Does Musinex Stimulate Lung Repair?

Mucoactive drugs

European Respiratory Review 2010 nineteen: 127-133; DOI: x.1183/09059180.00003510

Abstract

Mucus hypersecretion is a clinical feature of astringent respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives ascension to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase fungus product and viscosity. Mucoactive agents take been the medication of choice for the handling of respiratory diseases in which mucus hypersecretion is a clinical complication. The master purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and tin can exist classified co-ordinate to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our agreement of the specific effects of mucoactive agents, nosotros may result in improved therapeutic utilize of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of activity.

• North-Acetylcysteine
• carbocysteine
• erdosteine
• mucoactive
• mucus

In healthy individuals, fungus secretion is not excessive and mucus continuously removed past epithelial ciliated cells, then propelled towards the larynx for swallowing [i]. Still, an increase in airway mucus secretion can exist problematic, particularly if the rate of secretion exceeds the rate at which information technology can be removed by normal ciliary action. Increased mucus secretion (hypersecretion) is a clinical feature of severe respiratory diseases, such as asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Typically during infection and/or inflammation, the airway mucosa responds by increasing the volume of mucus that is secreted. This response is mainly due to hyperplasia and hypertrophy of goblet cells and the submucosal gland, a phenomenon recognised equally secretory hyperresponsiveness [2]. The inflammatory procedure results in loss of cells and ciliary function, destruction of the surfactant layer by airway phospholipases and amending of the biophysical backdrop of the mucus [3, iv]. In addition, by-products accumulated during the inflammatory process include neutrophil-derived DNA and filamentous actin (F-actin), dead/apoptotic cells, bacteria and jail cell debris. Collectively, these factors contribute to fungus purulence, and when expectorated, this mucus is termed sputum [5].

Mucus is a highly oligomerised mucin polymer composed of h2o and diverse macromolecular glycoproteins as part of its gel structure [6, 7]. Drugs that affect airway secretion have been produced for many years now, their main use being to cleanse the respiratory tract. Drugs that are designed to specifically alter the viscoelastic properties of mucus in addition to promoting secretion clearance are characterised equally "mucoactive". Previous attempts have been made to characterise agents that affect fungus, although they sometimes lacked simplicity [8, 9]. The main difficulty involved with characterising mucoactive agents is due to the fact that many drugs showroom overlapping effects. Regardless, mucoactive drugs can be broadly and simply characterised into several major groups according to their chief actions [2]. Mucoactive drugs tin can be classified equally expectorants, mucoregulators, mucolytics or mucokinetics, based on their potential mechanism of action (tabular array 1⇓ and fig. 1⇓).

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Tabular array. 1—

Mucoactive drugs and their potential mechanisms of action

EXPECTORANTS

An expectorant can be defined equally an agent that induces discharge or expulsion of mucus from the respiratory tract. This typically requires a cough or sneezing activity to loosen and bring upward the mucus from the lungs or upper respiratory tract. These events can be seen every bit benign if fungus plugs that obstruct large, medium or small airways are dislodged. Effects post-obit expectorant medication can improve alveolar aeration and provide relief from neural irritation triggered past mechanical properties of the mucus plugs or effects of their inflammatory components. Together, these may in turn reduce the mechanical endeavor of animate and dyspnoea. The precise mechanism by which expectorants exert their action is still unclear, although it is thought that they may act as irritants to gastric vagal receptors, and recruit efferent parasympathetic reflexes that induce glandular exocytosis of a less viscous mucus mixture [nine, 10]. Some frequently used expectorants include droplets (hypertonic saline), iodide-containing compounds, glyceryl guaiacolate (guaifenesin) and ion aqueduct modifiers, such as the P2Y2 purinergic agonists. These agents are addressed in particular below.

Hypertonic saline

Aerosol using hypertonic solution (saline, urea or ascorbic acid) has been previously idea to induce ciliary motility, proteolysis and mucus liquefaction [8]. This was attributed to intra- and intermolecular bounden and osmotic hydration of luminal fluid. Studies have shown that long-term utilise of inhaled hypertonic saline improves pulmonary office in patients with CF, and inhaled mannitol has too been shown to exist beneficial in not-CF bronchiectasis [11–13]. However, a meta-assay of brusk-term clinical studies suggested that nebulised hypertonic saline improved mucociliary clearance in CF only, merely was less constructive than DNase [14]. Regardless, this method (either with saline or mannitol) has been proven to be an extremely useful tool for the generation of sputum for diagnostic and research purposes [11–13].

