role of n-acetylcysteine · 7.2 protection from the effects of cigarette smoke or air-borne...

CurrentTherapeutics

Role of

in the treatment ofN-Acetylcysteine

AcuteRespiratoryDisorders

© 2005 Wolters Kluwer Health

Current Therapeutics. Registered on August 7th 1997. Registration n. 473

Publishing Director: Giulio Zuanetti

First printed in October 2005 dalle Arti Grafiche M. Bazzi S.p.A. Milano

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CURRENT THERAPEUTICSRole of N-Acetylcysteinein the treatment of Acute Respiratory Disorders

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1

Contents1. Introduction 3

2. Mucociliary System 4

3. Inflammatory Process 53.1 Role of Cigarette Smoke and Air Pollution 5

4. Immunomodulatory System 7

5. N-Acetylcysteine 85.1 Historical Use 85.2 Chemical Structure 85.3 Pharmacokinetic Profile 8

6. Mucolytic Activity 96.1 Clinical Trials 9

6.1.1 Children 12

7. Anti-Inflammatory and Antioxidant Activity 137.1 Patients with Chronic Obstructive Pulmonary Disease 147.2 Protection from the Effects of Cigarette Smoke or Air-borne Pollution 16

8. Immunomodulatory Activity 188.1 Clinical Trials 19

8.1.1 Effect on Influenza-like Symptoms 198.1.2 Effects on Aging-Related Changes in Immune Function 21

9. Tolerability 229.1 General Profile 229.2 Gastrointestinal Events 239.3 Laboratory Parameters 23

10. Dosage and Administration 24

11. Conclusions 25

12. References 26

Role of N-Acetylcysteinein the treatment of Acute Respiratory Disorders

Current Therapeutics

3

1. Introduction

The use of N-acetylcysteine (NAC) as an oral mucolyticin the treatment of respiratory disorders has become anaccepted and widespread treatment option in manycountries worldwide. The focus of this review is the use of oral NAC in treatingacute respiratory pathologies:• productive (wet) cough• acute bronchitis • influenza.The mechanisms of action of NAC in these indicationsinclude mucolytic, anti-inflammatory, antioxidant andimmunomodulatory effects. NAC is recommended forthe treatment of acute respiratory conditions in a range ofpatients including adults and children (figure 1).

NAC was first developed and used as a mucolytic inrespiratory diseases, but subsequent research revealed itsantioxidant properties. NAC is therefore also effective inreducing oxidative stress and inflammation in theairways and lungs, produced by cigarette smoke or air-borne pollution. Recently, NAC has also been shown tostimulate activation of the immune system.In addition to its use in the treatment of acute respiratoryconditions, NAC is used as part of the standard regimen inthemanagementofchronicobstructiverespiratorydisease,[1]

in the management of acetaminophen (paracetamol)poisoning and in other indications;[1] however, adiscussion of these indications is beyond the scope of thismonograph.

Patient presentswith acuterespiratory condition Productive (wet) cough,

catarrh

Influenza

Acute bronchitis

Recommendtreatment withoral NAC(tablets, granulesor ready to-use-syrup)

Adults and children aged> 12 years: 600 mg/day

Children aged < 12 years:300-600 mg/day

NAC

Fig. 1Acute respiratoryconditions for whichpharmacists can adviseusing N-acetylcysteine(NAC).

4

2. Mucociliary System

The mucociliary system has many functions including:[2-4]

• hydrating airways• uptaking and transporting inhaled particles to the

pharynx• biologically purifying against bacterial invasion• maintaining bronchial tone.Mucociliary transport is an important defensemechanism in the human body; it moves airway mucous,together with any trapped substances (e.g. inhaledparticles or endogenous debris), out of the lungs.[5] Whennecessary, cough also helps to remove excessive airwaysecretions. The fluidity of mucous is reduced by theformation of disulfide bridges; this, in turn, impairs theefficiency of mucociliary clearance and increases thedifficulty of expectoration (figure 2).[6,7]

Airways inflammation

Increased mucous production

Formation of disulfidebond and polymerization

Increased mucous viscosity

Difficulty in expectorationCough

Risk of infection

Fig. 2Effect of mucousproduction in acuterespiratory conditions.

In many acute respiratory conditions there is an excessivesecretion of mucous.[7,8] In addition, patients who smokecigarettes have an increase in tissues that secrete mucous,increases in mucous production, and increased mucousviscosity.[7]

Reducing excessive or thick mucous and improvingmucociliary transport is important as mucous retentionmay lead to bacterial colonization, which may result inpneumonia.[5-7] In influenza viral infections, rapidmovement of the mucous is useful in trapping andphysically removing the virus before it can penetrate theblanket of mucous.[9] As involuntary cough affects qualityof sleep, improving mucous clearance will also helpreduce coughing and improve the health-related qualityof life of the patient.


