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Bronchodilator therapy for chronic cough
Accepted Manuscript Bronchodilator therapy for chronic cough Maria Gabriella Matera, Paola Rogliani, Alessandro Zanasi, Mario Cazzola PII:
S1094-5539(17)30029-9
DOI:
10.1016/j.pupt.2017.05.011
Reference:
YPUPT 1629
To appear in:
Pulmonary Pharmacology & Therapeutics
Received Date: 18 January 2017 Revised Date:
12 May 2017
Accepted Date: 16 May 2017
Please cite this article as: Matera MG, Rogliani P, Zanasi A, Cazzola M, Bronchodilator therapy for chronic cough, Pulmonary Pharmacology & Therapeutics (2017), doi: 10.1016/j.pupt.2017.05.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Bronchodilator therapy for chronic cough
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Maria Gabriella Matera1, Paola Rogliani2, Alessandro Zanasi3, Mario Cazzola2
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Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples,
Italy 2
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Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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Italian Association for Cough Study (AIST), Bologna, Italy
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Correspondence: Mario Cazzola, e-mail [email protected]
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Summary Experimental studies indicate that airway calibre increases the sensitivity of the afferents involved in the cough reflex but it has proved difficult to demonstrate that airway calibre increases the sensitivity of the afferents involved in the cough reflex. Therefore, bronchodilators might have a role, although rather minor, in the treatment of cough.
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However, although bronchodilators represent the standard of care in the treatment of airway obstruction associated with asthma or COPD, controversy persists regarding the mechanism(s) by which these agents alleviate cough. Furthermore, the available evidence indicates that the effects of bronchodilators on cough are rather inconsistent in humans
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and casts doubt on the appropriateness of the common practice of using bronchodilators in the treatment of patients with cough without any other evidence of airway obstruction.
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Regrettably, appropriate long-term trials specifically aimed at evaluating the clinical efficacy of bronchodilators in pathologic cough have not yet been performed. Therefore, properly executed clinical studies of bronchodilators in various types of acute and chronic
Introduction
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pathologic cough are required.
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Although experimental studies indicate that decrease in airway calibre increases the sensitivity of the afferents involved in the cough reflex, it has proved difficult to demonstrate that airway calibre increases the sensitivity of the afferents involved in the cough reflex [1].
Actually, at least in guinea pigs, there is a group of afferent respiratory vagal “touchsensitive” Aδ-fibres, which are about five times faster than C-fibres [2], that lead to cough and terminate almost exclusively in the extrapulmonary bronchi, trachea, and larynx [3]. Within the Aδ fibre population two different nerve types that project to the nodose ganglion have been found including slow conducting Aδ fibres and rapidly adapting receptors
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ACCEPTED MANUSCRIPT (RARs), which innervate the larynx, trachea and extrapulmonary airway, with RARs also innervating intrapulmonary airways. Aδ fibres respond to a variety of stimuli to evoke cough, whilst the slowly conducting Aδ fibres do not respond to contraction of airway smooth muscle [4]. In effect, the “touch-sensitive” Aδ-fibres are indifferent to the physiological stimuli in the airways (air flow, changes in tracheal geometry during
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breathing) but are readily activated by the noxious stimuli associated with aspiration: the localized punctiform mechanical stimuli [5]. These terminals are also sensitive to acid, but only when there is a rapid drop in pH [6]. Nerves with similar structures have recently been described in human bronchi [7].
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Nonetheless, Ohkura et al. [8] showed a significant positive correlation between the increase in enhanced pause, an index of bronchoconstriction, and the number of coughs
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induced by methacholine inhalation in conscious guinea pigs. They also documented that bronchoconstriction causes cough via RARs, but not C-fibres. Interestingly, neither RARs nor C-fibres are involved in methacholine-induced bronchoconstriction itself. However, Mazzone and Undem [2] have recently suggested that either very specific stimuli for RARs is needed to alter their pattern of activation in a specific manner to encode for coughing or, alternatively, a specific subset of RARs or RAR-like fibres may be recruited in response to
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stimuli that evoke coughing. In fact, suggestion of RARs mediating cough is difficult to reconcile with the observation that stimuli effectively evoking bronchospasm, and which therefore robustly activate RARs, were poor inducers of cough [2]. In effect, in normal subjects, cough receptor sensitivity may not be directly influenced by
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bronchoconstriction or bronchodilatation [9]. However, Ohkura et al. [10] found that the more severe bronchoconstriction was provoked, the more bronchoconstriction-triggered
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cough occurred in normal subjects. Conversely, even if severe bronchoconstriction was provoked, bronchoconstriction-triggered cough hardly ever occurred in typical asthmatics. This indicates that typical asthmatics have bronchoconstriction hyperresponsiveness to methacholine, but their cough response to bronchoconstriction is insensitive. Woolnough and Ross reported that 25% of a group of their patients presenting with cough as their chief complaint were found to have bronchospasm [11]. Consequently, they suggested that bronchospasm should be suspected as a cause of cough if the cough comes in paroxysms, at night, is associated with recurrent upper respiratory infection, is brought on by exposure to noxious gases, or is brought on by exercise [11]. Obviously, the diagnosis may be confirmed by response to bronchodilators [11]. However, the response
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ACCEPTED MANUSCRIPT to bronchodilators does not distinguish coughers from wheezers [12] and often cough that can be resistant to bronchodilator therapy. Essentially, it is not generally appreciated that bronchospasm can be present as cough or that cough may be the only symptom of bronchospasm [11]. In the past, cough in asthma was assumed to be linked with bronchoconstriction and, consequently, usually treated with
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bronchodilating drugs [13]. After, it was recognized that cough might be the sole manifestation of asthma occurring even in subjects with minimal degree of dyspnoea, wheezing or bronchoconstriction [14]. Such a cough can be resistant to bronchodilator therapy and includes several definitions, like cough-variant asthma [14], eosinophilic
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bronchitis [15], and atopic cough [16]. This cough is usually treatable with corticosteroids, suggesting a link between asthmatic cough and inflammation.
