Table 1.
Treatment of Mucus Hypersecretion.
| Purpose and treatment | Comments |
|---|---|
| Decrease mucin production | |
| Available treatments | |
| Glucocorticoids | Allergen-induced increases in numbers of airway goblet cells are inhibited by glucocorticoids. In acute severe asthma, glucocorticoids may also reduce bronchovascular permeability and promote neutrophildriven mucus turnover.89 Glucocorticoids are much less effective in treating mucus in other airway diseases.93,107 |
| Agents in development | |
| ErbB-receptor inhibitors | A recent trial of inhaled BIBW 2948 BS, an epidermal growth factor receptor inhibitor (ClinicalTrials.gov number, NCT00423137), did not show a benefit in reducing airway mucin gene expression or epithelial mucin stores in patients with COPD, and the treatment was associated with adverse effects on lung and liver function.108 |
| Decrease mucin secretion | |
| Available treatments | |
| None | |
| Agents in development | |
| MARCKS inhibitors | MARCKS regulates the reconfiguration of actin filaments at the apical pole of goblet cells during mucin secretion.50,109 A peptide derived from the MARCKS N-terminal that is myristoylated so that it enters cells inhibits stimulated mucin secretion in mice.109 In a phase 2 trial (NCT00648245), this peptide is being administered by aerosol in patients with COPD who have mucus hypersecretion. |
| Botulinum neurotoxins | Botulinum neurotoxins are zinc proteases that cleave SNARE proteins to inhibit release of synaptic vesicles. The C and E neurotoxins have been engineered so that they are active against non-neuronal SNARE isoforms, inhibiting epithelial-cell mucin secretion, and the modified C toxin has been conjugated to epidermal growth factor to promote delivery to goblet cells, but no related clinical trial has been registered.110,111 |
| Promote mucus clearance | |
| Available treatments | |
| Physical measures | Chest percussion and postural drainage improve clearance of purulent airway mucus in cystic fibrosis.103 The value of alternative methods, including positive expiratory pressure, flutter valves, or high-frequency chest-compression vests, is difficult to assess objectively, although trials are in progress (e.g., NCT01057524). Mucus clearance is probably aided by any maneuver that promotes coughing and increased minute ventilation, including exercise. Since airflow generates shear stress on airway cell surfaces that stimulate release of nucleotides that interact with P2Y2 receptors to regulate mucus hydration, there are both mechanical and biochemical mechanisms of benefit from nonpharmacologic approaches to mucus clearance.63,103 |
| Bronchodilators | Bronchodilation with beta-adrenergic agonists or anticholinergic drugs may improve mucus clearance in the short term because of an enlarged luminal diameter. In addition, beta-adrenergic agonists increase the frequency of ciliary beats, and anticholinergic drugs may decrease surface mucin secretion and mucin secretion from the submucosal gland.17,62,64,73 However, beta-adrenergic agonists up-regulate mucin production in animal models,29,49 so they are not recommended for long-term treatment of mucus hypersecretion. The long-term effects of both classes of bronchodilators on mucus clearance warrant further study. |
| Inhaled dornase alfa | Inhaled dornase alfa hydrolyzes DNA, improves lung function, and decreases the frequency of exacerbation in patients with cystic fibrosis, in whom airway mucus concentrations of DNA are very high (5–10 mg/ml).84,101 The concentration of DNA in other airway diseases, including non−cystic fibrosis bronchiectasis, COPD, and asthma, is 1/5 to 1/10 as great84,88,112; dornase alfa does not have beneficial effects in these diseases and may even be harmful.113 |
| Inhaled hypertonic saline | Treatment twice daily with aerosolized 7% hypertonic saline solution is associated with significant improvements in mucus clearance, modest improvements in airflow, and clinically meaningful reductions in rates of exacerbation among patients with cystic fibrosis.114,115 The mechanism of benefit is thought to be rehydration of the periciliary layer through the drawing of water from epithelial cells, but other mechanisms such as promotion of cough and direct effects on mucus elasticity and entanglement may also contribute.69,116 Trials are under way for the treatment of other airway diseases with 3 to 7% hypertonic saline; these diseases include infantile bronchiolitis (NCT01016249, NCT00677729, NCT00729274, NCT00619918, NCT00151905, and NCT00696540), COPD (NCT00639236), atelectasis (NCT00671723), non−cystic fibrosis bronchiectasis (NCT00484263), and asthma (NCT01073527). |
