tiotropium-bromide and Cough

Cough in asthma predicts disease severity, prognosis, and is a common and troublesome symptom. Cough is the archetypal airway neuronal reflex, yet little is understood about the underlying neuronal mechanisms. It is generally assumed that symptoms arise because of airway hyper-responsiveness and/or airway inflammation, but despite using inhaled corticosteroids and bronchodilators targeting these pathologies, a large proportion of patients have persistent coughing. This review focuses on the prevalence and impact of cough in asthma and explores data from pre-clinical and clinical studies which have explored neuronal mechanisms of cough and asthma. We present evidence to suggest patients with asthma have evidence of neuronal dysfunction, which is further heightened and exaggerated by both bronchoconstriction and airway eosinophilia. Identifying patients with excessive coughing with asthma may represent a neuro-phenotype and hence developing treatment for this symptom is important for reducing the burden of disease on patients' lives and currently represents a major unmet clinical need.

Topics: Animals; Asthma; Axons; Bronchoconstriction; Bronchodilator Agents; Cough; Humans; Neurons, Efferent; Parasympathetic Nervous System; Tiotropium Bromide

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Topics: Acetylcholine; Animals; Bronchodilator Agents; Cholinergic Antagonists; Cough; Humans; Inflammation; Lung; Mucus; Parasympathetic Nervous System; Respiratory System; Scopolamine Derivatives; Tiotropium Bromide

We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS).. We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial.. A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 μg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS.. A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders.. Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma.. Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Capsaicin; Cough; Drug Therapy, Combination; Humans; Quality of Life; Reflex; Theophylline; Tiotropium Bromide

The use of long-acting bronchodilators is an essential component of the management of chronic obstructive pulmonary disease (COPD). The GOLDEN 5 Phase III, randomized, active-controlled, open-label study was conducted to evaluate the long-term safety and tolerability of a nebulized glycopyrrolate formulation (SUN-101) delivered via the investigational eFlow. Subjects were randomized in a 4:3 ratio to nebulized glycopyrrolate 50 μg twice daily (BID) or tiotropium 18 μg once daily (OD) and treated for 48 weeks. Subjects represented the general COPD population with real-world characteristics including severe disease, presence of comorbidities, and receiving background COPD therapy. Primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Secondary endpoints included the number of subjects with major adverse cardiovascular events (MACE); change from baseline in trough forced expiratory volume in 1 s (FEV. 1086 subjects received at least one dose of study drug. The overall incidence of TEAEs was comparable for subjects treated with glycopyrrolate (69.4%) or tiotropium (67.0%). Serious TEAEs occurred at similar rates in both treatment groups (glycopyrrolate, 12.3%; tiotropium, 10.5%). The most frequent TEAEs were COPD exacerbation/worsening and cough. Discontinuation due to TEAEs was higher in the glycopyrrolate group (10.0%) than the tiotropium group (2.8%) and related, in part, to the open-label study design, prior use of long-acting muscarinic antagonists and aerosol-airway interactions. Fewer subjects in the glycopyrrolate group experienced MACE (glycopyrrolate, n = 3 [0.5%]; tiotropium, n = 8 [1.7%]). Nebulized glycopyrrolate treatment resulted in improvements in trough FEV. Treatment with nebulized glycopyrrolate was well tolerated over 48 weeks with the most common adverse events being COPD worsening and cough. The overall and cardiac safety and tolerability profile and improvements in pulmonary function and patient-reported health outcomes support the use of nebulized glycopyrrolate as a maintenance treatment for moderate-to-very-severe COPD.. NCT02276222.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cough; Female; Forced Expiratory Volume; Gastrointestinal Diseases; Glycopyrrolate; Headache; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections; Severity of Illness Index; Tiotropium Bromide; Vital Capacity