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Inflammatory cells are capable to produce reactive oxygen species, potent stimulators and sensitizers of bronchopulmonary C-fibres [17]. C-fibres respond to capsaicin, bradykinin, citric acid, ATP, thrombin, adenosine and mechanosensitivity [18], although and it has been suggested that cough caused by capsaicin is due to secondary activation of RARs following odema and/or bronchoconstriction [4]. The activation of C-fibres in the intrapulmonary airways in guinea pigs can augment cough reflex responses, presumably
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by acting synergistically with Aδ fibre stimulation at the level of the brain stem [4]. In any case, the cough caused by bronchospasm is often present although the physical exam reveals normal findings. Actually, simple office tests of pulmonary function such as
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FEV1 may also be normal [11]. However, it has been suggested that the reversibility of the expiratory flow of the partial flow-volume curve at 40% above the residual volume level (PEF40) predicts the efficacy of bronchodilator therapy in treating chronic non productive
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cough [19].
All these findings suggest that bronchodilators might have a role, although rather minor, in the treatment of cough.
β2-agonists and cough β2-agonists attenuate citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs, an effect that was attributed to activation of β2-adrenoceptors on sensory nerves, leading to hyperpolarization of afferent endings [20]. Furthermore, they completely inhibit bronchoconstrictor response to inhaled capsaicin but do not influence
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ACCEPTED MANUSCRIPT the increased cough response 24 hours after antigen challenge in sensitized guinea pigs [21]. Nonetheless, there is documentation of an effect induced by terbutaline on capsaicinor low-pH-induced cough in the guinea pig in vivo [22]. Terbutaline suppresses the tussive response via a nonclassical cyclic adenosine monophosphate-dependent pathway that involves the activation of protein kinase G and, subsequently, the opening of large-
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conductance calcium-activated potassium channels. The discrepancy between the results of these last two studies may be due to a difference of methods to measure cough response in conscious guinea pigs. Freund-Michel et al. exposed capsaicin (10−4 M) for 5 min and measured the number of coughs for 10 min [22], whereas Liu et al. [21] exposed
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capsaicin (10−4 M) for 2 min and measured the number of coughs for 3 min. In fact, procaterol inhibited capsaicin-induced cough in the guinea pig in vivo when the number of
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coughs were measured using the method described by Freund-Michel et al. [23]. In normal subjects, β2-adrenoceptor stimulation has no direct effect on the sensitivity of the cough receptors [9]. However, the use of β2-agonists blocks both the fall in FEV1 and the frequency of coughing induced by LTD4 and the pre-treatment of subjects with β2-agonists influences the coughing associated with ultrasonically nebulized aqueous solutions low in chloride anions [1].
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Fujimura et al. [24] documented that in patients presenting with only nonproductive cough for more than 2 months, none of the clinical manifestations, atopic findings, or baseline pulmonary function test could predict the effect of clenbuterol on chronic nonproductive cough. Patients who responded to the bronchodilator therapy could not be distinguished
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from nonresponders by the level of bronchial responsiveness but there was a significant difference in cough receptor sensitivity between these two patient groups. Patients who
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failed to respond to the bronchodilator therapy had lower cough threshold to inhaled capsaicin than those who responded. In patients who failed to respond to the bronchodilator therapy, the capsaicin cough threshold increased when the cough completely improved. These findings suggest that nonproductive cough is elicited based on two different mechanisms: heightened airway cough receptor sensitivity in bronchodilator-resistant cough or bronchoconstriction in bronchodilator-responsive cough. Irwin et al [25] showed that after 1 week of inhaled β-agonist (metaproterenol), only the cough due to cough-variant asthma was significantly better. However, salbutamol had no effect on cough frequency or score, irrespective of the presence of airway hyperresponsiveness, in children with recurrent cough without other evidence of airway
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ACCEPTED MANUSCRIPT obstruction [26]. It must be mentioned that when the clinical impact on cough of regular treatment with inhaled salmeterol alone was compared with salmeterol/fluticasone propionate in patients with cough-variant asthma, both salmeterol/fluticasone and salmeterol alone significantly decreased cough scores and increased FEV1 and PEF, but the efficacy was more pronounced with salmeterol/fluticasone than salmeterol alone [27].
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The effect of salbutamol on smoking related cough has been evaluated in healthy adult smokers [28]. Salbutamol reduced cough frequency and evoked cough. This finding suggests that β-agonists have modest activity in smoking related cough. However, there is documentation of an effect of salmeterol on peripheral airway clearance in smokers with
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mild chronic bronchitis that seems to be primarily via mucociliary as opposed to cough mechanisms [29]. In effect, salbutamol had no significant effect on coughing in two studies
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that enrolled patients with acute or chronic cough not due to asthma in which cough was evaluated by subjective measurements. Bernard et al. [30] studied nonasthmatic children in whom the exact cause of cough was not determined, but cough resolved within 7 days in both the placebo and treatment groups. Littenberg et al [31] examined adults with either bronchitis or cough of undetermined origin. There was no significant difference between treated (salbutamol 4 mg by mouth three times daily for 7 days) and control subjects in any
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measure of efficacy including cough severity score, reduction in sleepless nights, utilization of health care, or return to full activity. It is not surprising, therefore, that a recent Cochrane review has questioned the use of β2agonists for acute cough or a clinical diagnosis of acute bronchitis [32]. The results of this
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meta-analysis have shown that there is no evidence to support the use of β2-agonists in children with acute cough who do not have evidence of airflow restriction. There is also
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little evidence that the routine use of β2-agonists is helpful for adults with acute cough. These agents may reduce symptoms, including cough, in people with evidence of airflow restriction. However, this potential benefit is not well supported by the available data and must be weighed against the adverse effects associated with their use. There is a lack of COPD studies that have used cough as outcomes per se. A metaanalysis with five randomized controlled trials of indacaterol in stable COPD patients showed that compared to placebo, a 12-week treatment of the long-acting β2-agonist, indacaterol has not a significant effect on cough or phlegm in stable COPD [33]. However, the authors were not able to evaluate the effect of indacaterol on cough in a subgroup of patients with mild to moderate COPD.
