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American Journal of Physiology. Lung... Dec 2012Maintenance of airway tone, prevention of airway obstruction, and acute relief from bronchospasm are key targets of asthma therapy. This role is currently performed by...
Maintenance of airway tone, prevention of airway obstruction, and acute relief from bronchospasm are key targets of asthma therapy. This role is currently performed by β-agonists. However, chronic use of β-agonists to treat asthma is associated with desensitization of β-agonist signaling and a resultant loss of bronchodilator effect, worsening of airway hyperreactivity, and increased incidence of asthma-related morbidity and mortality. There have been several attempts to identify novel non-β-agonist bronchodilators including ATP-sensitive potassium channel (K(ATP)) agonists such as cromakalim and its active enantiomer BRL-38227 and the cGMP activators atrial natriuretic peptide (ANP) and BAY 41-22722. However, these either have not made it to clinical trial, required high doses, had little effect in patients, or had a high incidence of side effects. Recent data suggests that a novel bronchodilator target exists, the bitter taste receptor TAS2R. Two recent studies [An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA Jr, Liggett SB. Am J Physiol Lung Cell Mol Physiol 303: L304-L311, 2012; Pulkkinen V, Manson ML, Säfholm J, Adner M, Dahlén SE. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00205.2012.] provide new understanding of the signaling pathways utilized by TAS2Rs to mediate their bronchodilatory effects and how TAS2R-mediated bronchodilation is affected by β-agonist signaling desensitization. As our understanding of TAS2Rs and their agonists increases, they move closer to a viable therapeutic option; however, further definition is still required and questions remain to be answered. This editorial focus discusses these studies within the context of existing literature and raises questions and challenges for the future development of bitter (better?) therapies for asthma.
Topics: Animals; Bronchodilator Agents; Chloroquine; Humans; Male; Muscle Relaxation; Muscle, Smooth; Quaternary Ammonium Compounds; Receptors, Adrenergic, beta-2; Receptors, G-Protein-Coupled; Respiratory Physiological Phenomena; Respiratory System; Tachyphylaxis; Trachea
PubMed: 23023969
DOI: 10.1152/ajplung.00303.2012 -
Pediatric Pulmonology Nov 2023Mechanisms underlying lung dysfunction after preterm birth are poorly understood. Studying phenotypes of prematurity-associated lung disease may aid understanding of...
INTRODUCTION
Mechanisms underlying lung dysfunction after preterm birth are poorly understood. Studying phenotypes of prematurity-associated lung disease may aid understanding of underlying mechanisms. Preterm-born children with and without lung dysfunction and term controls were assessed using oscillometry before and after exercise, and after postexercise bronchodilation.
METHODS
Preterm-born children, born at gestation of 34 weeks or less, were classified into those with prematurity-associated obstructive lung disease (POLD; FEV < LLN, FEV /FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (pPRISm; FEV < LLN, FEV /FVC ≥ LLN) and compared to preterm (FEV ≥ LLN) and term controls (%predicted FEV > 90%). All children underwent cardiopulmonary exercise, and oscillometry assessment at baseline, postexercise, and after postexercise bronchodilator administration.
RESULTS
From 241 participants aged 7-12 years, complete data were available from 179: 15 children with POLD and 11 with pPRISm were compared with 93 preterm and 60 term controls. POLD group, when compared to both control groups, had impaired impedance, greater resistance, more negative (greater magnitude) reactance at low frequencies, and also had decreased compliance. pPRISm group demonstrated impaired reactance and compliance compared to term controls. No differences were noted between the preterm and term controls. Exercise had little impact on oscillometry values, but children with POLD had greatest improvements after postexercise bronchodilator administration, with decreased resistance and decreased magnitude of reactance, particularly at low frequencies.
CONCLUSION
Preterm-born children with obstructive airway disease had the greatest oscillometry impairments and the largest improvements after postexercise bronchodilator compared to control groups. Oscillometry can potentially be used to identify preterm-born children with lung disease to institute treatment.
Topics: Child; Female; Humans; Infant, Newborn; Bronchodilator Agents; Oscillometry; Forced Expiratory Volume; Premature Birth; Lung; Lung Diseases; Lung Diseases, Obstructive; Spirometry; Infant, Newborn, Diseases
PubMed: 37701982
DOI: 10.1002/ppul.26658 -
International Journal of Chronic... Oct 2010Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 μg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Animals; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Evidence-Based Medicine; Formoterol Fumarate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Treatment Outcome; United States
PubMed: 21037960
DOI: 10.2147/COPD.S4215 -
Journal of Applied Physiology... Dec 2019Bronchodilation alters both respiratory system resistance (Rrs) and reactance (Xrs) in asthma, but how changes in Rrs and Xrs compare, and respond differently in health...