Iodide-containing compounds

Iodide-containing agents are considered to be expectorants that are thought to promote the secretion of airway fluid. Although iodides have long been used as expectorants, their clinical apply has been debated, due to their potential toxicity [eight, 10, 15]. Iodinated glycerol, kickoff introduced in 1915, reduces breast discomfort and offers anti-tussive effects in patients with chronic bronchitis, without affecting dyspnoea or lung function [16]. Domiodol, another iodinated organic chemical compound, has been shown to significantly increase secretion volume in adult subjects with chronic bronchitis [eight, 17]. Furthermore, domiodol has been shown to significantly reduce symptoms of acute infectious pulmonary diseases or acute flare-ups of chronic bronchitis effects in children [eighteen].

Guaifenesin (glyceryl guaiacolate)

Guaifenesin has no mucolytic activeness only may reduce bronchial sputum surface tension. No evidence is available to propose clarified or anti-tussive effects. The main benefit offered past guaifenesin appears to be as an expectorant for the symptomatic treatment of coughs, producing small quantities of thick viscous secretions. Guaifenesin can stimulate the cholinergic pathway and increment mucus secretion from the airway submucosal glands. Nonetheless, guaifenesin has not been shown to exist clinically constructive in randomised controlled trials [19, twenty].

Ion channel modifiers

Tricyclic nucleotides (uridine triphosphate and adenosine triphosphate) regulate ion send through P2Y2 purinergic receptors that increase intracellular calcium. Nebulised uridine triphosphate aerosol in the presence or absence of amiloride has been shown to provide enhanced mucociliary clearance in healthy subjects [21]. P2Y2 purinergic receptor agonists have been recently adult and stage 3 studies are currently in progress [22].

MUCOREGULATORS

Drugs that regulate fungus secretion or interfere with the DNA/F-actin network can exist described every bit mucregulatory agents. Among others, they include carbocysteine, anticholinergics, glucocorticoids and macrolide antibiotics. The mechanism of action of these compounds is broad ranging. For example, carbocysteine, an antioxidant, has the power to restore viscoelastic backdrop of mucus and provide anti-inflammatory effects, in addition to providing protective effects on respiratory cells. In contrast, Anticholinergic agents block parasympathetic nervus activity, thereby reducing mucus secretion. Instead, glucocorticoids are strong anti-inflammatory drugs that are purported to meliorate mucociliary clearance. These mucoregulatory agents are examined in greater detail beneath.

Carbocysteine

Southward-Carboxymethylcysteine (carbocysteine or SCMC; besides available in the lysinate form, SCMC-Lys) is a mucoactive drug (fig. i⇑), has antioxidant and anti-inflammatory properties, and is normally used for the treatment of COPD [23]. Pre-clinical and clinical studies on the pharmacological properties of SCMC have demonstrated that this cysteine derivative has the ability to increase the synthesis of sialomucins, important structural components of mucus. In event, SCMC resets the residuum between sialomucins and fucomucins, possibly past intracellular stimulation of sialyl transferase activity [24], restoring the viscoelastic properties of mucus [25]. SCMC is not thought to deed directly upon the mucus structure, in contrast to true mucolytic agents, such as N-acetylcysteine (NAC) or N-acystelyn (NAL). Show from animal studies suggests that SCMC increases chloride transport across the airway epithelium, which may contribute towards its mucoregulatory action [26]. In addition to the mucoregulatory activity exerted by carbocysteine, the mechanism of action by which information technology provides anti-inflammatory furnishings has too been investigated. In pre-clinical and clinical studies, carbocysteine has been shown to reduce neutrophil infiltration into the airway lumen [27], decrease levels of interleukin (IL)-8, IL-half dozen cytokine levels and 8-isoprostane exhaled in chronic obstructive pulmonary disease [28]. Since the chemotactic recruitment of peripheral blood mononuclear cells into the lung by IL-8 plays a crucial office in the development and maintenance of several inflammatory diseases, the inhibition of IL-8 product may contribute towards the therapeutic upshot of SCMC-Lys. These anti-inflammatory effects have previously been straight attributed to scavenging furnishings of the thioether drug group on reactive oxygen species (ROS) [29, 30]. Carbocysteine may also modulate airway inflammation by reducing the product of cytokines in rhinovirus infections [31]. Information technology has also been shown that carbocysteine inhibits the adherence of bacteria and viruses to ciliated epithelial cells in vitro [31, 32].

Additional evidence has shown that respiratory cells treated with SCMC-Lys stimulate a CF transmembrane conductance regulator (CFTR)-like channel that results in a significant increase in chloride and glutathione (GSH) membrane flux [33]. Furthermore, it has as well been recently demonstrated that SCMC-Lys provides protective effects on human respiratory cells during oxidative stress [34]. In this particular report, cells exposed to oxidative stress and and so treated with SCMC-Lys were shown to stimulate both GSH and chloride membrane flux, increase GSH concentration and buffer the increment in ROS in cells expressing the CFTR aqueduct [34]. These findings provide further mechanistic insights on how SCMC-Lys may exert its antioxidative protective effects.