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ACCEPTED MANUSCRIPT Although β2-agonists represent the standard of bronchodilator care in the treatment of airway obstruction associated with asthma or COPD, controversy persists regarding the mechanism(s) by which these agents alleviate cough [34]. The current opinion is that the anti-tussive properties of β2-agonists, if any, are mediated by acting directly on β2adrenoceptors on sensory nerve endings in the lung [35]. This activates adenylate
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cyclase, leading to cyclic adenosine monophosphate accumulation and activation of protein kinase G and the large conductance calcium-activated potassium channel which is thought to inhibit the sensory nerve activation and therefore the cough reflex. In any case, an explanation why a dominant antitussive property of β2-agonists has not been
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uncovered in clinic trials until now might be that many studies were conducted in healthy volunteers rather than in patients with pathological cough. In many studies with a negative outcome, cough was not the primary endpoint and β2-agonist doses were not designed to
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show antitussive effects. No objective measurement of cough was possible since objective cough monitoring devices have only recently been become available. Additional studies are needed examining whether an antitussive effect of the β2-agonists is due solely to their action as bronchodilators or if other mechanisms are relevant [34]. Further insight into this question may guide future research into a potential role for these agents in the treatment
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of other types of pathologic cough [34].
Antimuscarinic agents and cough
There is a substantial body of evidence from studies in animals and in experimentally
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induced cough in humans supporting antitussive activity of muscarinic antagonists [34]. Tiotropium inhibits citric acid-induced cough in conscious guinea pigs [36]. Tiotropium and
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ipratropium, which is structurally similar to tiotropium, cause also a significant inhibition of capsaicin-induced cough in guinea pig [37]. Aclidinium and tiotropium down-regulate the cough reflex in rabbits [38]. Furthermore, there is an evidence of a trend toward fewer cough episodes in cigarette smoke-exposed guinea pigs treated with 30 µg/ml aclidinium [39].
However, an old study showed that the effectiveness of voluntary cough for clearing mucus from the airways was diminished following ipratropium therapy [40]. Cough clearance of radiolabeled particles deposited in the airways was faster following placebo than ipratropium therapy despite a tendency for higher peak flow rates for coughing following the bronchodilator. Furthermore, ipratropium did not appear to significantly
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ACCEPTED MANUSCRIPT influence the number and the perception of cough following exercise in winter athletes [41]. However, a subgroup of athletes seemed to show a beneficial response to ipratropium, suggesting different cough responses in this population. Whatever the case may be, some small clinical studies have shown an effect of antimuscarinic agents on cough. Ipratropium significantly lowered symptom scores for both
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daytime and nighttime cough in patients with post-viral cough [42] or chronic bronchitis [43]. It also reduced cough number and cough index and increased the cough threshold to inhaled citric acid in asthmatic patients but not in normal subjects [44]. Oxitropium (200 µg) and ipratropium (80 µg) reduced cough frequency in response to inhalation of
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ultrasonically nebulized distilled water in both asthmatic and normal subjects [45]. There was no difference between oxitropium bromide and ipratropium bromide. However,
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oxitropium failed to reduce cough response to ultrasonically nebulised distilled water associated with upper respiratory tract infections in non-asthmatic volunteers [46]. On the contrary, tiotropium was able to inhibit cough reflex sensitivity to capsaicin in nonasthmatic subjects with upper respiratory tract infections [47]. Intriguingly, glycopyrrolate reduced capsaicin-induced cough in normal volunteers treated with captopril [48]. Results from phase III studies suggest that aclidinium 400 µg BID may provide
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improvements in cough and sputum expectoration in patients with COPD [49]. In particular, aclidinium seems to be able to reduce nighttime cough frequency and severity. At least patients with COPD complaining of sputum and cough, also tiotropium is able to decrease cough, an effect that may be related to the inhibition of airway mucus
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hypersecretion and improvement of airway mucociliary clearance [50]. A post-hoc analysis of a phase IV trial documented that 8-week-treatment with aclidinium 400 µg BID was able
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to cause a distinct and early benefit (within 4 weeks) on cough [51]. The mechanism by which muscarinic antagonists might inhibit cough reflex sensitivity remains unclear. Any their antitussive effect is unlikely to be a direct effect of airway tone on the cough reflex and seems to be probably unrelated to their anticholinergic activity because there are no muscarinic receptors on airway afferent nerves [34]. Tiotropium and ipratropium, but not glycopyrrolate and atropine, block single C-fibre firing in guinea pig to the transient receptor potential (TRP) vanilloid type 1 agonist capsaicin, but they do not modulate other TRP channel-mediated responses [37]. Modulation of TRPV1 is particular to certain antagonists rather than through the common mechanism of action of muscarinic receptor antagonism [36]. Furthermore, muscarinic antagonists have another possible
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ACCEPTED MANUSCRIPT antitussive mechanism of action that involves acid-sensing ion channels (ASICs) and mechanoreceptors of cough-related airway sensory afferents [38]. Other potential mechanisms include an effect on airway mucus glands, inflammatory mediators, inflammatory cells, epithelial permeability, vascular blood flow, and clearance of substances applied to the airway lumen, all of which could induce an alteration in cough-
Combining
β2-agonists
with
antimuscarinic
corticosteroids and cough
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receptor sensitivity [34].
agents
or
inhaled
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Evaluating the effect of different treatments on cough frequency in response to inhalation of nebulized hypotonic saline solution and water in both asthmatic and normal subjects,
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Lowry et al. [45] observed that all treatments significantly reduced the cough response to inhaled distilled water aerosol when compared with placebo, but the combination preparation ipratropium/fenoterol displayed a greater antitussive effect than either oxitropium or ipratropium. More recently, Zanasi et al [52] reported that a combination of inhaled ipratropium and salbutamol could effectively reduce post-viral cough. Although not specifically focused on cough, two
six-month, multicenter,
randomised studies
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(ACLIFORM and AUGMENT) showed that aclidinium/formoterol 400/12 µg significantly improves nighttime and early-morning cough severity compared with placebo in patients with moderate to severe COPD [53].
