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Molecular Pharmacology Oct 2021The drugs salmeterol, formoterol, and salbutamol constitute the frontline treatment of asthma and other chronic pulmonary diseases. These drugs activate the 2-adrenergic...
The drugs salmeterol, formoterol, and salbutamol constitute the frontline treatment of asthma and other chronic pulmonary diseases. These drugs activate the 2-adrenergic receptors (2-AR), a class A G protein-coupled receptor (GPCR), and differ significantly in their clinical onset and duration of actions. According to the microkinetic model, the long duration of action of salmeterol and formoterol compared with salbutamol were attributed, at least in part, to their high lipophilicity and increased local concentrations in the membrane near the receptor. However, the structural and molecular bases of how the lipophilic drugs reach the binding site of the receptor from the surrounding membrane remain unknown. Using a variety of classic and enhanced molecular dynamics simulation techniques, we investigated the membrane partitioning characteristics, binding, and unbinding mechanisms of the ligands. The obtained results offer remarkable insight into the functional role of membrane lipids in the ligand association process. Strikingly, salmeterol entered the binding site from the bilayer through transmembrane helices 1 and 7. The entry was preceded by membrane-facilitated rearrangement and presentation of its phenyl-alkoxy-alkyl tail as a passkey to an access route gated by F193, a residue known to be critical for salmeterol's affinity. Formoterol's access is through the aqueous path shared by other 2-AR agents. We observed a novel secondary path for salbutamol that is distinct from its primary route. Our study offers a mechanistic description for the membrane-facilitated access and binding of ligands to a membrane protein and establishes a groundwork for recognizing membrane lipids as an integral component in the molecular recognition process. SIGNIFICANCE STATEMENT: The cell membrane's functional role behind the duration of action of long-acting β2-adrenergic receptor (β2-AR) agonists such as salmeterol has been a subject of debate for a long time. This study investigated the binding and unbinding mechanisms of the three commonly used β2-AR agonists, salmeterol, formoterol, and salbutamol, using advanced simulation techniques. The obtained results offer unprecedented insights into the active role of membrane lipids in facilitating access and binding of the ligands, affecting the molecular recognition process and thus their pharmacology.
Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Binding Sites; Cell Membrane; Delayed-Action Preparations; Formoterol Fumarate; Humans; Molecular Docking Simulation; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Salmeterol Xinafoate
PubMed: 34334369
DOI: 10.1124/molpharm.121.000285 -
The American Journal of Case Reports Oct 2018BACKGROUND Asthma is a common disease in the U.S.
UNLABELLED
BACKGROUND Asthma is a common disease in the U.S.
POPULATION
Initial therapy in the stepwise approach for asthma management is short-acting β₂-agonist (SABA) therapy as needed for symptom control. However, a significant adverse event that can occur with administration is bronchospasm. Here, we report a case of paradoxical bronchospasm with administration of SABAs during multiple pulmonary function tests (PFTs). CASE REPORT A 25-year-old, non-smoking, African American male with a history of moderate asthma and allergic rhinitis treated with fluticasone/salmeterol diskus, albuterol hydrofluoroalkane (HFA) inhaler, and montelukast presented to our clinic complaining of recurrent episodes of acute shortness of breath immediately following each administration of albuterol for 4 weeks. PFTs were performed with levalbuterol (Xopenex) and albuterol (ProAir), yielding significant decrease in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Nebulized albuterol and ipratropium bromide also improved FEV1 and FVC. He was successfully transitioned to an ipratropium rescue inhaler for asthma exacerbations. CONCLUSIONS Paradoxical bronchoconstriction is the unexpected constriction of smooth muscle walls of the bronchi that occurs in the setting of an expected bronchodilatory response. This phenomenon has been observed with β₂-agonist-containing inhaler formulations and is an under-recognized adverse event. Theories suggest that the formulation excipients can trigger airway hyperresponsiveness in patients with allergically inflamed airways. Removal of excipients or use of anticholinergic inhalers improved respiratory function. Clinicians should be aware of paradoxical bronchospasm as an adverse effect with common inhaler formulations containing β₂-agonists and counsel patients accordingly in the appropriate clinical setting.
Topics: Adrenergic beta-2 Receptor Agonists; Adult; Airway Remodeling; Albuterol; Asthma; Bronchoconstriction; Humans; Male
PubMed: 30297688
DOI: 10.12659/AJCR.910888 -
British Journal of Pharmacology Nov 2021Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung...
