Mucoactive Agents in the Therapy of Upper Respiratory Airways Infections: Fair to Describe Them Just as Mucoactive?

Abstract

Background:

Upper and lower respiratory tract infections are common conditions for which medical advice is sought, and their management relies on the use of prescription and over-the-counter (OTC) medicines. Ambroxol, bromhexine, carbocysteine, erdosteine, N-acetyl cysteine (NAC), and sobrerol are mucoactive agents for which clinical trials have been conducted, have been awarded well-established status by regulatory authorities, and are available as OTC or prescription products.

Objective:

To briefly review the evidence-based efficacy and safety of these substances in the therapy of upper respiratory airways infections.

Methods:

We conducted searches in MEDLINE and other databases for clinical trials and reviews done on the efficacy and safety of ambroxol, bromhexine, carbocysteine, erdosteine, NAC, and sobrerol.

Results:

Clinical trials have shown that these mucolytics have an important place in the relief of cough symptoms by easing the elimination of mucus. All drugs have shown comparable efficacy in the symptomatic treatment of productive cough, with some shared characteristics and some specific features.

Conclusions and relevance:

All mucolytics reviewed have a good safety profile, although some precautions should be taken when using ambroxol and bromhexine, and the use of NAC and carbocysteine should be monitored in special patient groups. Overall, however, the available evidence from randomised, controlled, and observational trials, as well as pragmatic, real-life experience, suggests that these products are useful in the therapy of upper respiratory airways infections, including bronchitis, sinusitis, and rhinosinusitis.

Keywords

Ambroxol bromhexine carbocysteine erdosteine expectorants mucokinetics mucolytics sobrerol

Background

Respiratory tract diseases affect a large number of people worldwide: in the European Union (EU), for instance, 7% of hospital admissions are linked to respiratory illnesses, which are responsible for approximately 12% of all-cause deaths.¹

Upper and lower respiratory tract infections (RTIs) are common conditions for which medical advice is regularly sought, and their management relies on the use of prescription and over-the-counter (OTC) medicines.² Economically, RTI treatment is linked to significant expenses: in 2011, chronic obstructive pulmonary disease (COPD) and asthma, in the EU, caused €42.8 billion in direct (primary care, hospital outpatient and inpatient care, drugs, and oxygen) costs; indirect costs (lost production including work absence and early retirement) amounted to €39.5 billion.³

Mucoactive drugs are regularly used as a therapeutic option for mucus alterations, including hypersecretion. Mucus-thinning (mucolytics), cough-inducing (expectorants), and cough transport facilitating (mucokinetics) drugs have been available for clinical use to ease airway clearance in diverse indications such as bronchiectasis, COPD, acute, and chronic bronchitis or simply to relieve symptoms of acute cough caused by RTI.⁴ The effects of these drugs in the treatment of various acute and chronic inflammatory diseases of the upper and lower respiratory tract have been investigated in a large number of clinical studies, which, however, were designed and conducted well before the principles of Good Clinical Practice were established. Many trials were open and non-controlled, and only relatively few randomised controlled trials (RCTs) are available for each individual drug in each indication. For erdosteine and N-acetyl cysteine (NAC), however, well-designed, blinded, placebo-controlled trials have recently shown a reduction in the frequency and duration of exacerbations in patients with COPD.^5–10

In the past years, a number of systematic reviews have been published on the use of mucoactive agents in chronic bronchitis or COPD,¹¹ bronchiectasis,¹² acute cough,¹³ or as an adjunct to antibiotics in acute pneumonia.¹⁴ Almost all of them have concluded that mucolytics and mucokinetics have only a weak evidence-based support. The approach used in these reviews is scientifically sound and rigorous, but it reflects only the evidence provided by RCTs that were selected based on very strict criteria. No consideration has been given to results of other RCTs, and open, prospective, or retrospective studies, or to patient’s self-perceived and physician-assessed efficacy. In addition, all reviews are based on a very limited amount of studies and aggregate outcomes of trials conducted with different drugs.^11–14

Ambroxol, bromhexine, carbocysteine, erdosteine, NAC, and sobrerol have all been awarded well-established status by regulatory authorities and are available as OTC or prescription products for selected indications. This work aims to evaluate the evidence-based efficacy and safety of these substances in the therapy of upper respiratory airways infections was provided not only by RCTs but also by observational studies.

Methods

We conducted searches in MEDLINE and other databases (search terms: antitussiv*, cough, productive cough, expectorant, mucolytic, ambroxol, bromhexine, carbocysteine, erdosteine, N-acetyl cysteine, sobrerol) for clinical trials and reviews on the efficacy and safety of these substances. No time limit has been set for the search.

We included in our evaluation RCTs and open, controlled, and uncontrolled trials with the aim to evaluate the reported efficacy and safety of these mucolytics with no restrictions on trial design. For products for which recent analyses have been published, we have considered all studies discussed in the reviews, but for the sake of brevity, we do not list or provide specific comments on individual trials unless needed. We did not limit the analysis to the proportion of participants who were cured but we considered also subjective and objective end points.

Ambroxol

Ambroxol exerts stimulating effects on mucociliary clearance and it increases cough effectiveness through its mucokinetic properties and stimulating surfactant secretion.⁴ It has been available on the market for almost 50 years in several galenic forms, including ampules for parenteral use to treat the infant respiratory distress syndrome.