Increased sputum production is an important feature of COPD, in which a large amount of secretions stagnated in the respiratory lumen may aggravate airflow limitation, impair airway mucociliary transport, and cause recurrent respiratory infection and, hence, acute exacerbations of the diseases. There is evidence that airway mucus hypersecretion is associated with the severity and prognosis of COPD, but the symptoms are generally difficult to treat.. In an open, non-controlled study, we examined the effect of the anticholinergic agent tiotropium on airway mucus hypersecretion in 22 COPD patients. After a 4-week run-in period, the patients received 18 μg of tiotropium once daily delivered through the handihaler for 8 weeks, while symptoms and their impact associated with sputum were scored according to cough and sputum assessment questionnaire (CASA-Q). At week 0 and week 8, spirometry was performed before and 30 min after the administration of albuterol. To test the effect of tiotropium on airway mucociliary transport, nasal clearance time was measured. To evaluate airway mucus production, solid composition of the sputum (dry/wet weight ratio) was measured.. Treatment with tiotropium increased both prebronchodilator FEV1 and postbronchodilator FEV1. Tiotropium decreased cough symptom scores and provided with favorable influences on sputum-related symptoms, and none of the patients complained of worsening of the symptoms judging from the CASA-Q score. Both solid composition of the sputum and mucin contents decreased and nasal clearance time was shortened from 29.4 ± 5.1 to 20.6 ± 4.1min (p < 0.05) during the 8-week treatment.. Tiotropium decreases symptoms associated with sputum in COPD patients, an effect that may be related to the inhibition of airway mucus hypersecretion and improvement of airway mucociliary clearance.

Topics: Aged; Bronchodilator Agents; Cough; Female; Humans; Male; Mucociliary Clearance; Mucus; Pulmonary Disease, Chronic Obstructive; Spirometry; Sputum; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).. Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0-24) at week 6. Secondary and additional endpoints included FEV1 AUC12-24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety.. Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0-24 and FEV1 AUC12-24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group.. Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

Topics: Aged; Area Under Curve; Bronchodilator Agents; Circadian Rhythm; Cough; Disease Progression; Double-Blind Method; Dry Powder Inhalers; Dyspnea; Female; Forced Expiratory Volume; Headache; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Preference; Pharyngitis; Pulmonary Disease, Chronic Obstructive; Respiratory Sounds; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Tropanes; Xerostomia

Micronodular lesions are common findings in lung imaging. As an important differential diagnosis, we describe a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia; it is notable that the diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is often delayed. This case provides supporting evidence to establish lung biopsy by cryotechnique as the option of first choice when considering a diagnostic strategy for micronodular lung lesions.. We report a case of a 65-year-old white woman who presented with obstructive symptoms of chronic coughing and dyspnea confirmed by conventional lung function tests. A computed tomography scan presented disseminated micronodules in all the lobes of her lungs. With the help of bronchoscopic cryobiopsy it was possible to obtain a high yield sample of lung parenchyma. On histologic examination, the micronodules correlated with a diffuse neuroendocrine cell hyperplasia. In the context of clinical symptoms, radiological aspects, and histomorphological aspects we made the diagnosis of a diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Obstructive symptoms were treated with inhaled steroids and beta-2-mimetics continuously. A comparison between current computed tomography scans of our patient and scans of 2014 revealed no significant changes. Last ambulatory checks occurred in January and May of 2016. The course of disease and the extent of limitation of lung function have remained stable.. The diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is best made in a multidisciplinary review including clinical presentation, lung imaging, and histomorphological aspects. This report and current literature indicate that transbronchial lung cryobiopsy can be used as a safe and practicable tool to obtain high quality biopsies of lung parenchyma in order to diagnose micronodular lesions of the lung.