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Using two models of allergic inflammation (21 and 28 days long sensitization with ovalbumine) in guinea pigs, Pappová et al. found that that a half-dose combination therapy
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of budesonide and salmeterol shows comparable antitussive effect to a full dose therapy with budesonide alone [54]. A prospective, randomized, double-blind, placebo-controlled, multicenter trial showed that procaterol combined with budesonide was effective at improving cough symptoms in patients with cough-variant asthma [55]. Interestingly, there is also evidence that treatment with a β2-agonist plus an inhaled corticosteroid appears to be highly effective, without severe adverse effects, against the persistent cough suffered by patients after pulmonary resection [56].
Effects of theophylline on cough Experimental and clinical studies have suggested that theophylline, which is a weak
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ACCEPTED MANUSCRIPT bronchodilator, and another methylxanthine, theobromine act as antitussive agents. It is a long time that it has documented that theophylline possesses cough inhibitory effect and has a longer duration of action than that of reference compounds [57]. It is more potent than codeine and equipotent to dextramethorphan against citric acid aerosol-induced cough in conscious guinea pigs. In awake guinea pigs, pre-treatment with theophylline and
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theobromine decreased the number of coughs evoked by inhalation of citric acid aerosol in both healthy and ovalbumin-sensitized animals [58]. Always in awake guinea pigs, theobromine showed a dose-dependent antitussive effect on citric acid-induced cough, an effect that was similar to that elicited by codeine [59].
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In 10 healthy volunteers, theobromine significantly increased the capsaicin concentration required to induce five coughs when compared with placebo [59]. Also theophylline
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attenuated the capsaicin-induced cough number in 7 out of 10 hypertensive patients who had developed cough during treatment with an ACE inhibitor when compared with placebo [60]. Theophylline did not induce bronchodilation but induced complete remission of clinical symptoms in 8 out of these 10 subjects.
Recently it has been shown that theophylline inhibits capsaicin-induced cough by decreasing sensory nerve activation through activation of calcium-activated potassium
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channels (predominantly the small-conductance calcium-activated potassium channel or SK channel), at least in a guinea pig model [61]. Therapy with oral theophylline does improve cough in stable patients with chronic
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bronchitis [62]. For this reason the ACCP Evidence-Based Clinical Practice Guidelines on Diagnosis and Management of Cough recommend that in stable patients with chronic bronchitis, treatment with theophylline should be considered to control chronic cough;
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careful monitoring for complications is necessary [63]. On the contrary, according to the British Thoracic Society Cough Guideline Group there is still insufficient evidence to support the use of theophyllines in the treatment of persistent non-specific cough in children [64].
Conclusion The available evidence indicates that the effects of bronchodilators on cough are rather inconsistent in humans and casts doubt on the appropriateness of the common practice of using bronchodilators in the treatment of patients with cough without any other evidence of
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ACCEPTED MANUSCRIPT airway obstruction. Regrettably, appropriate long-term trials specifically aimed at evaluating the clinical efficacy of bronchodilators in pathologic cough have not yet been performed. Therefore, properly executed clinical studies of bronchodilators in various types of acute and chronic pathologic cough are required.
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45. Lowry R, Wood A, Johnson T, Higenbottam T. Antitussive properties of inhaled bronchodilators on induced cough. Chest 1988;93:1186-9
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46. Lowry R, Wood A, Higenbottam T. The effect of anticholinergic bronchodilator therapy on cough during upper respiratory tract infections. Br J Clin Pharmacol 1994;37:187-
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47. Dicpinigaitis PV, Spinner L, Santhyadka G, Negassa A. Effect of tiotropium on cough reflex sensitivity in acute viral cough. Lung 2008;186:369-74 48. van Wyk M, Sommers DK, Snyman JR. Effects of glycopyrrolate on capsaicin-induced cough in normal volunteers treated with captopril. Eur J Clin Pharmacol 1994;46:437-9 49. McGarvey L, Morice A, Smith J, Birring S, Chuecos F, Seoane B, Jarreta D. Effect of aclidinium bromide on cough and sputum symptoms in moderate-to-severe COPD in three phase III trials. BMJ Open Respir Res 2016;3:e000148 50. Tagaya E, Yagi O, Sato A, Arimura K, Takeyama K, Kondo M, Tamaoki J. Effect of tiotropium on mucus hypersecretion and airway clearance in patients with COPD. Pulm Pharmacol Ther 2016;39:81-4
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ACCEPTED MANUSCRIPT 51. Smith JA, McGarvey L, Mortice AH, Birring SS, Wedzicha JA, Notari M, Segarra R, Seoane B, Jarreta D. Efficacy of Aclidinium Bromide 400 µg on the Relief of Cough Symptoms in Symptomatic Patients with Chronic Obstructive Pulmonary Disease: A Cough Severity Subgroup Analysis [abstract]. Am J Respir Crit Care Med 2017;195:A5477
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52. Zanasi A, Lecchi M, Del Forno M, Fabbri E, Mastroroberto M, Mazzolini M, Pisani L, Pandolfi P, Nava S, Morselli-Labate AM. A randomized, placebo-controlled, doubleblind trial on the management of post-infective cough by inhaled ipratropium and salbutamol administered in combination. Pulm Pharmacol Ther 2014;29:224-32
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53. Bateman ED, Chapman KR, Singh D, D'Urzo AD, Molins E, Leselbaum A, Gil EG. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre,