Physiologically, ambroxol has been shown to exert secreto-lytic, antioxidant, and anaesthetic activities.¹⁵ This explains its usefulness in the prevention¹⁶ and treatment of upper RTIs (URTI) associated with abnormal mucus secretion or impaired mucus transport. Its efficacy has been shown in more than 100 clinical observational, uncontrolled, or randomised, controlled, double-blind trials on more than 15 000 adult and paediatric patients with various forms of acute and chronic diseases of the upper and lower respiratory tract.¹⁵ Animal and human studies have shown that ambroxol, administered concomitantly with amoxicillin, or ampicillin and erythromycin, increases the antibiotic levels in the lung.^17–20

The product is safe,¹⁵ although the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has recommended to update the ambroxol product information by including the risk of allergic reactions and serious cutaneous adverse reactions.²¹ Recently, a case of ambroxol-induced focal epileptic seizure in a patient with epilepsy has also been reported.²²

To our knowledge, no interactions of ambroxol with other drugs have so far been demonstrated. The use of ambroxol in children younger than 2 years is not recommended.

Bromhexine

Bromhexine, like ambroxol, is available in several galenic formulations. Animal and human studies suggest that bromhexine influences mucus production, sputum quality and quantity, ciliary activity, and cough severity and frequency.²³ Zanasi et al²³ evaluated approximately 40 clinical studies conducted in patients with COPD, chronic or acute bronchitis, URTI and lower RTI, and bronchiectasis. The study designs ranged from observational, uncontrolled, to randomised, controlled, double-blind trials and included adults as well as children. Overall, bromhexine showed a modest efficacy, but its use was associated with a clinically consistent and subjectively perceived improvement in mucus clearance.²³

As with ambroxol, antibiotic penetration seems to be enhanced by the concomitant administration of bromhexine.^24–26

The safety of bromhexine has been demonstrated by clinical studies and long-term use, but the PRAC recommendations issued for ambroxol apply to bromhexine as well.²¹ Bromhexine should not be used in children younger than 2 years.

Carbocysteine and NAC

N-acetyl cysteine and, to a lesser extent, carbocysteine (S-carboxymethyl-l-cysteine) are commonly prescribed as mucolytics in the treatment of COPD and bronchitis and are available as different galenic formulations. N-acetyl cysteine is also used in the management of paracetamol overdose.²⁷

Cysteine derivatives have been shown in vitro to break disulphide bridges between the macromolecules present in the mucus, thus leading to a reduced mucus viscosity.²⁸ They are also endowed with antioxidant activities that, for instance, have been linked to their beneficial action in the pharmacologic treatment of COPD.^29–32 In adult patients with COPD or chronic bronchitis, both drugs cause a small reduction in acute exacerbations;^5,10,33,34 2 studies have shown beneficial effects of carbocysteine on the quality of life of patients with COPD.^35,36 N-acetyl cysteine appears of no use in cystic fibrosis.³⁷ According to a review by Shen et al,¹⁰ long-term high-dose NAC treatment may lead to a lower rate of exacerbations in patients with COPD.

Regarding paediatric patients with acute bronchopulmonary disease, a recent Cochrane review described the efficacy of both drugs as limited.³⁸

N-acetyl cysteine and carbocysteine are generally recognised as safe in adults and children, but there have been reports of respiratory paradoxical adverse drug reactions associated with their systemic use in paediatric patients.³⁹ Two case reports have suggested that carbocysteine may cause pneumonia in predisposed patients.^40,41 This would question the risk/benefit ratio of these drugs in children and in selected groups of patients.

Erdosteine

Erdosteine is a thiol derivative with mucolytic⁴² and antioxidant activity.⁴³ It has been on the market for more than 20 years for the treatment of chronic obstructive bronchitis, including acute infective exacerbation of chronic bronchitis and COPD.^42,44 In clinical trials, erdosteine reduced frequency and severity of cough and sputum viscosity more effectively than placebo and was more efficient in reducing sputum adhesion than ambroxol.⁴⁴ Less (approximately 30) trials have been conducted with this drug than with the other mucolytics so far discussed,⁴⁵ but in recent well-designed, blinded, placebo-controlled trials, erdosteine has shown reduction in the frequency and duration of exacerbations in patients with COPD,^6–9 and, when administered concomitantly to standard treatment, symptom improvement and reduction in exacerbation of chronic bronchitis/COPD, associated with a reduction in hospitalisation rate and an improved quality of life.^42,44,45

Data on the use of erdosteine in indications other than COPD are very scant. Nevertheless, 2 studies have shown beneficial effects of an erdosteine/amoxicillin combination in the treatment of paediatric patients with acute RTI.^46,47 Erdosteine alone, however, had no effects on paediatric patients with rhinosinusitis.⁴⁸

The safety profile of erdosteine is generally quite good, the most common side effect being heartburn. No specific interactions with other drugs have been described.

Sobrerol

Sobrerol has been on the market of mainly European countries for almost 50 years. It has been shown in vivo to increase mucus production and ciliary motility, thus improving mucociliary clearance,⁴⁹ and to reduce the viscosity of tracheobronchial mucus without causing any alterations of the alveolar surfactants.⁵⁰ Radical scavenging activities have also been reported.⁵¹

Although recent, specific reviews exist for ambroxol,¹⁵ bromhexine,²³ NAC and carbocysteine,^38,52,53 and erdosteine,^44,45,54,55 sobrerol has not received much attention, probably because most studies have been published in Italian and often in difficult-to-access journals. Only 1 old, outdated review on sobrerol has so far been published.⁴⁹ For this reason, we have decided to compile a tabular presentation of all available studies conducted with this compound (Table 1). A total of 10 double-blind and 15 open (controlled and non-controlled) studies conducted on adults and children have been published, covering acute and chronic airways diseases.^{56,58–70,72–80,82,83} Sobrerol has been shown to be safe and effective also in paediatric patients and infants.^{56,66–68,77,80,83} One study conducted on paediatric patients with whooping cough⁸³ suggests a synergistic effect of sobrerol with antibiotics similar to that observed for other mucolytics; no negative interactions were observed.^63,77,78

Table 1.