Topics: Aged; Albuterol; Anti-Inflammatory Agents; Biopsy; Bronchodilator Agents; Budesonide; Cough; Cryosurgery; Dyspnea; Female; Formoterol Fumarate; Humans; Hyperplasia; Lung; Lung Diseases, Interstitial; Neuroendocrine Cells; Prognosis; Respiratory Function Tests; Thoracic Surgery, Video-Assisted; Tiotropium Bromide; Tomography, X-Ray Computed; Treatment Outcome

Long-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min). Aclidinium 4 mg/mL and tiotropium 200 μg/mL inhaled in 1 min proved to have similar protective effect on methacholine-induced bronchoconstriction in anesthetized animals. The total dosage employed for aclidinium and tiotropium was 4 mg and 200 μg, respectively. In awake animals, similar reductions in the cough number were observed following 10-min inhalation of each drug with a slight, not significant tendency to higher antitussive effects for aclidinium. In anesthetized animals, 1-min inhalation of each drug caused similar depressant effects on cough responses induced by both mechanical and chemical stimulation. A complete suppression of cough responses to mechanical stimuli was seen in some preparations. The results strongly suggest that the LAMA-induced downregulation of cough may be mediated not only by transient receptor potential vanilloid type 1 channels, as already reported, but also by acid-sensing ion channels and mechanoreceptors. The route of administration along with the more rapid hydrolysis of aclidinium into inactive metabolites minimize potential systemic side effects and give to this drug a very favorable safety profile.

Topics: Administration, Inhalation; Anesthesia; Animals; Antitussive Agents; Bronchoconstriction; Bronchodilator Agents; Cough; Delayed-Action Preparations; Disease Models, Animal; Male; Methacholine Chloride; Muscarinic Antagonists; Rabbits; Tiotropium Bromide; Tropanes; Wakefulness

Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.. The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.. We used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue- and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques.. Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel-mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes.. For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.

Topics: Animals; Bronchi; Calcium; Capsaicin; Cough; Cricetinae; HEK293 Cells; Humans; Muscarinic Antagonists; Nerve Fibers, Unmyelinated; Scopolamine Derivatives; Sensory Receptor Cells; Tiotropium Bromide; TRPV Cation Channels; Vagus Nerve

Topics: Adolescent; Asthma; Bronchodilator Agents; Child; Chronic Disease; Cough; Female; Humans; Male; Scopolamine Derivatives; Tiotropium Bromide

Recently, tiotropium Respimat® Soft Mist™ Inhaler has been developed. Respimat is a multidose and propellant-free kit. The aerosol generated from Respimat improved lung drug deposition and required a lower dose of drug than HandiHaler®. The aim of this study is to assess the effect of switching from tiotropium HandiHaler to Respimat in patients with chronic obstructive pulmonary disease (COPD).. Thirty-four patients with COPD who received 18 μg of tiotropium delivered by the HandiHaler once daily were enrolled in this study between May and September 2010. Symptoms, adverse events, pulmonary functions, and usability of inhaler devices were assessed before and 12 weeks after switching from HandiHaler to 5 μg of tiotropium delivered by the Respimat. Symptoms and adverse events were also assessed 4 and 12 weeks after switching. Dyspnea was evaluated using the British Medical Research Council dyspnea scale. The usability of inhaler devices was scored using a 12-step checklist.. Twenty-nine patients were followed until 12 weeks after switching. The median FEV1 (forced expiratory volume in 1 sec) values before and 12 weeks after switching to Respimat were 1.41 L and 1.60 L, respectively. Dry mouth appeared to improve after switching to Respimat. Cough just after inhalation was observed in seven patients until 4 weeks after switching. However, six patients overcame cough as they got used to Respimat. Regarding the handling of inhaler devices, patients were not good at breathing out before inhalation and holding their breath just after inhalation both with HandiHaler and with Respimat. However, in general, both inhalers were considered to be easy to use. Twenty-one patients replied that handling of Respimat was easier than that of HandiHaler.. There was no major problem in switching from tiotropium HandiHaler to Respimat. Respimat and HandiHaler showed similar effects and usability. However, we should be aware of cough just after inhalation with Respimat.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Cohort Studies; Cough; Dyspnea; Equipment Design; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Xerostomia