| N-acetylcysteine | N-acetylcysteine breaks the disulfide bonds that link mucin monomers to polymers, and it is very effective in vitro in solubilizing sputum. Case reports attest to its usefulness when applied through the bronchoscope to break up mucus plugs.117 Clinical studies of N-acetylcysteine and carbocysteine in COPD have shown some promise.118 Aerosolized N-acetylcysteine also can be irritating to the airway,119 so its routine use is not recommended. Oral N-acetylcysteine is under study as an antiinflammatory (glutathione-replenishing and antioxidant) treatment in cystic fibrosis and COPD (NCT00969904 and NCT00809094). |
| Agents in development | |
| Mannitol | Nonabsorbable osmotic agents have a theoretical advantage of drawing liquid into the periciliary layer for longer periods than sodium chloride. Inhaled mannitol is undergoing safety and efficacy testing in cystic fibrosis, COPD, and bronchiectasis (NCT00446680, NCT00117208, and NCT00669331). Its use in children with cystic fibrosis is associated with bronchoconstriction and cough, but a 3-month treatment protocol showed similar efficacy to that of dornase alfa.120 |
| P2Y2 agonists | P2Y2 agonists promote the activity of calcium-activated chloride channels and inhibit the activity of epithelial sodium channels, so they may normalize the height of the periciliary layer and improve mucus clearance, especially in cystic fibrosis. Phase 2 and 3 trials of denufusol in cystic fibrosis are ongoing (NCT00625612 and NCT00357279). |
| CFTR modulation | Several therapeutic agents are in development to augment the function of mutant CFTR, including ataluren to promote read-through of premature termination codons (NCT00803205), VX-809 to promote transport of misfolded CFTR protein to the cell surface (NCT00865904 and NCT00966602), and VX-770 to promote the opening of CFTR proteins expressed on the cell surface (NCT00909532 and NCT00966602). |
| Epithelial sodium-channel modulation | An aerosolized inhibitor of epithelial sodium-channel function, GS-9411, is being evaluated as a potential therapy to improve airway hydration and mucociliary clearance in cystic fibrosis (NCT00800579, NCT009999531, NCT01025713, and NCT00951522). |
| Actin filament depolymerizing agents, proteases, and antiproteases | Gelsolin and thymosin β4 depolymerize actin filaments,23,83 which could be helpful in promoting mucus clearance in cystic fibrosis; however, the results of clinical studies of recombinant human plasma gelsolin in cystic fibrosis in the 1990s were not promising, and no trials are currently registered. Proteases that digest gel-forming mucins could be helpful in treating mucus plugs in severe asthma,89 although no trials are yet under way. Inhaled alpha1-antitrypsin is being studied to prevent lung parenchymal damage from leukocyte proteases in cystic fibrosis (NCT00499837). |
| Treat airway infection | |
| Available treatments | |
| Inhaled antibiotics | Treatment with inhaled tobramycin is associated with improved lung function and reduced exacerbation frequency in patients with cystic fibrosis.101 |
| Oral antibiotics | Prolonged use of azithromycin improves lung function in cystic fibrosis, although it is associated with increased nausea and diarrhea.101 Long-term treatment with oral erythromycin reduces the frequency of exacerbation in COPD,121 and several groups, including the COPD Clinical Research Network (NCT00119860), are studying azithromycin in patients with this condition. The value of oral antibiotics in the short-term treatment of COPD exacerbations is questionable.122 In patients with bronchiectasis who do not have cystic fibrosis, long-term treatment with low-dose azithromycin reduces the frequency of exacerbation and improves lung function.123 |
| Intravenous antibiotics | Intravenous antibiotics directed against pseudomonas species infections are effective in the treatment of pulmonary exacerbations of cystic fibrosis.102,124 |
| Agents in development | |
| Inhaled antibiotics | Inhaled aztreonam reduced the time to exacerbation in cystic fibrosis in two phase 3 studies (NCT00112359, NCT00104520),125,126 and a study comparing inhaled aztreonam with inhaled tobramycin in cystic fibrosis is ongoing (NCT00757237). Also under study are inhaled ciprofloxacin (NCT00645788), liposomal amikacin (NCT00558844), and tobramycin combined with fosfomycin (NCT00794586). |
*
CFTR denotes cystic fibrosis transmembrane conductance regulator, COPD chronic obstructive pulmonary disease, MARCKS myristoylated alanine-rich C-kinase substrate, and SNARE soluble N-ethylmaleimide–sensitive factor attachment protein receptor.