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randomised studies (ACLIFORM and AUGMENT). Respir Res 2015;16:92 54. Pappová L, Jošková M, Kazimierová I, Šutovská M, Fraňová S. Combination Therapy with Budesonide and Salmeterol in Experimental Allergic Inflammation. Adv Exp Med Biol 2016;935:25-34
55. Bao W, Chen Q, Lin Y, Liu H, Zhao G, Chen Z, Zhou X. Efficacy of procaterol
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56. Sawada S, Suehisa H, Yamashita M. Inhalation of corticosteroid and β-agonist for persistent cough following pulmonary resection. Gen Thorac Cardiovasc Surg
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57. Szabó M, Körmöczy PS. The cough inhibitory effect of theophylline. Pharmacol Res
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58. Mokry J, Nosalova G, Mokra D. Influence of xanthine derivatives on cough and airway reactivity in guinea pigs. J Physiol Pharmacol 2008;60:87-91 59. Usmani OS, Belvisi MG, Patel HJ, Crispino N, Birrell MA, Korbonits M, Korbonits D, Barnes PJ. Theobromine inhibits sensory nerve activation and cough. FASEB J 2005;19:231-3 60. Cazzola M, Matera MG, Liccardi G, De Prisco F, D'Amato G, Rossi F. Theophylline in the inhibition of angiotensin-converting enzyme inhibitor-induced cough. Respiration 1993;60:212-5
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ACCEPTED MANUSCRIPT 61. Dubuis E, Wortley MA, Grace MS, Maher SA, Adcock JJ, Birrell MA, Belvisi MG. Theophylline inhibits the cough reflex through a novel mechanism of action. J Allergy Clin Immunol 2014;133:1588-98 62. Ram FS, Jones PW, Castro AA, De Brito JA, Atallah AN, Lacasse Y, Mazzini R, Goldstein R, Cendon S. Oral theophylline for chronic obstructive pulmonary disease.
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Pratter MR, Rosen MJ, Schulman E, Shannon JJ, Smith Hammond C, Tarlo SM. Diagnosis and Management of Cough Executive Summary: ACCP Evidence-Based Clinical Practice Guidelines. Chest 2006; 129(1 Suppl):1S-23S
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64. Shields MD, Bush A, Everard ML, McKenzie S, Primhak R. BTS guidelines: Recommendations for the assessment and management of cough in children. Thorax
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2008;63 Suppl 3:iii1-iii15
S1094-5539(17)30029-9
DOI:
10.1016/j.pupt.2017.05.011
Reference:
YPUPT 1629
To appear in:
Pulmonary Pharmacology & Therapeutics
Received Date: 18 January 2017 Revised Date:
12 May 2017
Accepted Date: 16 May 2017
Please cite this article as: Matera MG, Rogliani P, Zanasi A, Cazzola M, Bronchodilator therapy for chronic cough, Pulmonary Pharmacology & Therapeutics (2017), doi: 10.1016/j.pupt.2017.05.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Bronchodilator therapy for chronic cough
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Maria Gabriella Matera1, Paola Rogliani2, Alessandro Zanasi3, Mario Cazzola2
1
Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples,
Italy 2
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Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
3
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Italian Association for Cough Study (AIST), Bologna, Italy
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Correspondence: Mario Cazzola, e-mail [email protected]
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Summary Experimental studies indicate that airway calibre increases the sensitivity of the afferents involved in the cough reflex but it has proved difficult to demonstrate that airway calibre increases the sensitivity of the afferents involved in the cough reflex. Therefore, bronchodilators might have a role, although rather minor, in the treatment of cough.
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However, although bronchodilators represent the standard of care in the treatment of airway obstruction associated with asthma or COPD, controversy persists regarding the mechanism(s) by which these agents alleviate cough. Furthermore, the available evidence indicates that the effects of bronchodilators on cough are rather inconsistent in humans
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and casts doubt on the appropriateness of the common practice of using bronchodilators in the treatment of patients with cough without any other evidence of airway obstruction.
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Regrettably, appropriate long-term trials specifically aimed at evaluating the clinical efficacy of bronchodilators in pathologic cough have not yet been performed. Therefore, properly executed clinical studies of bronchodilators in various types of acute and chronic
Introduction
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pathologic cough are required.
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Although experimental studies indicate that decrease in airway calibre increases the sensitivity of the afferents involved in the cough reflex, it has proved difficult to demonstrate that airway calibre increases the sensitivity of the afferents involved in the cough reflex [1].
Actually, at least in guinea pigs, there is a group of afferent respiratory vagal “touchsensitive” Aδ-fibres, which are about five times faster than C-fibres [2], that lead to cough and terminate almost exclusively in the extrapulmonary bronchi, trachea, and larynx [3]. Within the Aδ fibre population two different nerve types that project to the nodose ganglion have been found including slow conducting Aδ fibres and rapidly adapting receptors
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ACCEPTED MANUSCRIPT (RARs), which innervate the larynx, trachea and extrapulmonary airway, with RARs also innervating intrapulmonary airways. Aδ fibres respond to a variety of stimuli to evoke cough, whilst the slowly conducting Aδ fibres do not respond to contraction of airway smooth muscle [4]. In effect, the “touch-sensitive” Aδ-fibres are indifferent to the physiological stimuli in the airways (air flow, changes in tracheal geometry during
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breathing) but are readily activated by the noxious stimuli associated with aspiration: the localized punctiform mechanical stimuli [5]. These terminals are also sensitive to acid, but only when there is a rapid drop in pH [6]. Nerves with similar structures have recently been described in human bronchi [7].