BACKGROUND AND PURPOSE
Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration.
EXPERIMENTAL APPROACH
Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol and fluticasone propionate (n = 12), or oral salbutamol and propranolol (n = 6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 h). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 h after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings.
KEY RESULTS
Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung than in plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable. For orally administered drugs, epithelial-lining-fluid concentrations were overestimated in bronchoalveolar-lavage-generated profiles.
CONCLUSION AND IMPLICATIONS
Combining pharmacokinetic data derived from several individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.
Topics: Albuterol; Fluticasone; Humans; Lung; Pharmaceutical Preparations; Salmeterol Xinafoate
PubMed: 34250588
DOI: 10.1111/bph.15621 -
Journal of Applied Physiology... Apr 2023We analyzed the fractal dimension (Df) of lung gas and blood distribution imaged with synchrotron radiation K-edge subtraction (KES), in six anesthetized adult New...
We analyzed the fractal dimension (Df) of lung gas and blood distribution imaged with synchrotron radiation K-edge subtraction (KES), in six anesthetized adult New Zealand White rabbits. KES imaging was performed in upright position during stable Xe gas (64% in O) inhalation and iodine infusion (Iomeron, 350 mg/mL), respectively, at baseline and after induced bronchoconstriction by aerosolized methacholine (125 mg/mL, 90 s) and bronchodilator (salbutamol, 10 mg/mL, 90 s) inhalation, at two axial image levels. Lung Xe and iodine images were segmented, and maps of regional lung gas and blood fractions were computed. The Df of lung gas (Df) and blood (Df) distribution was computed based on a log-log plot of variation coefficient as a function of region volume. Df decreased significantly during bronchoconstriction ( < 0.0001), and remained low after salbutamol. Df depended on the axial image level ( < 0.0001), but did not change with bronchoconstriction. Df was significantly associated with arterial [Formula: see text] ( = 0.67, = 0.002), and negatively associated with [Formula: see text] ( = -0.62, = 0.006), respiratory resistance ( = -0.58, = 0.011), and elastance ( = -0.55, = 0.023). These data demonstrate the reduced Df of gas distribution during acute bronchoconstriction, and the association of this parameter with physiologically meaningful variables. This finding suggests a decreased complexity and space-filling properties of lung ventilation during bronchoconstriction, and could serve as a functional imaging biomarker in obstructive airway diseases. Here, we used an energy-subtractive imaging technique to assess the fractal dimension (Df) of lung gas and blood distribution and the effect of acute bronchoconstriction. We found that Df of gas significantly decreases in bronchoconstriction. Conversely, Df of blood exhibits gravity-dependent changes only, and is not affected by acute bronchoconstriction. Our data show that the fractal dimension of lung gas detects the emergence of clustered rather than scattered loss of ventilatory units during bronchoconstriction.
Topics: Animals; Rabbits; Bronchoconstriction; Asthma; Synchrotrons; Fractals; Pulmonary Ventilation; Lung; Albuterol; Iodine
PubMed: 36927142
DOI: 10.1152/japplphysiol.00051.2023 -
Molecules (Basel, Switzerland) Oct 2023The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human...
Development of an HPLC-MS/MS Method for Chiral Separation and Quantitation of ()- and ()-Salbutamol and Their Sulfoconjugated Metabolites in Urine to Investigate Stereoselective Sulfonation.
The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human urine to allow for bioanalytical quantitation of the targeted analytes and investigations of stereoselectivity in the sulfonation pathway of human phase Ⅱ metabolism. For analytical method development, a systematic screening of columns and mobile phases to develop a separation via enantiomerically selective high performance liquid chromatography was performed. Electrospray ionization settings were optimized via multiple-step screening and a full factorial design-of-experiment. Both approaches were performed matrix-assisted and the predicted values were compared. The full factorial design was superior in terms of prediction power and knowledge generation. Performing a longitudinal excretion study in one healthy volunteer allowed for the calculation of excretion rates for all four targeted analytes. For this proof-of-concept, either racemic salbutamol or enantiopure levosalbutamol was administered perorally or via inhalation, respectively. A strong preference for sulfonation of ()-salbutamol for inhalation and peroral application was found in experiments. In previous studies phenol sulfotransferase 1A3 was described to be mainly responsible for salbutamol sulfonation in humans. Thus, in vitro and in silico investigations of the stereoselectivity of sulfotransferase 1A3 complemented the study and confirmed these findings.