Synopsis of clinical studies conducted with sobrerol.

Indication/reference	Study design	Main end points	Dosage/comparator/duration of treatment	Subjects (SOB/comparator)Age	Outcome
Double-blind studies
Acute airways diseases⁵⁶	Double-blind, randomised, controlled	Cough, dyspnoea, rheological examination of expectorates, laboratory parameters	SOB granules 100 mg orally 3 times daily NAC granules 100 mg orally 3 times daily 7 d	40 (paediatric; 20/20) 3-12 y	Both treatments were effective and comparable. SOB was statistically significantly more active than NAC on the rheological values of sputum No serious AEs were reported for any treatment
Antipyretic activity in patients with RTI⁵⁷	Double-blind, randomised, controlled	Clinical signs, fever	Combination tablets (paracetamol 300 mg and SOB 150 mg) orally 2 to 4 times daily or suppositories (500 and 200 mg) twice daily Paracetamol tablets alone, orally (500 mg 3-4 times daily) or suppositories (1000 mg 2-3 times daily) 5 d	287 (148/139) Age not clearly defined, mostly between 20 and 59 y	Efficacy of combination superior to paracetamol alone regarding cough and expectoration; faster resolution of fever with combination No serious AEs observed
Chronic and acute bronchitis⁵⁸	Double-blind, comparative	Mucolytic activity	SOB orally Domiodol orally		Improvement in the subjective measures of ease of expectoration, severity of coughing, and sputum consistencyNo AEs reported
Chronic bronchitis^59,60,61	Double-blind, randomised, crossover	Subjective symptoms, pulmonary function parameters, sputum characteristics	SOB 100 mg orally 4 times dailyPlacebo14 d with 1 wk washout	30 (23 concluding the study)64.5 y	No effects of SOB as an expectorant. Seven patients in the placebo dropped out of studyNo serious AEs observedSOB 2 patients with mild AEs. Placebo 6 patients with mild AEs
Chronic bronchitis⁶²	Double-blind, randomised, controlled	Pulmonary function parameters, alveolar-arterial O₂ and CO₂ gradients	SOB 800 mg orally dailyPlacebo7 d	20 (10/10)	Reduction in bronchial obstruction after SOB treatmentNot significant modification of pulmonary functions
Chronic bronchitis⁶³	Double-blind, randomised, placebo-controlled	Frequency of exacerbations and respiratory function indices	SOB 300 mg orally twice dailyPlacebo3 mo	707, 673 completers (334/339)Mean age: SOB 55.6, placebo 57.5 y	No exacerbations in 76% patients of the SOB group as compared with 58% in the placebo group. Response of respiratory function indices significantly higher in the SOB groupNo serious AEs reported. SOB: 53 patients with side effects. Placebo: 66 pts with side effects
Chronic catarrhal rhinosinusitis⁶⁴	Double-blind, randomised, placebo-controlled	Frontal headache and rhinorrhoea	SOB granules, orally, 900 mg/dPlaceboUp to 10 d	40 (20/20)Mean age: SOB 40.6, placebo 43.9 y	Significant reduction in frontal headache and rhinorrhoeaNo serious or severe AEs reported
COPD⁶⁵	Double-blind, placebo-controlled	Rheological mucus parameters	Combination (carbocysteine 375 mg + SOB 260 mg) orally (daily dose not specified)Placebo10 d	32 (16/16)	Combination affected favourably the most important rheological parameters of mucus, including spinnability. Improvement of the most important respiratory function indicesNo AEs reported
Upper and lower acute or chronic RTIs⁶⁶	Double-blind, randomised, controlled	Rheological mucus parameters, respiratory function indices	Combination (carbocysteine 375 mg + SOB 260 mg) orally 4 times dailyPlaceboSyrup: 21 dCapsules: 14 d	100 (50/50)12 to 74 y	Significant improvement of objective and subjective symptoms and respiratory function indices as compared with placeboNo AEs observed
Whooping cough⁶⁷	Double-blind, randomised, controlled	Clinical signs, respiratory function indices	Combination (clofedanol 1.62 mg/kg/d + SOB 3.6 mg/kg/d)Placebo15 d	30 (paediatric; 15/15)10 mo to 12 y	Rapid symptoms and respiratory function parameters improvement (in 60% for cough in SOB, 20% in PL)No AEs observed
Open studies (controlled and non-controlled)
Acute, asthmatic, and recurrent bronchitis⁶⁸	Open, randomised, parallel group	Improvement rates	SOB 50 to 100 mg orally twice dailyBRH 2 to 4 mg orally 3 times daily2 wk	40 (paediatric)<5 y	Both treatments effective, with similar improvement rates (SOB: 90%; BRH: 80%)No serious AEs reported. SOB: 2 patients with mild AEs. BRH: 3 patients with mild AEs
Acute, chronic and recurrent bronchitis, infectious bronchitis, pneumonia, bronchiectasis⁶⁹	Open, observational	Mucus viscosity and symptoms improvement	SOB intramuscular twice daily, 120 mg daily5 to 45 d	55 (34 F, 21 M)15 to 87 y	Mucus viscosity reduced and symptoms improvedNo AEs reported
Bronchitis, bronchiectasis^70,71	Open, case series	Cough, expectoration, dyspnoea	SOB suppositories (200 mg) and/or parenterally (60 mg) twice daily (60 cases) or nebuliser (2000 mg/100 mL H₂O) once daily or twice daily (30 cases)3 to 6 d	90Age not defined	Improvement of symptoms in most cases. Reduction in dyspnoea, eased expectoration. Improvements less pronounced with nebuliserNo reports of AEs