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Nonetheless, Ohkura et al. [8] showed a significant positive correlation between the increase in enhanced pause, an index of bronchoconstriction, and the number of coughs
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induced by methacholine inhalation in conscious guinea pigs. They also documented that bronchoconstriction causes cough via RARs, but not C-fibres. Interestingly, neither RARs nor C-fibres are involved in methacholine-induced bronchoconstriction itself. However, Mazzone and Undem [2] have recently suggested that either very specific stimuli for RARs is needed to alter their pattern of activation in a specific manner to encode for coughing or, alternatively, a specific subset of RARs or RAR-like fibres may be recruited in response to
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stimuli that evoke coughing. In fact, suggestion of RARs mediating cough is difficult to reconcile with the observation that stimuli effectively evoking bronchospasm, and which therefore robustly activate RARs, were poor inducers of cough [2]. In effect, in normal subjects, cough receptor sensitivity may not be directly influenced by
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bronchoconstriction or bronchodilatation [9]. However, Ohkura et al. [10] found that the more severe bronchoconstriction was provoked, the more bronchoconstriction-triggered
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cough occurred in normal subjects. Conversely, even if severe bronchoconstriction was provoked, bronchoconstriction-triggered cough hardly ever occurred in typical asthmatics. This indicates that typical asthmatics have bronchoconstriction hyperresponsiveness to methacholine, but their cough response to bronchoconstriction is insensitive. Woolnough and Ross reported that 25% of a group of their patients presenting with cough as their chief complaint were found to have bronchospasm [11]. Consequently, they suggested that bronchospasm should be suspected as a cause of cough if the cough comes in paroxysms, at night, is associated with recurrent upper respiratory infection, is brought on by exposure to noxious gases, or is brought on by exercise [11]. Obviously, the diagnosis may be confirmed by response to bronchodilators [11]. However, the response
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ACCEPTED MANUSCRIPT to bronchodilators does not distinguish coughers from wheezers [12] and often cough that can be resistant to bronchodilator therapy. Essentially, it is not generally appreciated that bronchospasm can be present as cough or that cough may be the only symptom of bronchospasm [11]. In the past, cough in asthma was assumed to be linked with bronchoconstriction and, consequently, usually treated with
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bronchodilating drugs [13]. After, it was recognized that cough might be the sole manifestation of asthma occurring even in subjects with minimal degree of dyspnoea, wheezing or bronchoconstriction [14]. Such a cough can be resistant to bronchodilator therapy and includes several definitions, like cough-variant asthma [14], eosinophilic
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bronchitis [15], and atopic cough [16]. This cough is usually treatable with corticosteroids, suggesting a link between asthmatic cough and inflammation.
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Inflammatory cells are capable to produce reactive oxygen species, potent stimulators and sensitizers of bronchopulmonary C-fibres [17]. C-fibres respond to capsaicin, bradykinin, citric acid, ATP, thrombin, adenosine and mechanosensitivity [18], although and it has been suggested that cough caused by capsaicin is due to secondary activation of RARs following odema and/or bronchoconstriction [4]. The activation of C-fibres in the intrapulmonary airways in guinea pigs can augment cough reflex responses, presumably
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by acting synergistically with Aδ fibre stimulation at the level of the brain stem [4]. In any case, the cough caused by bronchospasm is often present although the physical exam reveals normal findings. Actually, simple office tests of pulmonary function such as
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FEV1 may also be normal [11]. However, it has been suggested that the reversibility of the expiratory flow of the partial flow-volume curve at 40% above the residual volume level (PEF40) predicts the efficacy of bronchodilator therapy in treating chronic non productive
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cough [19].
All these findings suggest that bronchodilators might have a role, although rather minor, in the treatment of cough.
β2-agonists and cough β2-agonists attenuate citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs, an effect that was attributed to activation of β2-adrenoceptors on sensory nerves, leading to hyperpolarization of afferent endings [20]. Furthermore, they completely inhibit bronchoconstrictor response to inhaled capsaicin but do not influence
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ACCEPTED MANUSCRIPT the increased cough response 24 hours after antigen challenge in sensitized guinea pigs [21]. Nonetheless, there is documentation of an effect induced by terbutaline on capsaicinor low-pH-induced cough in the guinea pig in vivo [22]. Terbutaline suppresses the tussive response via a nonclassical cyclic adenosine monophosphate-dependent pathway that involves the activation of protein kinase G and, subsequently, the opening of large-
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conductance calcium-activated potassium channels. The discrepancy between the results of these last two studies may be due to a difference of methods to measure cough response in conscious guinea pigs. Freund-Michel et al. exposed capsaicin (10−4 M) for 5 min and measured the number of coughs for 10 min [22], whereas Liu et al. [21] exposed
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capsaicin (10−4 M) for 2 min and measured the number of coughs for 3 min. In fact, procaterol inhibited capsaicin-induced cough in the guinea pig in vivo when the number of
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coughs were measured using the method described by Freund-Michel et al. [23]. In normal subjects, β2-adrenoceptor stimulation has no direct effect on the sensitivity of the cough receptors [9]. However, the use of β2-agonists blocks both the fall in FEV1 and the frequency of coughing induced by LTD4 and the pre-treatment of subjects with β2-agonists influences the coughing associated with ultrasonically nebulized aqueous solutions low in chloride anions [1].
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Fujimura et al. [24] documented that in patients presenting with only nonproductive cough for more than 2 months, none of the clinical manifestations, atopic findings, or baseline pulmonary function test could predict the effect of clenbuterol on chronic nonproductive cough. Patients who responded to the bronchodilator therapy could not be distinguished
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from nonresponders by the level of bronchial responsiveness but there was a significant difference in cough receptor sensitivity between these two patient groups. Patients who
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failed to respond to the bronchodilator therapy had lower cough threshold to inhaled capsaicin than those who responded. In patients who failed to respond to the bronchodilator therapy, the capsaicin cough threshold increased when the cough completely improved. These findings suggest that nonproductive cough is elicited based on two different mechanisms: heightened airway cough receptor sensitivity in bronchodilator-resistant cough or bronchoconstriction in bronchodilator-responsive cough. Irwin et al [25] showed that after 1 week of inhaled β-agonist (metaproterenol), only the cough due to cough-variant asthma was significantly better. However, salbutamol had no effect on cough frequency or score, irrespective of the presence of airway hyperresponsiveness, in children with recurrent cough without other evidence of airway
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ACCEPTED MANUSCRIPT obstruction [26]. It must be mentioned that when the clinical impact on cough of regular treatment with inhaled salmeterol alone was compared with salmeterol/fluticasone propionate in patients with cough-variant asthma, both salmeterol/fluticasone and salmeterol alone significantly decreased cough scores and increased FEV1 and PEF, but the efficacy was more pronounced with salmeterol/fluticasone than salmeterol alone [27].
