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Pulmonary Pharmacology & Therapeutics Oct 2020Cough variant asthma (CVA) is the most common cause of chronic cough and responds well to bronchodilator therapy. Previous studies on methacholine -induced cough have...
BACKGROUND
Cough variant asthma (CVA) is the most common cause of chronic cough and responds well to bronchodilator therapy. Previous studies on methacholine -induced cough have shown that heightened cough response due to bronchoconstriction is a feature of CVA. The aim of this study was to assess Mch-induced cough as an indicator of bronchodilator-responsive cough (BRC).
METHODS
This was a single-center retrospective study of prolonged/chronic cough cases who underwent evaluation via spirometry, FeNO and bronchial challenge testing using Mch and capsaicin (C5). Resultant bronchoconstriction after Mch challenge was assessed by flow-volume curves measuring the expiratory flow of the partial flow-volume curve 40% above residual volume (PEF) and FEV. BRC was defined as a decrease in cough with bronchodilator therapy by 30% or more on a visual analog scoring scale.
RESULTS
Of the 100 patients evaluated, 63 were diagnosed with BRC. Mch-induced cough at a decrease in PEF of 35% (PC-PEF) was predictive of BRC on AUROC analysis with an AUC of 0.82 (95% CI 0.73-0.90) and cut-off of 24. The AUC for C5, FeNO and PC-FEV were 0.65, 0.47, and 0.58, respectively.
CONCLUSION
Compared to C5, FeNO and PC-FEV, Mch-induced cough better supports a diagnosis of BRC.
Topics: Bronchial Provocation Tests; Bronchodilator Agents; Cough; Forced Expiratory Volume; Humans; Methacholine Chloride; Retrospective Studies
PubMed: 33039668
DOI: 10.1016/j.pupt.2020.101962 -
Journal of Applied Physiology... Jan 1999To determine whether methacholine causes vagally mediated reflex constriction of airway smooth muscle, we administered methacholine to sheep either via the bronchial...
To determine whether methacholine causes vagally mediated reflex constriction of airway smooth muscle, we administered methacholine to sheep either via the bronchial artery or as an aerosol via tracheostomy into the lower airways. We then measured the contraction of an isolated, in situ segment of trachealis smooth muscle and determined the effect of vagotomy on the trachealis response. Administering methacholine to the subcarinal airways via the bronchial artery (0.5-10.0 microg/ml) caused dose-dependent bronchoconstriction and contraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased an average of 186% over baseline. Aerosolized methacholine (5-7 breaths of 100 mg/ml) increased trachealis tension by 58% and airways resistance by 183%. As the bronchial circulation in the sheep does not supply the trachea, we postulated that the trachealis contraction was caused by a reflex response to methacholine in the lower airways. Bilateral vagotomy essentially eliminated the trachealis response and the airways resistance change after lower airways challenge (either via the bronchial artery or via aerosol) with methacholine. We conclude that 1) methacholine causes a substantial reflex contraction of airway smooth muscle and 2) the assumption may not be valid that a response to methacholine in humans or experimental animals represents solely the direct effect on smooth muscle.
Topics: Aerosols; Animals; Bronchi; Bronchoconstrictor Agents; Infusions, Intra-Arterial; Methacholine Chloride; Reflex; Regional Blood Flow; Respiratory Muscles; Sheep; Vagus Nerve
PubMed: 9887142
DOI: 10.1152/jappl.1999.86.1.294 -
Cleveland Clinic Journal of Medicine Jan 2008
Review
Topics: Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Diagnosis, Differential; Health Status Indicators; Humans; Methacholine Chloride
PubMed: 18236728
DOI: 10.3949/ccjm.75.1.37 -
Allergy Dec 2001
Review
Topics: Bronchial Provocation Tests; Humans; Methacholine Chloride; Respiratory Hypersensitivity
PubMed: 11736739
DOI: 10.1034/j.1398-9995.2001.00148.x -
Respiratory Research Jul 2023Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested...
INTRODUCTION
Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested effects of Chronic Intermittent Hypoxia (CIH) - a hallmark of OSA - on airway hyperresponsiveness (AHR), in a rat model of chronic allergen-induced inflammation.
METHODS
Brown Norway rats were exposed to six weeks of CIH or normoxia (NORM) concurrent with weekly house dust mites (HDM) or saline (SAL) challenges. At endpoint, we assessed responses to seven Methacholine (Mch) doses (0, 4, 8, 16, 32, 64, 128 mg/mL) on a FlexiVent system (Scireq). Maximal (or plateau) responses (reactivity) for total respiratory system Resistance (R) and Elastance (E), Newtonian airway resistance (R a measure of central airways function) and tissue damping (G, a measure of distal airways function) were plotted.
RESULTS
HDM/CIH-treated animals demonstrated the highest reactivity to Mch in R and E compared to all other groups (HDM/NORM, SAL/CIH and SAL/NORM p < 0.05 for all comparisons, for doses 5-7 for R, and for doses 4-7 for E). The enhanced R response was due to an increase in G (doses 4-7, p < 0.05 for comparisons to all other groups), whereas R was not affected by CIH.
CONCLUSIONS
In rats chronically challenged with HDM, concurrent CIH exposure induces AHR primarily in the distal airways, which affects the respiratory system frequency-dependent elastic properties.
Topics: Rats; Animals; Pyroglyphidae; Allergens; Respiratory Hypersensitivity; Lung; Hypoxia; Methacholine Chloride; Inflammation; Sleep Apnea, Obstructive; Disease Models, Animal
PubMed: 37468919
DOI: 10.1186/s12931-023-02493-4 -
The cumulative effect of methacholine on large and small airways when deep inspirations are avoided.Respirology (Carlton, Vic.) Mar 2023The effect of serial incremental concentrations of methacholine is only slightly cumulative when assessed by spirometry. This limited cumulative effect may be attributed...