Chronic bronchitis and emphysema⁷²	Open, comparative (no treatment as control)	Respiratory function indices, rheological mucus parameters	SOB (nebuliser)SOB intramuscular15 d	84 (50 nebuliser, 12 intramuscular, 22 no treatment)43-69 y	Improvement of respiratory indices, decrease in mucus after 4-5 d, modification of rheological parametersNo AEs reported
Chronic bronchitis⁷³	Open, comparative, observational	Clinical signs, respiratory function parameters	Aerosolised SOB 80 mg/d and theophylline 600 mg/d orallyTheophylline 600 mg/d orally15 d	20 (10/10)44 to 70 y	Mucus viscosity and respiratory function parameters better in the combination group. No severe AEs observed
Chronic bronchitis⁷⁴	Single-blind, comparative	Mucus rheology and expectorate characteristics, cough	Combination (carbocysteine 375 mg + SOB 60 mg) orally 3 times dailySOB 100 mg orally 3 times daily10 d	3637 to 73 (mean: 60) y	Faster improvement of expectorate, clinical symptoms and respiratory functions with combination, no differences between the 2 treatments in mucus rheology and general outcomeNo AEs observed
Chronic bronchitis⁷⁵	Open, comparative (no treatment as control)	Frequency of exacerbations	Combination (carbocysteine 375 mg + SOB 160 mg orally 3 times daily6 mo	167 (116/51)Mean age: treated 60.3, control 62.1 y	Significantly lower number of exacerbation episodes in the treated group. Significant positive changes of the rheology of bronchial secretionNo AEs reported
Chronic obstructive bronchitis⁷⁶	Open, observational, multicentre	Clinical parameters, respiratory function indices	Combination (carbocysteine 375 mg + SOB 60 mg) orally 3 times daily10 d	348Median age: 61.6 y	Improvement of cough symptoms, expectoration, and dyspnoea as well as of respiratory function indicesNo severe or serious AEs observed
Chronic upper RTI⁷⁷	Open, retrospective, comparative	Severity, frequency and duration of productive cough	Comparison between treatment with antibiotics vs treatment with mucolytic drugs (SOB or NAC)	59 (paediatric) (29/15/15)3-14 (mean: 9) y	Antimicrobial therapy did not modify resolution of cough. Symptomatic therapy improved cough during treatment
Chronic upper RTI⁷⁸	Open, observational, prospective	Severity, frequency and duration of productive cough (patient diaries)	SOB orallyAntibiotic therapy + SOB orallyAntibiotic therapy only28 d	150 (50/50/50) (144 completers)Mean age: 48 y	Treatment with mucolytics improved subjective symptoms better than with antibiotics alone, with no difference between SOB alone and SOB + antibiotics. A positive effect of SOB in cough reduction and resolution was observedNo serious AEs were reported
Obstructive airways diseases⁷⁹	Open, randomised, controlled	Sputum characteristics and volume, difficulty in expectorating, cough	SOB orally (granulate)Neltenexine orally (granulate)20 d	30 (15/15)Mean age: SOB 70.2, neltenexine 65.1 y29 to 82 y	Both drugs had similar efficacy, with no statistically significant differences in all measured parameters at end of treatmentNo AEs reported for neltenexine. SOB: 2 patients with AEs of moderate severity
Otitis media⁸⁰	Open, observational	Nasal obstruction, earache, and deafness	SOB once daily, 40 mg/3 mL daily10 d	30 (paediatric)5 to 10 y	Significant reduction in nasal obstruction, earache and deafnessNo serious AEs reported. Two patients with probably related moderate asthma attack, resolved with 50% dose reduction
Safety, antipyretic activity⁸¹	Open, observational, multicentre	Clinical parameters	Paracetamol and SOB suppositories (56%) or orally (44%) (dosage not available)1 to 2 d: 5%, 3 to 4 d: 69%, >4 d: 26%	3501 (1916 treated with the paracetamol-SOB association)Age not clearly defined	Paracetamol-SOB combination was more effective than other treatments in reducing feverNo serious AEs observed. Incidence of AEs in the paracetamol-SOB group significantly lower than in other treatment groups
Upper and lower acute or chronic RTIs⁸²	Open, observational	Rheological mucus parameters, respiratory function indices	Combination (carbocysteine 375 mg + SOB 60 mg) orally 4 times daily14 d	5020 to 70 (mean: 42) y	Improvement of sputum fluidity and favourable evolution of respiratory function parametersNo AEs observed
Whooping cough⁸³	Open, observational	Time course to symptom resolution	SOB orally or suppositoriesSalbutamol 0.30 to 0.50 mg/kg/d, orally, 4 times dailyErythromycin 40 mg/kg/d, orally 3 times dailyTreatment: until resolution of symptoms (erythromycin 6-8 d)	20 (paediatric)6 mo to 2 y	Treatment outcome was superior to historic controls (use of antibiotic alone or associated with hyperimmune gamma globulins and/or sedatives)No AEs reported

Abbreviations: AE, adverse event; BRH, bromhexine; NAC: N-acetyl cysteine; SOB, sobrerol.