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The effect of salbutamol on smoking related cough has been evaluated in healthy adult smokers [28]. Salbutamol reduced cough frequency and evoked cough. This finding suggests that β-agonists have modest activity in smoking related cough. However, there is documentation of an effect of salmeterol on peripheral airway clearance in smokers with
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mild chronic bronchitis that seems to be primarily via mucociliary as opposed to cough mechanisms [29]. In effect, salbutamol had no significant effect on coughing in two studies
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that enrolled patients with acute or chronic cough not due to asthma in which cough was evaluated by subjective measurements. Bernard et al. [30] studied nonasthmatic children in whom the exact cause of cough was not determined, but cough resolved within 7 days in both the placebo and treatment groups. Littenberg et al [31] examined adults with either bronchitis or cough of undetermined origin. There was no significant difference between treated (salbutamol 4 mg by mouth three times daily for 7 days) and control subjects in any
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measure of efficacy including cough severity score, reduction in sleepless nights, utilization of health care, or return to full activity. It is not surprising, therefore, that a recent Cochrane review has questioned the use of β2agonists for acute cough or a clinical diagnosis of acute bronchitis [32]. The results of this
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meta-analysis have shown that there is no evidence to support the use of β2-agonists in children with acute cough who do not have evidence of airflow restriction. There is also
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little evidence that the routine use of β2-agonists is helpful for adults with acute cough. These agents may reduce symptoms, including cough, in people with evidence of airflow restriction. However, this potential benefit is not well supported by the available data and must be weighed against the adverse effects associated with their use. There is a lack of COPD studies that have used cough as outcomes per se. A metaanalysis with five randomized controlled trials of indacaterol in stable COPD patients showed that compared to placebo, a 12-week treatment of the long-acting β2-agonist, indacaterol has not a significant effect on cough or phlegm in stable COPD [33]. However, the authors were not able to evaluate the effect of indacaterol on cough in a subgroup of patients with mild to moderate COPD.
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ACCEPTED MANUSCRIPT Although β2-agonists represent the standard of bronchodilator care in the treatment of airway obstruction associated with asthma or COPD, controversy persists regarding the mechanism(s) by which these agents alleviate cough [34]. The current opinion is that the anti-tussive properties of β2-agonists, if any, are mediated by acting directly on β2adrenoceptors on sensory nerve endings in the lung [35]. This activates adenylate
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cyclase, leading to cyclic adenosine monophosphate accumulation and activation of protein kinase G and the large conductance calcium-activated potassium channel which is thought to inhibit the sensory nerve activation and therefore the cough reflex. In any case, an explanation why a dominant antitussive property of β2-agonists has not been
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uncovered in clinic trials until now might be that many studies were conducted in healthy volunteers rather than in patients with pathological cough. In many studies with a negative outcome, cough was not the primary endpoint and β2-agonist doses were not designed to
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show antitussive effects. No objective measurement of cough was possible since objective cough monitoring devices have only recently been become available. Additional studies are needed examining whether an antitussive effect of the β2-agonists is due solely to their action as bronchodilators or if other mechanisms are relevant [34]. Further insight into this question may guide future research into a potential role for these agents in the treatment
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of other types of pathologic cough [34].
Antimuscarinic agents and cough
There is a substantial body of evidence from studies in animals and in experimentally
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induced cough in humans supporting antitussive activity of muscarinic antagonists [34]. Tiotropium inhibits citric acid-induced cough in conscious guinea pigs [36]. Tiotropium and
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ipratropium, which is structurally similar to tiotropium, cause also a significant inhibition of capsaicin-induced cough in guinea pig [37]. Aclidinium and tiotropium down-regulate the cough reflex in rabbits [38]. Furthermore, there is an evidence of a trend toward fewer cough episodes in cigarette smoke-exposed guinea pigs treated with 30 µg/ml aclidinium [39].