Bronchodilation alters both respiratory system resistance (Rrs) and reactance (Xrs) in asthma, but how changes in Rrs and Xrs compare, and respond differently in health and asthma, in reflecting the contributions from the large and small airways has not been assessed. We assessed reversibility using spirometry and oscillometry in healthy and asthma subjects. Using a multibranch airway-tree model with the mechanics of upper airway shunt, we compared the effects of airway dilation and small airways recruitment to explain the changes in Rrs and Xrs. Bronchodilator decreased Rrs by 23.0 (19.0)% in 18 asthma subjects and by 13.5 (19.5)% in 18 healthy subjects. Estimated respiratory system elastance (Ers) decreased by 23.2 (21.4)% in asthma, with no significant decrease in healthy subjects. With the use of the model, airway recruitment of 15% across a generation of the small airways could explain the changes in Ers in asthma with no recruitment in healthy subjects. In asthma, recruitment accounted for 40% of the changes in Rrs, with the remaining explained by airway dilation of 6.8% attributable largely to the central airways. Interestingly, the same dilation magnitude explained the changes in Rrs in healthy subjects. Shunt only affected Rrs of the model. Ers was unaltered in health and unaffected by shunt in both groups. In asthma, Ers changed comparably to Rrs and could be attributed to small airways, while the change in Rrs was split between large and small airways. This implies that in asthma Ers sensed through Xrs may be a more effective measure of small airways obstruction and recruitment than Rrs. This is the first study to quantify to relative contributions of small and large airways to bronchodilator response in healthy subjects and patients with asthma. The response of the central airways to bronchodilator was similar in magnitude in both study groups, whereas the response of the small airways was significant among patients with asthma. These results suggest that low-frequency reactance and derived elastance are both sensitive measures of small airway function in asthma.
Topics: Adult; Airway Resistance; Asthma; Bronchioles; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Models, Biological; Young Adult
PubMed: 31647721
DOI: 10.1152/japplphysiol.01131.2018 -
American Journal of Health-system... Feb 2020Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality in the United States. Exacerbations- acute worsening of COPD symptoms-can... (Review)
Review
PURPOSE
Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality in the United States. Exacerbations- acute worsening of COPD symptoms-can be mild to severe in nature. Increased healthcare resource use is common among patients with frequent exacerbations, and exacerbations are a major cause of the high 30-day hospital readmission rates associated with COPD.
SUMMARY
This review provides a concise overview of the literature regarding the impact of COPD exacerbations on both the patient and the healthcare system, the recommendations for pharmacologic management of COPD, and the strategies employed to improve patient care and reduce hospitalizations and readmissions. COPD exacerbations significantly impact patients' health-related quality of life and disease progression; healthcare costs associated with severe exacerbation-related hospitalization range from $7,000 to $39,200. Timely and appropriate maintenance pharmacotherapy, particularly dual bronchodilators for maximizing bronchodilation, can significantly reduce exacerbations in patients with COPD. Additionally, multidisciplinary disease-management programs include pulmonary rehabilitation, follow-up appointments, aftercare, inhaler training, and patient education that can reduce hospitalizations and readmissions for patients with COPD.
CONCLUSION
Maximizing bronchodilation by the appropriate use of maintenance therapy, together with multidisciplinary disease-management and patient education programs, offers opportunities to reduce exacerbations, hospitalizations, and readmissions for patients with COPD.
Topics: Bronchodilator Agents; Hospitalization; Humans; Patient Readmission; Pulmonary Disease, Chronic Obstructive; United States
PubMed: 31930287
DOI: 10.1093/ajhp/zxz306 -
The American Journal of Managed Care Oct 2000Asthma is a chronic inflammatory disorder of the airways with a spectrum of presentations--from intermittent but mild symptoms to persistent symptoms with chronicity.... (Review)
Review
Asthma is a chronic inflammatory disorder of the airways with a spectrum of presentations--from intermittent but mild symptoms to persistent symptoms with chronicity. The key to successful management of the disease process is not only to treat the acute symptoms of wheezing, breathlessness, chest tightness, and cough but also to suppress the underlying inflammatory component. Management requires an integrated approach that incorporates patient education, control of environmental triggers, the judicious use of an appropriate agent to suppress underlying inflammation, addition of adjunctive therapy to optimize primary control, and the supplemental use of a bronchodilator to control breakthrough symptoms. Inhaled corticosteroids are the most effective agents for primary control of patients with persistent asthma. The nonsteroidal antiinflammatory agents cromolyn and nedocromil are alternative choices for primary control. Adjunctive or secondary controllers include maintenance bronchodilators such as salmeterol and long-acting theophylline as well as leukotriene modifiers. Concurrent therapy with an inhaled corticosteroid and a long-acting beta agonist has been shown to provide better asthma control than therapy with either an inhaled corticosteroid plus a leukotriene modifier, an inhaled corticosteroid plus theophylline, or higher doses of an inhaled corticosteroid alone.