In addition to demonstrating beneficial furnishings in vitro, SCMC is too recognised to provide benefit to patients. SCMC has been shown to be an effective and safe drug for the treatment of COPD in randomised clinical trials, reducing the incidence of exacerbations and improving patient quality of life [35–38]. Nonetheless, information technology should be noted for the PEACE (Preventive Effect on Astute Exacerbation) report that subjects were Chinese (25% nonsmokers) who had express access to other drugs that target exacerbations (e.g. long-acting bronchodilators and inhaled corticosteroids) [35]. No significant toxicity has been reported either in fauna models or following prolonged use in humans, and no drug interactions take been identified. Moreover, SCMC has been shown to improve oxidative stress and chronic inflammation associated with severe chronic diseases, in detail advanced cancer and cancer-related syndromes, both alone and in combination with other antioxidant drugs [30, 39, 40].

Anticholinergic agents

Anticholinergic drugs are ofttimes used every bit mucoregulators. Cholinergic parasympathetic nerve activity is an active stimulus for mucus secretion in human airways. This secretary response is mediated via M3 muscarinic receptor, expressed on submucosal airway cells. Anticholinergic medication, including atropine, ipratropium, scopolamine, glycopyrrolate and tiotropium, block these secretory reflexes, and reduce glandular output and sputum book [41–43]. Atropine (oft administered as atropine methonitrate) has been shown to block mucociliary clearance of the gel, but not the mucus sol phase. In dissimilarity, ipratropium bromide does not appear to affect mucociliary transport [8]. The M1 receptor is non involved with fungus secretion just, in combination with M3, may command water secretion [44, 45].

Glucocorticoids

Glucocorticoids are potent anti-inflammatory agents and widely used in the direction of acute exacerbations in patients with asthma or COPD. Glucocorticoids are purported to influence mucociliary clearance. Prednisolone is a glucocorticoid that has been shown to provide improvement in lung clearance in stable asthmatics [46]. All the same, it is more often than not accepted that steroids only have limited effects on mucus hypersecretion.

Macrolide antiobiotics

Macrolide antibiotics accept been successfully used to treat a range of chronic, inflammatory lung disorders [47]. Macrolide antibiotics include erythromycin, azithromycin, clarithromycin, roxithromycin. Macrolide therapy using either azithromycin or clarithromycin is now considered standard care therapy for CF. Clinically, macrolides accept been shown to reduce sputum product in astringent bronchorrhea, diffuse panbronchitis, sinobronchial syndrome and otitis [48]. The precise mechanism(s) of activeness of macrolide antibiotics still requires farther investigation, although their specific effects include inhibition of neutrophil chemotaxis, lymphocyte and macrophage function and modulation of airway shine muscle and neural tone [48]. Data in COPD patients are express and sometimes contradictory but more often than not advise a potential clinical benefit [46, 49]. However, the long-term safety of these antibiotics for the handling of COPD nonetheless needs to exist addressed [50].

MUCOLYTICS

Mucolytic can exist defined as drugs that subtract mucus viscosity and can exist categorised into either "classic" if they depolymerise mucin glycoproteins or "peptide" mucolytics that depolymerise DNA and F-actin polymer networks.

Classic mucolytics

NAC is a mucolytic drug (fig. 1⇑), in addition to possessing antioxidant and anti-inflammatory properties, that is commonly used for the treatment of COPD [23]. Aerosol assistants of NAC may dissociate mucin disulphide bonds and other disulphide bond cross-linked gel components to reduce viscosity. A number of observations on NAC advise that information technology not only exerts mucolytic properties, but also antioxidant effects, which may protect against free radical harm [viii, 51–54]. NAC has besides been shown to decrease airway inflammation by reducing lysozyme and lactoferrin concentrations in smokers [55], inhibiting neutrophil and monocyte chemotaxis and oxidative flare-up responses in vitro [56], reducing the activation and number of neutrophils and macrophages in bronchoalveolar lavage fluid in smokers [57, 58], and inhibiting the adherence of bacteria to ciliated epithelial cells in vitro [59]. Some bear witness suggests that oral NAC may reduce exacerbation rates in chronic bronchitis [60, 61]. However, a more recent controlled randomised clinical trial did not demonstrate a reduction in the frequency of exacerbations with NAC in patients with COPD, merely simply in the subgroup not taking inhaled corticosteroids [62]. Furthermore, NAC handling of patients with stable, moderate-to-astringent COPD has been shown to do good physical performance, which may exist attributed to air trapping [63]. However, like carbocysteine, little testify is currently bachelor in humans showing that NAC exerts its action past straight effects on mucus.