In 2 studies, concomitant administration of sobrerol and paracetamol led to a better febrifuge action than the use of paracetamol alone.^57,81

No clinical study reported any noteworthy AEs for sobrerol; the most common AEs reported (gastrointestinal problems and allergic reactions) were mostly of mild nature.

Discussion and Conclusions

Observational studies and real-life use have shown that mucolytics have an important place in the relief of upper respiratory tract symptoms by easing the elimination of mucus, even though the published literature regarding their effectiveness has been defined as inconsistent.⁸⁴ All drugs reviewed have shown comparable efficacy in the symptomatic treatment of productive cough, with some shared characteristics and some more specific features (Table 2).

Table 2.

Main features of the mucolytic drugs reviewed.

	Ambroxol	Bromhexine	Carbocysteine	N-acetyl cysteine	Erdosteine	Sobrerol
Indications covered by studies	BE, BR, CF, COPD, (IRDS)^a, RTI	BE, BR, CF, COPD, (IRDS)^a, RTI	BR, COPD, RTI	BR, COPD, RTI	BR, COPD, RTI	BE, BR, CF, COPD, O, R, RTI, W
Safety^b	Allergic skin reactions	Allergic skin reactions	Paradoxical AEs in paediatric patients	Paradoxical AEs in paediatric patients	n.k.	n.k.
Paediatric use^c	NR2	NR2	NR2	NR2	NR2	NR2
Interactions/synergies
Antibiotics	Increases levels	Increases levels	n.k.	n.k.	n.k.	Increases levels
Antipyretics (paracetamol)	n.k.	n.k.	n.k.	n.k.		Increases efficacy
Other	n.k.	n.k.	n.k.	n.k.	n.k.	n.k.

Abbreviations: BE, bronchiectasis; BR, bronchitis; C, common cold; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IRDS, infant respiratory distress syndrome; O, otitis media; R, rhinosinusitis; RTIs, respiratory tract infections (not specified); W, whooping cough. Galenic forms: A, ampoules; Ca, capsules, pastilles, lozenges; Gr, granulate; Ne, nebuliser; Su, suppositories; Sy, syrup. n.k., not known or not reported. NR2: not recommended in children <2 years old.

References are listed in the corresponding sections.

No longer first-line treatment option.

Only major safety issues.

Use in infants in some countries allowed.

Current guidelines and reviews of non-bacterial RTI recommend symptomatic cough relief treatment only.^85–87 The primary goal of treatment in case of productive cough is to support expectoration and thereby to indirectly reduce cough. To improve the patient’s general condition, the treatment should also aim at a rapid recovery from symptoms secondary to cough such as sleep disturbance, impaired well-being, dyspnoea, and chest pain.⁸⁷

All mucolytics reviewed here provide symptomatic cough relief and possibly shorten the duration of symptoms. They are also endowed with additional pharmacologic properties that may well contribute to their clinical benefit in the treatment of respiratory diseases such as bronchitis and COPD. The conflicting clinical evidence mentioned in recent reviews^{11–14,33,88} is probably the consequence of several factors, such as the study designs used, the self-limiting nature of the disease, as well as the lack of well-defined study standards. There is also no clear consensus on end points to be used in clinical efficacy trials with mucolytics; for instance, the correlations between some efficacy end points are very poor, the acute or long-term effects of mucoactive therapy cannot be measured reliably, and the intra- and interpatient variability can be very high.⁸⁴

The galenic form may also influence the effectiveness of a mucolytic drug but only little comparative evidence has been gathered with this drug class. One trial featuring a well-designed head-to-head comparison has studied nebulised products containing ambroxol, NAC, or sobrerol and has shown substantial differences among the 3 apparently identical galenic forms, with the sobrerol concentration in the aerosolised form being larger than that of ambroxol or NAC.⁸⁹ This may suggest, for instance, that a shorter sobrerol nebulisation could achieve the same results obtained with a longer nebulisation with ambroxol or NAC.

Positive interactions with antibiotics have been reported for ambroxol,^17–20 bromhexine,^24–26 and sobrerol.⁸³ In the context of the indications for which mucolytics are used, however, this property is of limited usefulness.

However, 2 studies report a positive interaction of sobrerol with an antipyretic.^57,81 This synergistic effect should be further investigated. Paracetamol is often used by patients with common cold symptoms to reduce fever, and if the concomitant treatment of both drugs leads to a better antipyretic action of paracetamol than administration of paracetamol alone, the paracetamol dosage could be decreased without loss of efficacy and possibly with a reduction in potential AEs.⁵⁷

All mucolytics discussed in this review have a good safety profile, although some precautions should be taken when using ambroxol and bromhexine²¹ and the use of NAC and carbocysteine should be monitored in special patient groups.^21,39–41

Ambroxol, bromhexine, carbocysteine, erdosteine, NAC, and sobrerol may alter the volume of secretions or their composition; therefore, they can effectively ease symptoms of respiratory tract diseases such as productive cough. Their mucolytic, anti-inflammatory, and antioxidant properties all contribute to their clinical benefit. In patients with COPD, they may help to reduce frequency and duration of exacerbations. Upper RTIs being a multifaceted disease, treatment must rely on the simultaneous treatment of all symptoms. In addition, the overall treatment success is dependent on a number of additional factors. For instance, in indications such as COPD or chronic bronchitis, adherence to treatment and simultaneous targeting of different pathological mechanisms are crucial to achieve symptoms resolution. Overall, the available evidence from randomised, controlled, and observational trials, as well as pragmatic, real-life experience, suggest that these mucolytics, taken at the recommended dosages, are useful in the therapy of lower respiratory diseases such as COPD and bronchiectasis, as well as of upper respiratory airways infections, including bronchitis, sinusitis, and rhinosinusitis.