Topics: Humans; Albuterol; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Levalbuterol; Administration, Inhalation; Stereoisomerism
PubMed: 37894685
DOI: 10.3390/molecules28207206 -
The Cochrane Database of Systematic... Jan 2017Inhaled short-acting anticholinergics (SAAC) and short-acting beta₂-agonists (SABA) are effective therapies for adult patients with acute asthma who present to the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Inhaled short-acting anticholinergics (SAAC) and short-acting beta₂-agonists (SABA) are effective therapies for adult patients with acute asthma who present to the emergency department (ED). It is unclear, however, whether the combination of SAAC and SABA treatment is more effective in reducing hospitalisations compared to treatment with SABA alone.
OBJECTIVES
To conduct an up-to-date systematic search and meta-analysis on the effectiveness of combined inhaled therapy (SAAC + SABA agents) vs. SABA alone to reduce hospitalisations in adult patients presenting to the ED with an exacerbation of asthma.
SEARCH METHODS
We searched MEDLINE, Embase, CINAHL, SCOPUS, LILACS, ProQuest Dissertations & Theses Global and evidence-based medicine (EBM) databases using controlled vocabulary, natural language terms, and a variety of specific and general terms for inhaled SAAC and SABA drugs. The search spanned from 1946 to July 2015. The Cochrane Airways Group provided search results from the Cochrane Airways Group Register of Trials which was most recently conducted in July 2016. An extensive search of the grey literature was completed to identify any other potentially relevant studies.
SELECTION CRITERIA
Included studies were randomised or controlled clinical trials comparing the effectiveness of combined inhaled therapy (SAAC and SABA) to SABA treatment alone to prevent hospitalisations in adults with acute asthma in the emergency department. Two independent review authors assessed studies for inclusion using pre-determined criteria.
DATA COLLECTION AND ANALYSIS
For dichotomous outcomes, we calculated individual and pooled statistics as risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) using a random-effects model and reporting heterogeneity (I²). For continuous outcomes, we reported individual trial results using mean differences (MD) and pooled results as weighted mean differences (WMD) or standardised mean differences (SMD) with 95% CIs using a random-effects model.
MAIN RESULTS
We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias.Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I² = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02).Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV₁) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I² = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I² = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I² = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I² = 0%; moderate quality of evidence) than participants receiving SABA alone.Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I² = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone.
AUTHORS' CONCLUSIONS
Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild-moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone.
Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Anti-Asthmatic Agents; Asthma; Atropine; Cholinergic Antagonists; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Ipratropium; Levalbuterol; Metaproterenol; Randomized Controlled Trials as Topic; Scopolamine Derivatives
PubMed: 28076656
DOI: 10.1002/14651858.CD001284.pub2 -
Journal of Veterinary Internal Medicine Jul 2016The (R)-enantiomer of racemic albuterol (levalbuterol) has bronchodilatory properties whereas the (S)-enantiomer causes adverse effects in human airways, animal models,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The (R)-enantiomer of racemic albuterol (levalbuterol) has bronchodilatory properties whereas the (S)-enantiomer causes adverse effects in human airways, animal models, and isolated equine bronchi. Levalbuterol is commercially available and improves pulmonary function of asthmatic patients with a longer duration of effect than albuterol.
OBJECTIVE
To determine the dose at which inhaled levalbuterol produces maximal bronchodilatory effect (EDmax) and determine its duration of action in recurrent airway obstruction (RAO)-affected horses in comparison to racemic albuterol.
ANIMALS
Nine horses with inducible and reversible RAO.
METHODS
Randomized, crossover trial. Horses were challenged with moldy hay to induce airway obstruction. Horses were treated with nebulized albuterol or levalbuterol chosen randomly. Pulmonary function testing (PFT) was measured before and for up to 3 hours after bronchodilatation challenge. Maximum change in transpulmonary pressure (DPmax ) was measured to assess the dose effect and duration of action of each drug. After a 24 hours washout period, the bronchodilatation challenge was repeated with the second bronchodilator.
RESULTS
The duration of effect was 60 minutes for albuterol and 120 minutes for levalbuterol. The dose of bronchodilator EDmax was not significantly different between albuterol and levalbuterol (EDmax = 125.0 [125-125 μg] and EDmax = 188 [125-188 μg] respectively; P = .068). The magnitude of bronchodilatation was not significantly different between the 2 treatments (61.1 and 59.9% decrease in DPmax for albuterol and levalbuterol respectively; P = .86).