However, an old study showed that the effectiveness of voluntary cough for clearing mucus from the airways was diminished following ipratropium therapy [40]. Cough clearance of radiolabeled particles deposited in the airways was faster following placebo than ipratropium therapy despite a tendency for higher peak flow rates for coughing following the bronchodilator. Furthermore, ipratropium did not appear to significantly
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ACCEPTED MANUSCRIPT influence the number and the perception of cough following exercise in winter athletes [41]. However, a subgroup of athletes seemed to show a beneficial response to ipratropium, suggesting different cough responses in this population. Whatever the case may be, some small clinical studies have shown an effect of antimuscarinic agents on cough. Ipratropium significantly lowered symptom scores for both
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daytime and nighttime cough in patients with post-viral cough [42] or chronic bronchitis [43]. It also reduced cough number and cough index and increased the cough threshold to inhaled citric acid in asthmatic patients but not in normal subjects [44]. Oxitropium (200 µg) and ipratropium (80 µg) reduced cough frequency in response to inhalation of
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ultrasonically nebulized distilled water in both asthmatic and normal subjects [45]. There was no difference between oxitropium bromide and ipratropium bromide. However,
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oxitropium failed to reduce cough response to ultrasonically nebulised distilled water associated with upper respiratory tract infections in non-asthmatic volunteers [46]. On the contrary, tiotropium was able to inhibit cough reflex sensitivity to capsaicin in nonasthmatic subjects with upper respiratory tract infections [47]. Intriguingly, glycopyrrolate reduced capsaicin-induced cough in normal volunteers treated with captopril [48]. Results from phase III studies suggest that aclidinium 400 µg BID may provide
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improvements in cough and sputum expectoration in patients with COPD [49]. In particular, aclidinium seems to be able to reduce nighttime cough frequency and severity. At least patients with COPD complaining of sputum and cough, also tiotropium is able to decrease cough, an effect that may be related to the inhibition of airway mucus
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hypersecretion and improvement of airway mucociliary clearance [50]. A post-hoc analysis of a phase IV trial documented that 8-week-treatment with aclidinium 400 µg BID was able
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to cause a distinct and early benefit (within 4 weeks) on cough [51]. The mechanism by which muscarinic antagonists might inhibit cough reflex sensitivity remains unclear. Any their antitussive effect is unlikely to be a direct effect of airway tone on the cough reflex and seems to be probably unrelated to their anticholinergic activity because there are no muscarinic receptors on airway afferent nerves [34]. Tiotropium and ipratropium, but not glycopyrrolate and atropine, block single C-fibre firing in guinea pig to the transient receptor potential (TRP) vanilloid type 1 agonist capsaicin, but they do not modulate other TRP channel-mediated responses [37]. Modulation of TRPV1 is particular to certain antagonists rather than through the common mechanism of action of muscarinic receptor antagonism [36]. Furthermore, muscarinic antagonists have another possible
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ACCEPTED MANUSCRIPT antitussive mechanism of action that involves acid-sensing ion channels (ASICs) and mechanoreceptors of cough-related airway sensory afferents [38]. Other potential mechanisms include an effect on airway mucus glands, inflammatory mediators, inflammatory cells, epithelial permeability, vascular blood flow, and clearance of substances applied to the airway lumen, all of which could induce an alteration in cough-
Combining
β2-agonists
with
antimuscarinic
corticosteroids and cough
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receptor sensitivity [34].
agents
or
inhaled
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Evaluating the effect of different treatments on cough frequency in response to inhalation of nebulized hypotonic saline solution and water in both asthmatic and normal subjects,
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Lowry et al. [45] observed that all treatments significantly reduced the cough response to inhaled distilled water aerosol when compared with placebo, but the combination preparation ipratropium/fenoterol displayed a greater antitussive effect than either oxitropium or ipratropium. More recently, Zanasi et al [52] reported that a combination of inhaled ipratropium and salbutamol could effectively reduce post-viral cough. Although not specifically focused on cough, two
six-month, multicenter,
randomised studies
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(ACLIFORM and AUGMENT) showed that aclidinium/formoterol 400/12 µg significantly improves nighttime and early-morning cough severity compared with placebo in patients with moderate to severe COPD [53].
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Using two models of allergic inflammation (21 and 28 days long sensitization with ovalbumine) in guinea pigs, Pappová et al. found that that a half-dose combination therapy
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of budesonide and salmeterol shows comparable antitussive effect to a full dose therapy with budesonide alone [54]. A prospective, randomized, double-blind, placebo-controlled, multicenter trial showed that procaterol combined with budesonide was effective at improving cough symptoms in patients with cough-variant asthma [55]. Interestingly, there is also evidence that treatment with a β2-agonist plus an inhaled corticosteroid appears to be highly effective, without severe adverse effects, against the persistent cough suffered by patients after pulmonary resection [56].
Effects of theophylline on cough Experimental and clinical studies have suggested that theophylline, which is a weak
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ACCEPTED MANUSCRIPT bronchodilator, and another methylxanthine, theobromine act as antitussive agents. It is a long time that it has documented that theophylline possesses cough inhibitory effect and has a longer duration of action than that of reference compounds [57]. It is more potent than codeine and equipotent to dextramethorphan against citric acid aerosol-induced cough in conscious guinea pigs. In awake guinea pigs, pre-treatment with theophylline and
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theobromine decreased the number of coughs evoked by inhalation of citric acid aerosol in both healthy and ovalbumin-sensitized animals [58]. Always in awake guinea pigs, theobromine showed a dose-dependent antitussive effect on citric acid-induced cough, an effect that was similar to that elicited by codeine [59].
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In 10 healthy volunteers, theobromine significantly increased the capsaicin concentration required to induce five coughs when compared with placebo [59]. Also theophylline
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attenuated the capsaicin-induced cough number in 7 out of 10 hypertensive patients who had developed cough during treatment with an ACE inhibitor when compared with placebo [60]. Theophylline did not induce bronchodilation but induced complete remission of clinical symptoms in 8 out of these 10 subjects.
Recently it has been shown that theophylline inhibits capsaicin-induced cough by decreasing sensory nerve activation through activation of calcium-activated potassium
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channels (predominantly the small-conductance calcium-activated potassium channel or SK channel), at least in a guinea pig model [61]. Therapy with oral theophylline does improve cough in stable patients with chronic
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bronchitis [62]. For this reason the ACCP Evidence-Based Clinical Practice Guidelines on Diagnosis and Management of Cough recommend that in stable patients with chronic bronchitis, treatment with theophylline should be considered to control chronic cough;
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careful monitoring for complications is necessary [63]. On the contrary, according to the British Thoracic Society Cough Guideline Group there is still insufficient evidence to support the use of theophyllines in the treatment of persistent non-specific cough in children [64].
Conclusion The available evidence indicates that the effects of bronchodilators on cough are rather inconsistent in humans and casts doubt on the appropriateness of the common practice of using bronchodilators in the treatment of patients with cough without any other evidence of
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ACCEPTED MANUSCRIPT airway obstruction. Regrettably, appropriate long-term trials specifically aimed at evaluating the clinical efficacy of bronchodilators in pathologic cough have not yet been performed. Therefore, properly executed clinical studies of bronchodilators in various types of acute and chronic pathologic cough are required.
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