Footnotes

Funding:

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The preparation of this article was possible by an unrestricted grant by Pharmaidea s.r.l., Travagliato, Italy.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

Both authors contributed equally to the design, preparation and writing of this review.

ORCID iD

Orlando Petrini

References

The burden of lung disease. https://www.erswhitebook.org/chapters/the-economic-burden-of-lung-disease/. Accessed September 10, 2018.

Hamoen

Broekhuizen

Little

et al . Medication use in European primary care patients with lower respiratory tract infection: an observational study. Br J Gen Pract. 2014;64:e81–e91.

The economic burden of lung disease. https://www.erswhitebook.org/chapters/the-economic-burden-of-lung-disease/. Accessed September 10, 2018.

Rogers

DF.

Mucoactive agents for airway mucus hypersecretory diseases. Respir Care. 2007;52:1176–1193; discussion 1193–1197.

Zeng

Yang

Huang

Xiao

Effect of carbocisteine on patients with COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2017;12:2277–2283.

Dal Negro

Wedzicha

Iversen

et al . Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study. Eur Respir J. 2017;50:1700711.

Dal Negro

Visconti

Erdosteine reduces the exercise-induced oxidative stress in patients with severe COPD: results of a placebo-controlled trial. Pulm Pharmacol Ther. 2016;41:48–51.

Moretti

Fagnani

Erdosteine reduces inflammation and time to first exacerbation postdischarge in hospitalized patients with AECOPD. Int J Chron Obstruct Pulmon Dis. 2015;10:2319–2325.

Dal Negro

Visconti

Turco

Efficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: results of a double blind, placebo-controlled trial. Pulm Pharmacol Ther. 2015;33:47–51.

10.

Shen

Cai

Lei

Zhang

Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD. 2014;11:351–358.

11.

Poole

Chong

Cates

CJ.

Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015;7:CD001287.

12.

Welsh

Evans

Fowler

Spencer

Interventions for bronchiectasis: an overview of Cochrane systematic reviews. Cochrane Database Syst Rev 2015;7:CD010337.

13.

Smith

Schroeder

Fahey

Over-the-counter (OTC) medications for acute cough in children and adults in community settings. Cochrane Database Syst Rev 2014;11:CD001831.

14.

Chang

Cheng

Chang

AB.

Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database Syst Rev 2014;3:CD006088.

15.

Malerba

Ragnoli

Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug Metab Toxicol. 2008;4:1119–1129.

16.

Nobata

Fujimura

Ishiura

Myou

Nakao

Ambroxol for the prevention of acute upper respiratory disease. Clin Exp Med. 2006;6:79–83.

17.

Gene

Poderoso

Corazza

et al . Influence of ambroxol on amoxicillin levels in bronchoalveolar lavage fluid. Arzneimittelforschung. 1987;37:967–968.

18.

Principi

Zavattini

Daniotti

Possibility of interaction among antibiotics and mucolytics in children. Int J Clin Pharmacol Res. 1986;6:369–372.

19.

Spatola

Poderoso

Wiemeyer

Fernandez

Guerreiro

Corazza

Influence of ambroxol on lung tissue penetration of amoxicillin. Arzneimittelforschung. 1987;37:965–966.

20.

Wiemeyer

JC.

Influence of ambroxol on the bronchopulmonary level of antibiotics. Arzneimittelforschung. 1981;31:974–976.

21.

European Medicines Agency (EMA). Revised assessment report—procedure under article 31 of directive 2001/83/EC resulting from pharmacovigilance data. Ambroxol and bromhexine containing medicinal products. https://www.ema.europa.eu/documents/referral/ambroxol-bromhexine-article-31-referral-prac-assessment-report_en.pdf.EMA/PRAC/800767/2015. Published September 10, 2015.

22.

Lapenta

Morano

Fattouch

et al . Ambroxol-induced focal epileptic seizure. Clin Neuropharmacol. 2014;37:84–87.

23.

Zanasi

Mazzolini

Kantar

A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip Respir Med. 2017;12:7.

24.

Bergogne-Berezin

Pierre

Dournovo

. Experimental study of the possible influence of a fluidifying agent (bromhexine) on the penetration of erythromycine into bronchial secretions (author’s transl.). Therapie. 1979;34:705–711.

25.

Martin

Loveday

Marriott

Bromhexine plus oxytetracycline: the effect of combined administration upon the rheological properties of mucus from the mini-pig. J Pharm Pharmacol. 1993;45:126–130.

26.

Roa

Jr Dantes

RB.

Clinical effectiveness of a combination of bromhexine and amoxicillin in lower respiratory tract infection. A randomized controlled trial. Arzneimittelforschung. 1995;45:267–272.

27.

Kozer

Koren

Management of paracetamol overdose: current controversies. Drug Saf. 2001;24:503–512.

28.

Medici

Radielovic

Effects of drugs on mucus glycoproteins and water in bronchial secretion. J Int Med Res. 1979;7:434–442.

29.

Rahman

Pharmacological antioxidant strategies as therapeutic interventions for COPD. Biochim Biophys Acta. 2012;1822:714–728.

30.

Rahman

Adcock

IM.

Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. 2006;28:219–242.

31.

Rahman

Kilty

Antioxidant therapeutic targets in COPD. Curr Drug Targets. 2006;7:707–720.

32.

Rahman

MacNee

Antioxidant pharmacological therapies for COPD. Curr Opin Pharmacol. 2012;12:256–265.

33.

Poole

Black

Cates

CJ.

Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;8:CD001287.