CONCLUSIONS AND CLINICAL IMPORTANCE
Levalbuterol is as effective a bronchodilator as albuterol; although levalbuterol lasts twice as long as albuterol, its duration of action is still too short to make it practical for RAO treatment.
Topics: Albuterol; Animals; Bronchodilator Agents; Cross-Over Studies; Female; Horse Diseases; Horses; Levalbuterol; Lung Diseases, Obstructive; Male
PubMed: 27282625
DOI: 10.1111/jvim.14320 -
Life Science Alliance Mar 2023The transient receptor potential vanilloid 4 (TRPV4) ion channel is present in different tissues including those of the airways. This channel is activated in response to...
The transient receptor potential vanilloid 4 (TRPV4) ion channel is present in different tissues including those of the airways. This channel is activated in response to stimuli such as changes in temperature, hypoosmotic conditions, mechanical stress, and chemicals from plants, lipids, and others. TRPV4's overactivity and/or dysfunction has been associated with several diseases, such as skeletal dysplasias, neuromuscular disorders, and lung pathologies such as asthma and cardiogenic lung edema and COVID-19-related respiratory malfunction. TRPV4 antagonists and blockers have been described; nonetheless, the mechanisms involved in achieving inhibition of the channel remain scarce, and the search for safe use of these molecules in humans continues. Here, we show that the widely used bronchodilator salbutamol and other ligands of β-adrenergic receptors inhibit TRPV4's activation. We also demonstrate that inhibition of TRPV4 by salbutamol is achieved through interaction with two residues located in the outer region of the pore and that salbutamol leads to channel closing, consistent with an allosteric mechanism. Our study provides molecular insights into the mechanisms that regulate the activity of this physiopathologically important ion channel.
Topics: Humans; Transient Receptor Potential Channels; TRPV Cation Channels; Receptors, Adrenergic, beta; Ligands; COVID-19; Albuterol
PubMed: 36549871
DOI: 10.26508/lsa.202201704 -
Journal of Neurology Jun 2023Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between...
OBJECTIVES
Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ. Based on these findings, we identified cases of motor neuropathy with NMJ dysfunction and assessed the effect of salbutamol on motor function.
METHODS
Cases of motor neuropathy with significant NMJ dysfunction, were identified using repetitive nerve stimulation and single fibre electromyography. Oral salbutamol was administered for 12 months. Repeat neurophysiological and clinical assessments were undertaken at baseline, 6 months and 12 months.
RESULTS
Significant defects of neuromuscular transmission were identified in 15 patients harbouring a range of genetic defects, including mutations in GARS1, DNM2, SYT2 and DYNC1H. No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue. In addition, no clear effect on neurophysiological parameters was seen in patients treated with salbutamol. Side-effects due to off-target beta-adrenergic effects were significant in the patient cohort.
CONCLUSION
These results highlight the involvement of the NMJ in several subtypes of motor neuropathies, including subtypes of neuropathy due to deficits in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetases. Whether the NMJ dysfunction is simply due to muscle reinnervation or a pathology unrelated to denervation is unknown. The involvement of the NMJ may represent a novel therapeutic target in these conditions. However, treatment regimens will need to be more targeted for patients with primary inherited defects of neuromuscular transmission.
Topics: Humans; Albuterol; Genetic Heterogeneity; Neuromuscular Junction; Myasthenic Syndromes, Congenital; Charcot-Marie-Tooth Disease
PubMed: 36869887
DOI: 10.1007/s00415-023-11643-z -
The European Respiratory Journal Nov 1994Dizziness, together with hypotension and faintness, are well-known adverse drug reactions of salbutamol that have been related to its cardiovascular effects. However, we...
Dizziness, together with hypotension and faintness, are well-known adverse drug reactions of salbutamol that have been related to its cardiovascular effects. However, we could find no published reference to vertigo in patients taking salmeterol, in the absence of cardiovascular alterations. We present the case of a woman who experienced four independent episodes of vertigo lasting 36 h each, following four inhalations of salmeterol several months apart. The close temporal relationship between the inhalation of salmeterol and the onset of symptoms, as well as the positive re-exposures, reinforce this alleged association.
Topics: Administration, Inhalation; Aged; Albuterol; Asthma; Bronchodilator Agents; Female; Humans; Salmeterol Xinafoate; Vertigo
PubMed: 7875287
DOI: No ID Found