Effects of S-salbutamol on Human Isolated Bronchus

doi:10.1006/pupt.1998.0110

Pulmonary Pharmacology & Therapeutics

Volume 11, Issue 1, February 1998, Pages 1-6

https://doi.org/10.1006/pupt.1998.0110 Get rights and content

Abstract

A range of stimuli have been used to determine the effect of S-salbutamol on contractile responses of human isolated bronchus. Significant augmentation of contraction was evident during responses to histamine or LTC₄but responses to EFS, methacholine, bradykinin and capsaicin were not influenced and allergic bronchospasm was significantly impaired by prior exposure to S-salbutamol. Since R-salbutamol relaxes human isolated bronchus, the capacity of S-salbutamol to enhance contractile responses to histamine or LTC₄cannot be attributed to activation of β₂-adrenoceptors. It is concluded, therefore, that these effects of S-salbutamol represent distinct pharmacological actions of the distomer. It is also suggested that the capacity of S-salbutamol to augment contraction of airway smooth muscle may contribute to hyperreactivity towards spasmogens when racemic salbutamol is used for symptom relief in asthma and chronic obstructive pulmonary disease (COPD).

References (0)

Cited by (68)

Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action
2018, Journal of Pharmaceutical and Biomedical Analysis
Citation Excerpt :
Rare but serious, and as yet unexplained, paradoxical asthma exacerbations have been associated with LABAs, and chronic use is associated with increased bronchial hyperresponsiveness (BHR) and loss of bronchoprotection [4]. While little is known about the adverse pharmacodynamics of (S)-salmeterol, there are convincing in vitro studies showing that (S)- enantiomers of short acting beta2-agonists are associated with a range of adverse airways effects including enhanced contraction of isolated human bronchial tissue [5] and increased airway responsiveness [6]. Rac-salmeterol does appear to be enantioselective in terms of pharmacodynamics, but interestingly not to the same extent as other beta2-agonists [7].
Salmeterol (a long acting beta2-agonist) is a chiral molecule. (RR)-salmeterol is responsible for pharmacological effect, but basic knowledge of enantioselective pulmonary pharmacodynamics and pharmacokinetics of salmeterol remains unknown. There are safety concerns with (S)-enantiomers of beta2-agonists, with suggestions that these enantiomers may increase bronchial hyperresponsivneness in asthma patients.
Horses (n = 12) received racemic (rac-) salmeterol 250 μg via inhalation. Enantioselective UPLC–MS/MS was used to determine (R)- and (S)-salmeterol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples.
Physiologically relevant tissue concentrations were found for both enantiomers, with median levels greater in central than peripheral lung (equivalent to 32 and 5 mM (R)-salmeterol for central and peripheral lung respectively). Levels in PELF decreased around 50% over 15 min and enantioselective distribution was observed in the central lung with levels of (R)-salmeterol around 30% higher than (S)-salmeterol.
Salmeterol distribution is enantioselective in the central lung. This suggests duration of action is more likely associated with specific B2ADR localisation effects rather than non-specific physiochemical factors which would not be enantioselective.
The influence of propofol, remifentanil and lidocaine on the tone of human bronchial smooth muscle
2013, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
In further experiments, the isolated bronchi were pre-treated for 45 min with the selective inhibitor of inducible nitric oxide (NO) synthase (iNOS), aminoguanidine (100 μmol) and then treated with propofol [23]. Moreover, the EFS responsiveness in the presence of remifentanil was tested in desensitized tissues [15,16]. The analysis of the potential synergism/antagonism between propofol, lidocaine and remifentanil was measured by applying the Bliss Independence (BI) theory.
Bronchoscopy is generally a safe procedure, but the induction of anaesthesia can induce bronchospasm. Consequently we investigated the influence of propofol, remifentanil and lidocaine on the tone of the human bronchial smooth muscle.
The influence of propofol, remifentanil and lidocaine on the contractile response of human bronchial smooth muscle to electrical field stimulation (EFS) has been evaluated. The role of capsaicin-sensitive sensory nerves and of inducible nitric oxide synthase has also been assessed. Furthermore, the interaction between these three dugs has been measured by Bliss Independence (BI) theory. Statistical significance (P < 0.05) was assessed by Student's t test or ANOVA.