BACKGROUND AND OBJECTIVE
The effect of serial incremental concentrations of methacholine is only slightly cumulative when assessed by spirometry. This limited cumulative effect may be attributed to the bronchodilator effect of deep inspirations that are required between concentrations to measure lung function. Using oscillometry, the response to methacholine can be measured without deep inspirations. Conveniently, oscillometry can also dissociate the contribution of large versus small airways. Herein, oscillometry was used to assess the cumulative effect of methacholine in the absence of deep inspirations on large and small airways.
METHODS
Healthy and asthmatic volunteers underwent a multiple-concentration methacholine challenge on visit 1 and a single-concentration challenge on visit 2 using the highest concentration of visit 1. The maximal response was compared between visits to assess the cumulative effect of methacholine. The lung volume was also measured after the final concentration to assess hyperinflation.
RESULTS
In both healthy and asthmatic subjects, increases in resistance at 19 Hz (R ), reflecting large airway narrowing, did not differ between the multiple- and the single-concentration challenge. However, increases in resistance at 5 Hz (R ) minus R , reflecting small airway narrowing, were 117 and 270% greater in the multiple- than the single-concentration challenge in healthy (p = 0.006) and asthmatic (p < 0.0001) subjects, respectively. Hyperinflation occurred with both challenges and was greater in the multiple- than the single-concentration challenge in both groups.
CONCLUSION
Without deep inspirations, the effect of methacholine is cumulative on small airways but not on large airways. Lung hyperinflation and derecruitment may partially explain these different responses.
Topics: Humans; Methacholine Chloride; Asthma; Respiratory System; Bronchial Provocation Tests; Lung Volume Measurements; Airway Resistance; Forced Expiratory Volume
PubMed: 36210352
DOI: 10.1111/resp.14387 -
Respirology (Carlton, Vic.) Jul 2019
Topics: Aged; Asthma; Humans; Methacholine Chloride; Obesity; Phenotype; Respiratory System
PubMed: 30901134
DOI: 10.1111/resp.13533 -
The Journal of Allergy and Clinical... Jun 2006Methacholine tests are widely used as a diagnostic aid for asthma. Their strength has been reputed to be the high sensitivity and very infrequent occurrence of... (Review)
Review
Methacholine tests are widely used as a diagnostic aid for asthma. Their strength has been reputed to be the high sensitivity and very infrequent occurrence of false-negative test results (ie, high negative predictive value). There are 2 commonly used methods that have been outlined by the American Thoracic Society. These methods were thought to give equivalent results. However, in 3 investigations in which we have compared the 2 methods, we have demonstrated a marked lack of comparability. In subjects with borderline to mild airway responsiveness (tidal breathing, methacholine PC20 >2 mg/mL), the 5 deep inhalations required of the dosimeter method produce marked bronchoprotection in some subjects with asthma. The result of this bronchoprotection is that in 55 subjects with asthma, 50% of those whose tidal breathing PC20 value was greater than 2 mg/mL and 25% of the total had negative methacholine challenge results. This indicates that the standardized dosimeter method has an unacceptable loss of diagnostic sensitivity. We recommend that the dosimeter method not be performed as outlined by the American Thoracic Society and that methacholine should be administered by means of submaximal inhalations or tidal breathing.
Topics: Administration, Inhalation; Asthma; Bronchoconstrictor Agents; Humans; Methacholine Chloride; Reproducibility of Results; Total Lung Capacity
PubMed: 16750982
DOI: 10.1016/j.jaci.2006.02.038 -
The Annals of Pharmacotherapy 1993To report the occurrence of acute bronchospasm in one asthmatic patient and increased bronchial reactivity in another following the administration of a single dose of...
OBJECTIVE
To report the occurrence of acute bronchospasm in one asthmatic patient and increased bronchial reactivity in another following the administration of a single dose of oral baclofen.
CASE SUMMARY
On two separate occasions, a 46-year-old asymptomatic asthmatic man developed dyspnea and chest tightness one hour after the ingestion of baclofen 40 mg. Pulmonary function studies revealed a significant decrease in airflow relative to baseline. A 33-year-old asymptomatic woman with a history of exercise-induced dyspnea and wheezing displayed bronchial hyperresponsiveness to inhaled metacholine 2 hours after ingesting 40 mg of baclofen. The patient had had a negative methacholine challenge test 72 hours earlier.
DISCUSSION
The gamma-aminobutyric acid-agonist baclofen has been shown to reduce airway responsiveness to various bronchoconstricting agents in animal studies. The etiology of this seemingly paradoxical response in two patients is unclear, but may offer insight into the neurally mediated airway constriction that occurs in asthma.
CONCLUSIONS
Clinicians should be aware of the possibility of baclofen-induced bronchospasm, especially in asthmatic patients.
Topics: Adult; Baclofen; Bronchial Spasm; Bronchoconstriction; Drug Interactions; Female; Humans; Male; Methacholine Chloride; Middle Aged
PubMed: 8364269
DOI: 10.1177/106002809302700713 -
The Journal of Clinical Investigation Sep 2023Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with...
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.
Topics: Humans; Mice; Animals; Guinea Pigs; Methacholine Chloride; Ligands; Asthma; Lung; Binding Sites; Receptors, Adrenergic, beta-2
PubMed: 37432742
DOI: 10.1172/JCI167337