The lysine salt alternative to NAC is NAL, also a mucolytic and antioxidant thiol compound. The main reward of NAL over NAC might be that it has a neutral pH in solution, whereas NAC is acidic, and therefore an irritant when inhaled. Like NAC, NAL also exerts anti-inflammatory furnishings both in vitro and in vivo [64], and although big randomised trials have yet to be undertaken, this mucolytic drug could be interesting for the handling of COPD.

More recently, other mucolytics like erdosteine and fudosteine, known as novel thiols, accept too been synthesised [65, 66], to overcome problems observed with thiols such as NAC and NAL. Erdosteine is as an antioxidant and has mucolytic properties, in addition to the ability to reduce bacterial adhesiveness. A small randomised command trial showed fewer exacerbations, reduced infirmary time and improved quality of life in patients with COPD that were treated with erdosteine when compared with placebo [67]; all the same, time to come clinical trials will be needed to confirm these preliminary results. In improver, in COPD patients that fume, erdosteine has also been observed to reduce levels of ROS and cytokines (IL-half dozen and -8) in peripheral blood and bronchial secretions, respectively [68]. Fudosteine is a cysteine-altruistic compound with greater bioavailability than NAC. It reduces hypersecretion by downregulation of mucin cistron expression.

Peptide mucolytics

Unlike classic mucolytics that interruption down mucin networks, peptide mucolytics are designed to break down the highly polymerised Deoxyribonucleic acid and F-actin network that is characteristic of pus. The proteolytic enzyme dornase alfa cleaves Dna polymers and has been developed for the long-term handling of mucus hypersecretion in CF [69]. Furthermore, children with CF evidence improved lung function and outcome following handling with dornase alfa [70]. Both gelsolin and thymosin β4, conversely, are recognised to specifically depolymerise F-actin polymers in CF sputum, therefore reducing its' viscosity [71, 72]; however, these agents need to exist further evaluated in clinical trials.

Not-destructive mucolytics

Unlike other mucolytics that cleave chemical bonds, non-destructive mucolytics dissociate or disrupt the polyionic oligosaccharide mucin network by a machinery termed "charge shielding". Examples of these mucolytics include dextran and heparin, and although clinical studies are even so to exist undertaken, in vitro and pre-clinical studies have demonstrated their efficacy [73–75].

MUCOKINETICS

The majority of mucokinetic agents (sometimes referred to every bit cough clearance promoters) increase mucociliary clearance by acting on the cilia. Although a wide range of mucokinetics that increment ciliary vanquish frequency are available, these agents accept piddling effect on mucociliary clearance in patients with pulmonary illness [76]. Mucokinetic medications include broncodilators, tricyclic nucleotides and ambroxol (fig. ane⇑). Surfactants also promote cough clearance of mucus past decreasing the surface adhesion between mucus and airway epithelium [77].

Bronchodilators

At that place is prove in favour of the use of β₂-adrenergic agonists to heighten mucociliary clearance [78, 79]; however, other reports take observed fiddling effect on mucociliary clearance [80]. Interestingly, recent reports have shown that salmeterol could restore secretory functions in CF airway submucosal gland serous cells [81], and that β₂-adrenergic agonists can enhance mucociliary clearance in patients with airway reversibility [82].

Ambroxol

Ambroxol is thought to stimulate surfactant and mucus secretion, yet promote normalisation of mucus viscosity in mucilaginous secretions. The results of clinical studies of ambroxol are alien in that some institute clinical benefit [83], whereas others did not [84]. Even so, a recent systematic review provides testify of a generalised benefit using ambroxol for a range of parameters, including secretolytic activity (promoting fungus clearance), anti-inflammatory and antioxidant activeness and exerts local anaesthetic outcome [85].

SUMMARY

The present review provides a summary of the most clinically relevant mucoactive drugs used worldwide in the management of several acute and chronic respiratory diseases, with detail reference to their potential mechanisms of action. Although the precise mechanism of action of several mucoactive drugs is fairly well established, difficulty still exists regarding how they are sometimes classified, due to overlapping effects that they showroom. Only by developing our understanding of the mechanism of action and specific effects exerted by mucoactive agents, we may in turn offering improved therapeutic use of these drugs.

Statement of interest

R. Balsamo and L. Lanata are employees of Dompé SPA, Italy.

Provenance

Publication of this peer-reviewed article was supported past Dompé SPA, Italian republic (unrestricted grant, European Respiratory Review event 116).

• Received March 24, 2010.
• Accepted April 12, 2010.

• © ERS

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Does Musinex Stimulate Lung Repair?,

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