Propofol (1.3 μg ml⁻¹) and lidocaine (1 mg ml⁻¹) reduced the baseline tone of bronchial rings (−14.45 ± 4.53% and −33.40 ± 1.07%, respectively, P < 0.05), whereas remifentanil had not such effect. Aminoguanidine prevented the relaxant effect of propofol. Propofol did not alter the bronchial contractile response to EFS following 30 min of treatment, whereas remifentanil enhanced the bronchial tension (133.83 ± 9.38%, control 101.93 ± 6.82%, P < 0.05 P < 0.05) and lidocaine completely abolished the contractility at 1 mg ml⁻¹ (P < 0.05). The desensitization of capsaicin-sensitive sensory nerves normalized the hyperresponsiveness induced by remifentanil (−26.77 ± 1.68%, P < 0.05). Significant BI antagonism (P < 0.001) was detected for propofol and lidocaine on the bronchial hyperresponsiveness induced by remifentanil.
Propofol and remifentanil may be used safely for bronchoscopy, although remifentanil should be associated with propofol or lidocaine to prevent the potential opioid-mediated bronchospasm.
Levalbuterol versus albuterol for acute asthma: A systematic review and meta-analysis
2013, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Levalbuterol has approximately 100 times greater affinity for the beta2-adrenergic receptor than (S)-albuterol [13]. Till recently, the (S)-albuterol was considered inert part of racemic albuterol but now in vitro and in vivo experimental models have shown that (S)-albuterol results in immune cell proliferation, cytokine production and increases intracellular calcium in airway smooth muscle cells leading to bronchoconstriction [14–17]. Further, (S)-albuterol persists longer in plasma and lung tissue of patients because of its slower metabolism and elimination as compared to levalbuterol [18,19].
Conventional albuterol is a racemic mixture of (S)-albuterol and (R)-albuterol (levalbuterol). Levalbuterol is therapeutically active component of albuterol whereas (S)-albuterol is considered inert with some unwanted effects.
To evaluate efficacy and safety of levalbuterol versus albuterol in acute asthma.
Systematic review and meta-analysis.
Pubmed and Cochrane databases.
Randomized control trials comparing levalbuterol versus albuterol for acute asthma in all age groups.
Two authors extracted data independently. Meta-analyses were performed using Review Manager Software.
Seven trials including a total of 1625 participants fulfilled the eligibility criteria. Respiratory rate, oxygen saturation, and percentage change in FEV1 and clinical asthma score were not significantly different between the groups with mean difference (95% CI) of 0.35 (−0.81, 1.51), −0.29 (−0.68, 0.10), −28.3 (−59.95, 3.33) and −1.01 (−5.30, 3.28) respectively. There were no significant differences in side effects between groups.
Data were not available for two probable eligible trials. A few assumptions and some calculated values were used for meta-analysis.
Levalbuterol was not superior to albuterol regarding efficacy and safety in subjects with acute asthma. We suggest that levalbuterol should not be used over albuterol for acute asthma.
Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma
2007, Annals of Allergy, Asthma and Immunology
Previous studies have raised concerns regarding the safety of regular use of β₂-agonists for treating asthma. Few studies have explored the safety of at least 1 year of use of racemic albuterol, and none have examined long-term dosing of levalbuterol.
To examine the long-term safety of levalbuterol hydrofluoroalkane (HFA) vs racemic albuterol HFA administered via metered-dose inhaler (MDI) in patients with stable asthma.
Patients with mild to moderate asthma (mean forced expiratory volume in 1 second [FEV₁], 68.3% of predicted) 12 years or older participated in a multicenter, parallel-group, open-label study. Patients were randomized to levalbuterol HFA MDI (90 μg; 2 actuations of 45 μg; n = 496) or racemic albuterol HFA MDI (180 μg; 2 actuations of 90 μg; n = 250) for 52 weeks of 4 times daily dosing. The primary end point was the incidence of postrandomization adverse events. Asthma exacerbations and pulmonary parameters were also assessed.
The overall incidence of adverse events was similar for levalbuterol (72.0%) and racemic albuterol (76.8%). Rates of β-mediated adverse events, serious adverse events, and discontinuations because of adverse events were low (<15%) and were comparable between groups. Rates of asthma adverse events for levalbuterol and racemic albuterol were 18.3% and 19.6%, respectively. Mean percentage of predicted FEV₁ improved after dosing and was stable for both groups.
In this trial, up to 52 weeks of regular use of levalbuterol HFA MDI or racemic albuterol HFA MDI was well tolerated, and no deterioration of lung function was detected during the study period.
Effects of (R,R)- and (R,R/S,S)-Formoterol on Airway Relaxation and Contraction in an Experimental Rat Model
2007, Current Therapeutic Research - Clinical and Experimental
Background: Racemic (R,R/S,S)-formoterol is a long-acting β-agonist composed of a 50:50 mixture of (R,R)- and (S,S)-enantiomers.
