adults comparing single inhaler therapy with current best practice are awaited.Three studies including 4,209 adults compared single inhaler therapy with higher dose budesonide maintenance and terbutaline for symptom relief. No significant reduction was found with single inhaler therapy in the risk of patients suffering an asthma exacerbation leading to hospitalisation (Peto OR 0.56; 95% CI 0.28 to 1.09), but fewer patients on single inhaler therapy needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64). These results translate into an eleven month number needed to treat of 14 (95% CI 12 to 18), to prevent one patient being treated with oral corticosteroids for an exacerbation. The run-in for these studies involved withdrawal of long-acting beta(2)-agonists, and patients were recruited who were symptomatic during run-in.One study included children (N = 224), in which single inhaler therapy was compared to higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with single inhaler therapy, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the single inhaler therapy group and the annual height gain was also 1 cm greater in the single inhaler therapy group, [95% CI 0.3 to 1.7 cm].There was no significant difference found in fatal or non-fatal serious adverse events for any of the comparisons.
AUTHORS' CONCLUSIONS
Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance inhaled corticosteroids. Guidelines and common best practice suggest the addition of regular long-acting beta(2)-agonist to inhaled corticosteroids for uncontrolled asthma, and single inhaler therapy has not been demonstrated to significantly reduce exacerbations in comparison with current best practice, although results of five large trials are awaiting full publication. Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Chronic Disease; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Terbutaline
PubMed: 19370682
DOI: 10.1002/14651858.CD007313.pub2 -
British Journal of Clinical Pharmacology Aug 19811 Cardiac, neuromuscular (tremor) and pulmonary effects of multiple single oral doses of clenbuterol (40, 60 and 80 micrograms) and terbutaline (2.5 and 5 mg) were... (Clinical Trial)
Clinical Trial Comparative Study
1 Cardiac, neuromuscular (tremor) and pulmonary effects of multiple single oral doses of clenbuterol (40, 60 and 80 micrograms) and terbutaline (2.5 and 5 mg) were compared with placebo in thirteen patients with reversible obstructive airways disease. 2 The percent change in the bronchodilator and neuromuscular effects of clenbuterol and terbutaline were greater than that of the cardiac activity. 3 Both drugs decreased T wave amplitude and occasionally caused J point ST segment depression. These changes were considered typical of this class of drugs and clinically insignificant. 4 While these drugs had comparable cardiac, pulmonary and neuromuscular effects, clenbuterol, at larger doses, had a higher incidence of transient headaches and nervousness.
Topics: Adult; Clenbuterol; Electrocardiography; Ethanolamines; Female; Heart; Humans; Lung; Male; Middle Aged; Neuromuscular Junction; Terbutaline
PubMed: 7306434
DOI: 10.1111/j.1365-2125.1981.tb01200.x -
The Cochrane Database of Systematic... May 2013Magnesium maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (usually treated with an initial dose of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Magnesium maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (usually treated with an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions.
OBJECTIVES
To assess whether magnesium maintenance therapy is effective in preventing preterm birth after the initial threatened preterm labour is arrested.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013).
SELECTION CRITERIA
Randomised controlled trials of magnesium therapy given to women after threatened preterm labour.
DATA COLLECTION AND ANALYSIS
The review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We checked data entry.
MAIN RESULTS
We included four trials involving 422 women. Three trials had high risk of bias and none included any long-term follow-up of infants. No differences in the incidence of preterm birth or perinatal mortality were seen when magnesium maintenance therapy was compared with placebo or no treatment; or alternative therapies (ritodrine or terbutaline). The risk ratio (RR) for preterm birth (less than 37 weeks) for magnesium compared with placebo or no treatment was 1.05, 95% confidence interval (CI) 0.80 to 1.40 (two trials, 99 women); and 0.99, 95% CI 0.57 to 1.72 (two trials, 100 women) for magnesium compared with alternative therapies. The RR for perinatal mortality for magnesium compared with placebo or no treatment was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants); and 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants) for magnesium compared with alternative treatments.Women taking magnesium preparations were less likely to report side effects (RR 0.67, 95% CI 0.47 to 0.96, three trials, 237 women), including palpitations or tachycardia (RR 0.26, 95% CI 0.13 to 0.52, three trials, 237 women) than women receiving alternative therapies. Women receiving magnesium were however, more likely to experience diarrhoea (RR 6.79, 95% CI 1.26 to 36.72, three trials, 237 women).
AUTHORS' CONCLUSIONS
There is not enough evidence to show any difference between magnesium maintenance therapy compared with either placebo or no treatment, or alternative therapies (ritodrine or terbutaline) in preventing preterm birth after an episode of threatened preterm labour.
Topics: Female; Humans; Magnesium Chloride; Magnesium Compounds; Magnesium Oxide; Magnesium Sulfate; Obstetric Labor, Premature; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Ritodrine; Terbutaline; Tocolysis; Tocolytic Agents
PubMed: 23728634
DOI: 10.1002/14651858.CD000940.pub3 -
The European Respiratory Journal Jan 2000
Topics: Asthma; Bronchodilator Agents; Clinical Trials as Topic; Humans; Infusions, Parenteral; Injections, Subcutaneous; Terbutaline; Treatment Outcome
PubMed: 10678652
DOI: 10.1183/09031936.00.15123300 -
The Journal of Allergy and Clinical... Aug 2021Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta-agonists, similar to the reduction with maintenance budesonide.
OBJECTIVE
This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents.
METHODS
SYGMA 1 and 2 were 52-week, double-blind studies (NCT022149199; NCT02224157) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 μg, twice-daily BUD 200 μg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to <18 years).
RESULTS
Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to <14 years was significantly greater with as-needed BUD-FORM (4.8 cm) versus BUD maintenance (3.9 cm) (pooled: P < .046), and was similar between as-needed BUD-FORM (4.5 cm) and as-needed terbutaline (4.1 cm) (SYGMA 1: P = .500). No new or unexpected safety concerns were identified.
CONCLUSIONS
In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.
Topics: Administration, Inhalation; Adolescent; Asthma; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Double-Blind Method; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Terbutaline; Treatment Outcome
PubMed: 33895362
DOI: 10.1016/j.jaip.2021.04.016