Topics: Adult; Air Pollution, Indoor; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Disease Management; Drug Therapy, Combination; Humans; Patient Education as Topic; Practice Guidelines as Topic; United States
PubMed: 11184565
DOI: No ID Found -
Respiratory Research Oct 2023The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional...
INTRODUCTION
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS
After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS
Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSION
Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
Topics: Mice; Rats; Humans; Animals; Guinea Pigs; Bronchoconstriction; Methacholine Chloride; Amitriptyline; Histamine; Bronchodilator Agents; Serotonin; Acetylcholine; Sympathomimetics; 1-Methyl-3-isobutylxanthine; Dilatation; Lung; Asthma; Albuterol; Endothelins; Thromboxanes
PubMed: 37907918
DOI: 10.1186/s12931-023-02580-6 -
International Journal of Chronic... 2013Bronchodilators are central drugs in the management of patients with chronic obstructive pulmonary disease (COPD). Indacaterol was the first agent of the novel family of... (Review)
Review
Bronchodilators are central drugs in the management of patients with chronic obstructive pulmonary disease (COPD). Indacaterol was the first agent of the novel family of very long-acting β2-agonists to be used as an inhaled bronchodilator for COPD and provides 24-hour therapeutic action, thus allowing once-daily administration. Data from clinical trials show that indacaterol has a bronchodilator effect similar to that of the anticholinergic tiotropium bromide and slightly higher efficacy compared with the long-acting β2-agonists, salmeterol and formoterol. Moreover, the safety profile is excellent and comparable with that of placebo. Concerning adherence with drug treatment and real-life management in respect to long-acting β2-agonists, once-daily dosing makes indacaterol more convenient for COPD patients and is likely to enhance patient adherence. Other very long-acting β2-agonists currently in development include vilanterol, olodaterol, and carmoterol, and these have shown good characteristics for clinical use in the studies reported thus far.
Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Administration Schedule; Drug Design; Humans; Indans; Lung; Medication Adherence; Pulmonary Disease, Chronic Obstructive; Quinolones; Time Factors; Treatment Outcome
PubMed: 24082783
DOI: 10.2147/COPD.S49179 -
F1000Research 2019Bronchodilators, corticosteroids, and antibiotics are still key elements for treating chronic obstructive pulmonary disease in the 2019 Global Initiative for Chronic... (Review)
Review
Bronchodilators, corticosteroids, and antibiotics are still key elements for treating chronic obstructive pulmonary disease in the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations and this is due in part to our current inability to discover new drugs capable of decisively influencing the course of the disease. However, in recent years, information has been produced that, if used correctly, can allow us to improve the use of the available therapies.
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive
PubMed: 31508197
DOI: 10.12688/f1000research.19811.1 -
Respiratory Research Jan 2017As emphasized by international recommendations and largely confirmed by clinical experience, long-acting bronchodilators play a central role in the maintenance treatment... (Review)
Review
BACKGROUND
As emphasized by international recommendations and largely confirmed by clinical experience, long-acting bronchodilators play a central role in the maintenance treatment of chronic obstructive pulmonary disease (COPD) due to their proven efficacy in reducing airflow obstruction and improving symptoms.
MAIN BODY
There are some important aspects to define with regard to inhalation therapy for COPD, particularly those concerning the selection criteria and the optimal use of long-acting bronchodilators. First of all, it needs to be determined in which patients and clinical situations monotherapy with one bronchodilator, such as a long-acting muscarinic antagonist (LAMA), should be considered adequate, and in which cases the use of combination therapies, such as the "double bronchodilation" with a LAMA and a long-acting β2-agonist (LABA), should be preferred. Another critical issue concerns the effect of the frequency of daily administration of inhaled agents on the control of symptoms during the 24 h. COPD symptoms are known to exhibit considerable circadian variability with worsening in the early morning, and a significant proportion of patients have disease-related sleep disorders which can adversely affect their quality of life. The worsening of symptoms in the early morning may be due, at least in part, to a reduction in airway caliber caused by an increased "cholinergic tone" at night. As such, the coverage of nighttime and early morning symptoms is a reasonable therapeutic goal, which can be achieved by many patients using LAMAs such as aclidinium bromide twice daily (BID). Therapeutic adherence is known to be a multifactorial phenomenon that is frequently affected by other aspects than dosing frequency, including the technical features and ease of use of the inhalers. To this end, it should be mentioned that certain new-generation inhalers such as Genuair® have been associated in clinical trials with higher patient preference.
CONCLUSION
In this work, in addition to presenting an overview of the main evidence on the efficacy of COPD treatment with the LAMA aclidinium bromide BID, we suggest some selection criteria for the monotherapy with one long-acting bronchodilator or the combination therapy with LAMA and LABA in COPD patients, with particular reference to specific clinical scenarios.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Clinical Decision-Making; Dose-Response Relationship, Drug; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Tropanes
PubMed: 28100244
DOI: 10.1186/s12931-017-0506-0