34.

Poole

Black

PN.

Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. BMJ. 2001;322:1271–1274.

35.

Tatsumi

Fukuchi

Carbocisteine improves quality of life in patients with chronic obstructive pulmonary disease. J Am Geriatr Soc. 2007;55:1884–1886.

36.

Yasuda

Yamaya

Sasaki

et al . Carbocisteine reduces frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease. J Am Geriatr Soc. 2006;54:378–380.

37.

Duijvestijn

Brand

PL.

Systematic review of N-acetylcysteine in cystic fibrosis. Acta Paediatr. 1999;88:38–41.

38.

Chalumeau

Duijvestijn

YCM

. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease. Cochrane Database Syst Rev. 2013;5:CD003124.

39.

Mallet

Mourdi

Dubus

et al . Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey. PLoS ONE. 2011;6:e22792.

40.

Koreeda

Tanoue

Kumamoto

et al . A possible case of drug-induced pneumonia due to L-carbocisteine. Nihon Kokyuki Gakkai Zasshi. 2007;45:609–614.

41.

Kudo

Ichihara

Hisamoto

et al . A definite case of (L)-carbocisteine-induced pneumonia with CATCH22 syndrome. Intern Med. 2013;52:97–100.

42.

Moretti

Erdosteine: its relevance in COPD treatment. Expert Opin Drug Metab Toxicol. 2009;5:333–343.

43.

Hillas

Nikolakopoulou

Hussain

Vassilakopoulos

Antioxidants and mucolytics in COPD management: when (if ever) and in whom?

Curr Drug Targets. 2013;14:225–234.

44.

Dechant

Noble

Erdosteine. Drugs. 1996;52:875–881; discussion 882.

45.

Cazzola

Floriani

Page

CP.

The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data. Pulm Pharmacol Ther. 2010;23:135–144.

46.

Balli

Bergamini

Calistru

et al . Clinical effects of erdosteine in the treatment of acute respiratory tract diseases in children. Int J Clin Pharmacol Ther. 2007;45:16–22.

47.

Titti

Lizzio

Termini

Negri

Fazzio

Mancini

A controlled multicenter pediatric study in the treatment of acute respiratory tract diseases with the aid of a new specific compound, erdosteine (IPSE, Italian Pediatric Study Erdosteine). Int J Clin Pharmacol Ther. 2000;38:402–407.

48.

Unuvar

Tamay

Yildiz

et al . Effectiveness of erdosteine, a second generation mucolytic agent, in children with acute rhinosinusitis: a randomized, placebo controlled, double-blinded clinical study. Acta Paediatr. 2010;99:585–589.

49.

Braga

Allegra

Bossi

Scuri

Castiglioni

Romandini

Review on sobrerol as a muco-modifying drug: experimental data and clinical findings in hypersecretory bronchopulmonary diseases. Int J Clin Pharmacol Res. 1987;7:381–400.

50.

Dalla Valle

. L impiego in terapie del dl-sobrerolo. Boll Chim Farm. 1970;109:761–765.

51.

Braga

Culici

Dal Sasso

Falch

Spallino

Antiradical activity of sobrerol investigated by electron paramagnetic resonance (EPR). Giorn It Mal Tor. 2009;63:263–267.

52.

Duijvestijn

Mourdi

Smucny

Pons

Chalumeau

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease. Cochrane Database Syst Rev 2009;1:CD003124.

53.

Minov

Karadzinska-Bislimovska

Petrova

et al . Carbocysteine in the management of stable COPD: are its antioxidant and anti-inflammatory properties clinically relevant? South East Eur J Immunol. 2017;2017:1–7.

54.

Erdosteine for COPD exacerbations. Drug Ther Bull. 2008;46:79–80.

55.

Dal Negro

. Erdosteine: antitussive and anti-inflammatory effects. Lung. 2008;186:S70–S73.

56.

Seidita

Deiana

Careddu

Acute bronchial diseases in paediatrics: therapeutic approach with sobrerol granules. G Ital Mal Torace. 1984;38:191–194.

57.

Marchioni

Gramolini

Guerzoni

Corona

Corradini

Efficacy and tolerability of paracetamol-sobrerol combination in patients with hyperpyrexia. Clin Ter. 1990;135:105–113.

58.

Finiguerra

De Martini

Negri

Simonelli

Clinical and functional effects of domiodol and sobrerol in hypersecretory bronchopneumonias. Minerva Med. 1981;72:1353–1360.

59.

Medici

Shang

Grosgurin

Berg

Achermann

Wehrli

No demonstrable effect of sobrerol as an expectorant in patients with stable chronic bronchial diseases. Bull Eur Physiopathol Respir. 1985;21:477–483.

60.

Meyer-Shang

Grosgurin

Medici

TC.

Sobrerol as an expectorant in patients with stable chronic airway diseases: a controlled study. Prax Klin Pneumol. 1983;37:936–938.

61.

Shang

Grosgurin

Medici

TC.

Sobrerol as expectorant in patients with stable chronic respiratory tract infections. A controlled study. Schweiz Med Wochenschr. 1982;112:1846–1848.

62.

Pulerà

Santolicandro

Bernard

Solfanelli

Giuntini

Monodisperse labeled aerosol to visualize airflow redistribution in the lung after a mucokinetic drug. J Nucl Med Allied Sci. 1989;33:258–263.

63.

Castiglioni

Gramolini

Effect of long-term treatment with sobrerol on the exacerbations of chronic bronchitis. Respiration. 1986;50:202-217.

64.