Objective: The aim of this study was to determine whether (R,R)-formoterol and (R,R/S,S)-formoterol have differing effects on airway contraction and relaxation in vitro.
Methods: Cylindrical airway segments 3-mm long were isolated from the mid-trachea of healthy Sprague-Dawley rats and placed in a modified Krebs-Henseleit solution. Dose-response curves of bethanechol-induced contraction (measured as milligrams of tension) and the concentration of bethanechol that elicited 50% to 75% of maximal contraction (EC_50–75) were determined. The air-way cylinders were then precontracted with bethanechol at the EC_50–75 and exposed to different concentrations of (R,R)-formoterol (0.0001–1.0 μM) or (R,R/S,S)-formoterol (0.0002–2.0 μM). Each concentration of the 2 formoterol formulations contained the same amount of (R,R)-enantiomer (eg, [R,R]-formoterol 0.0001 μM and [R,R/S,S]-formoterol 0.0002 1JM contained the same amount of [R,R]-enantiomer). The relaxation percentage in response to formoterol was calculated as a reduction in tension (in milligrams) in relation to baseline tension in the precontracted state, with each tracheal cylinder serving as its own control. To determine the effect of (R,R)-formoterol on airway contraction, tracheal cylinders were incubated with (R,R)- or (R,R/S,S)-formoterol before electrical field stimulation (EFS).
Results: Tracheae from 56 three-week-old Sprague-Dawley rats were used in the study. The relaxation percentage of precontracted trachea was significantly greater after exposure to (R,R)-formoterol than to (R,R/S,S)-formoterol at a 2-fold higher concentration (P = 0.03; general linear model with repeated measures analysis comparing the 2 groups of animals). However, in a post hoc analysis, the mean (SE) relaxation percentage of precontracted trachea was significantly greater only after exposure to (R,R)-formoterol 0.01 μM than to (R,R/S,S)-formoterol 0.02 μM (15.6% [5.8%] vs 39.0% [5.6%]; P < 0.05, unpaired t test). EFS-induced airway contraction was significantly less in tracheal cylinders incubated in (R,R)-formoterol compared with those incubated in (R,R/S,S)-formoterol at a 2-fold higher concentration (P = 0.05; general linear model with repeated measures analysis comparing the 2 groups of animals). However, in the post hoc analysis, mean (SE) EFS-induced tracheal contraction was significantly less only in (R,R)-formoterol 0.01 μM compared with (R,R/S,S)-formoterol 0.02 μM at 10 V (1070 [55] mgvs 1225 [28] mg; P < 0.05, unpaired t test).
Conclusion: We found that (R,R)-formoterol may induce greater relaxation of precontracted airway smooth muscle cells than (R,R/S,S)-formoterol and that (R,R)-formoterol may have a greater inhibitory effect on the endogenous cholinergic and excitatory nonadrenergic, noncholinergic contractile airway responses than (R,R/S,S)-formoterol. We speculate that the presence of the (S,S)-enantiomer in (R,R/S,S)-formoterol may impair airway relaxation of pre-contracted trachea in rats.
16 Drugs acting on the respiratory tract
2007, Side Effects of Drugs Annual
Citation Excerpt :
Since the most effective dose of racemic salbutamol was not given, the equipotent dose ratio (racemic salbutamol/levosalbutamol) might be higher than has previously been estimated. S salbutamol plasma concentrations correlated negatively with FEV1, which may be ascribed to opposite actions of the two isomers, as has been suggested in preclinical studies (51E–53E). In contrast, the change in peak expiratory flow after the administration of home inhaled or nebulized levosalbutamol versus racemic salbutamol before admission to the emergency department was not different in 298 patients with acute bronchospastic or obstructive pulmonary conditions in another prospective, open study (54c).
This chapter elaborates the drugs acting on the respiratory tract. Overall safety data show that the use of inhaled glucocorticoids is associated with systemic ad-verse effects in clinical practice, encompassing an approximately twofold increased risk of skin bruising and diminished bone mineral density in patients with COPD using moderate to high doses of inhaled triamcinolone, and reduced short-term growth velocity in children using budesonide 200 μg/day. Oropharyngeal candidiasis has an incidence of up to 70% in users of inhaled glucocorticoids, depending on the diagnostic criteria. The use of breath-actuated metered-dose inhalers leads to high oropharyngeal deposition of glucocorticoids, which can be 80% of the delivered dose. The effects of budesonide aqueous nasal spray on adrenal function was studied in a 6-week double-blind, placebo-controlled study in 78 patients with allergic rhinitis aged 2–5 years. The pulmonary and extra-pulmonary effects of cumulative doses of formoterol and salbutamol have also been compared.

View all citing articles on Scopus

^f1: Author for correspondence.

View full text

ReviewEffects of S-salbutamol on Human Isolated Bronchus

Abstract

Review
Effects of S-salbutamol on Human Isolated Bronchus