Bellussi

Manini

Buccella

Cacchi

Evaluation of the efficacy and safety of sobrerol granules in patients suffering from chronic rhinosinusitis. J Int Med Res. 1990;18:454–459.

65.

Distefano

Palermo

Crimi

Mistretta

Pamparana

Messa

Evaluation of the activity of the carbocysteine-sobrerol combination on mucus spinnability. Int J Clin Pharmacol Res. 1988;8:31–35.

66.

Milvio

Di Tommaso

Mader

Traitement des hypersécretions bronchiques dans les bronchopneumopathies aiguës et chroniques—étude contrôlée d’un nouveau composé à action mucolytique. Acta Ther. 1981;7:243–260.

67.

Miraglia del Giudice

Capristo

Mirra

Maiello

Coppola

Controlled double-blind study on the efficacy of clofedanol-sobrerol in the treatment of pediatric pertussis. Minerva Pediatr. 1984;36:1199–1206.

68.

Azzollini

Bosi

Mantegazza

Piceci

Careddu

Sobrerol (Sobrepim) administered dropwise to children with acute hypersecretory bronchopulmonary disease—a controlled trial v bromhexine. Clin Trials J. 1990;27:241–249.

69.

Balzano

De Gaetani

D1-sobrerol in the treatment of acute and chronic bronchopulmonary phlogoses. Minerva Med. 1973;64:1995–2002.

70.

Monzali

Marchioni

CF.

Utilità di una nuova sostanza, il sobrerolo, nella terapia delle sequele della tubercolosi polmonare. Riv Pat Clin Tuberc. 1970;43:562–563.

71.

Marchioni

Monzali

Sperimentazione di un nuovo fluidificante e analettico di sintesi: il sobrerolo. Sua utilità nelle broncopneumopatie flogistiche. Clin Ter. 1972;60:135–142.

72.

Dotta

Bianchi

Il sobrerolo nel trattamento delle broncopneumopatie croniche ostruttive [Sobrerol for the treatment of chronic obstructive bronchopneumopathies (clinical and functional observations)]. Policlin Med. 1971;78:82–90.

73.

Morandini

Finiguerra

Conti

Bernocchi

Manini

Treatment of chronic bronchitis—combined therapy with sustained-release theophylline (Teonova) and a mucoactive drug sobrerol (Sobrepin). Clin Trials J. 1989;26:163–174.

74.

Morandini

Finiguerra

Messa

Pamparana

L’associazione carbocisteina-sobrerolo nel trattamento della patologia cronico-ostruttiva dell’apparato respiratorio. Min Pneum. 1986;25:127–133.

75.

Catena

Marcatili

Ciaccia

et al . L’associazione carbocisteina-sobrerolo—studio clinico long-term nella profilassi delle riacutizzazioni da bronchite cronica. Med Toracica. 1989;11:83–100.

76.

Gramiccioni

Pamparana

Messa

Mucolytic agents. Polycentric study of a carbocysteine-sobrerol combination. Arch Monaldi Mal Torace. 1989;44:791–793.

77.

Zanasi

Cazzato

Aprile

Mazzolini

Zenezini

Pandolfi

Are antibiotics effective in treating children with acute moist cough? a retrospective study vs symptomatic therapy. Multidiscip Respir Med. 2012;7:1–5.

78.

Zanasi

Lecchi

Mazzolini

Mastroroberto

Nardi

Morselli-Labate

Observational prospective study comparing mucoactive and antibiotic treatment in the management of acute cough from upper respiratory tract infections. Minerva Med. 2015;106:239–246.

79.

Fadda

Oral neltenexine in patients with obstructive airways diseases: an open, randomised, controlled comparison versus sobrerol. Minerva Med. 2001;92:269–275.

80.

Bellussi

Bernocchi

Ciferri

Manini

Passali

Sobrerol in the treatment of secretory otitis media in childhood. J Int Med Res. 1989;17:277–286.

81.

Gramolini

Manini

Pharmacosurveillance of antipyretics. Evaluation of the risk-benefit ratio of a combination of paracetamol and sobrerol. Monitoring of 3501 ambulatory patients. Clin Ter. 1990;132:151–166.

82.

Milder

Massari

Étude clinique d’un nouveau composé à activité mucolytique dans les bronchopneumopathies aiguës et chroniques. Acta Ther. 1981;7:391–408.

83.

Crosca

Ajello

Crosca

Minniti

Salbutamol combined with erythromycin and sobrerol in the therapy of pertussis. Arch Sci Med (Torino). 1982;139:247–250.

84.

Rubin

BK.

Mucolytics, expectorants, and mucokinetic medications. Respir Care. 2007;52:859–865.

85.

Braman

SS.

Chronic cough due to chronic bronchitis: ACCP evidence-based clinical practice guidelines. Chest 2006;129:104S–115S.

86.

Braman

SS.

Chronic cough due to acute bronchitis: ACCP evidence-based clinical practice guidelines. Chest 2006;129:95S–103S.

87.

Kardos

Berck

Fuchs

et al . Guidelines of the German respiratory society for diagnosis and treatment of adults suffering from acute or chronic cough. Pneumologie. 2010;64:701–711.

88.

Wilkinson

Sugumar

Milan

Hart

Crockett

Crossingham

Mucolytics for bronchiectasis. Cochrane Database Syst Rev 2014;5:CD001289.

89.

Zanasi

Cutrera

Cazzato

Alemanni

Farmaci mucoattivi nebulizzati: differenze nelle caratteristiche dell’aerosol ed effetto della combinazione con broncodilatatori e cortisonici. Milano, Italy: Sinergie edizioni scientifiche; 2014.