5

3. Inflammatory Process

Many mechanisms are involved in the inflammatoryprocess including mediators, gene expression, oxidativestress and free radicals.[7,10-12] Oxidative stress, animportant part of the inflammatory response to bothenvironmental and internal signals, results from theproduction of oxygen-free radicals and other oxidantagents. Endogenous and exogenous oxidants (anymolecule with an unpaired electron on its outer orbit) arecapable of injuring the lung.[10,13] Free radicals are highlyreactive molecules that can either donate (reduce) orabstract (oxidize) an electron to other nearby molecules.These reactive species also activate transcription factors,leading to the release of proinflammatory cytokines andthus an increase in the inflammatory response.[7,14]

Therefore, it appears that oxidative stress andinflammation are inseparable phenomena (figure 3).Oxidative stress is responsible for alterations in manycomponents of the lungs, including the airway wall,alveolar epithelial cell layer, lung matrix, pulmonarymicrocirculation and transcription factors.[14] Oxidative

Oxidative stressOxygen-free and nitrogen-free

radicals produced

Lipid peroxidation

Modified cellular redox equilibrium

Release of proinflammatory cytokines

Cell membranedamage

Inflammation ofairways and lung

Fig. 3Role of oxidative stressand free radicals inacute inflammation.

stress causes an amplified inflammatory response, lipidperoxidation and cell membrane damage, which resultsin acute inflammation, increased mucous secretion andtissue damage (figure 3). In turn, each of these results inclinical effects, such as difficult expectoration and risk ofinfection, cough, bronchoconstriction, and decline in lungfunction. In addition to initiating inflammation, cell andtissue injury caused by oxidative stress maintainsinflammation.[12]

Antioxidants neutralize free radicals and restore thereductive-oxidative (redox) balance and, therefore,reduce the damage to cells and DNA caused by freeradicals.[10,13]

3.1 Role of Cigarette Smoke and AirPollution

Oxidants are produced by cells in the human body, butcigarette smoke and atmospheric pollution are also asource (figure 4).[7,10,13,15,16] Free radicals and potentcatalyzers of oxidation reactions (e.g. iron and other

Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders

6

transition metals) are present in large amounts incigarette smoke, leading to oxidative stress and airwayinflammation. Smokers have greater levels of somesystemic inflammatory markers than nonsmokers. Air-borne pollutants (e.g. from fossil fuel combustionproducts, diesel exhaust particles and residual oil fly ash)contribute to respiratory illness in urban and industrialareas.[7] Particulate air pollution has proinflammatoryactivities (e.g. release of inflammatory markers and

generation of free radicals) similar to those seen withcigarette smoke. The lung can be protected by:[10,13,16,17]

• reducing the oxidant burden (e.g. limiting exposure tocigarette smoke or air-borne pollutants)

• increasing antioxidant defenses by increasing normalantioxidants (e.g. enzymes [superoxide dismutases,catalase, glutathione peroxidase] and vitamins E and C)or by administering exogenous antioxidants, such asNAC, that have well established antioxidant properties.

Inhaled by individualOxygen- and nitrogen-free

radicals and other highly reactivecompounds

Cigarette smoke

Air-borne pollution(e.g. particulate air pollution,

ozone, heavy metals)

Acute inflammationof airways and lungs

Oxidative stress

Fig. 4Role of cigarette smokeand atmosphericpollution on oxidativestress and inflammationin airways and lung.


7

4. Immunomodulatory System

The pathogenesis of influenza and other viral infectionsand the age-related deterioration of the immuno-modulatory system are related, in part, to:[14,18-23]

• redox imbalance• oxidative stress• increases in inflammatory mediators.The epithelial cell layer of the respiratory tract undergoespathological change during influenza virus infection.[20]

When respiratory cells are infected with pathogenicviruses, oxidant production in respiratory cells increases.At the same time, stores of naturally occurringantioxidants, in particular glutathione, are depleted.Oxidants are involved in the activation of transcriptionfactors for inflammatory protein genes and thedevelopment of pulmonary cell damage.[19-21] Moreover,

oxidative stress alters the local immune response,increasing the risk of infection.[14,21]

Therefore, antioxidants have a role in the treatment ofviral infections: they defend against viral-inducedoxidation by reactive species and also prevent the releaseof inflammatory mediators.[14,19] This improves immunefunction and prevents pulmonary cell damage underconditions of oxidative stress.[19]

A redox imbalance, which leads to oxidative stressresulting in a deterioration of the function of immunecells (e.g. neutrophil and lymphocyte activity) occurswith aging.[22,23] Antioxidant treatment may, therefore,restore the function of some immune systems in olderpatients by directly affecting the immune system orindirectly as a result of its antioxidant properties.


8

5. N-Acetylcysteine

5.1 Historical UseNAC has been used in clinical practice since the 1960s.[1]

A 5% to 10% NAC solution administered by aerosol orinstillation into the bronchopulmonary tree was shown tobe an effective mucolytic in various respiratory diseases.Since the 1970s, pleasant-tasting oral NAC preparationshave been available in many countries of the world. Theoral formulations are effective in treating respiratorydisorders with thick and productive cough, and are wellaccepted by patients.

5.2 Chemical StructureNAC is a precursor of both the naturally occurringsimple amino acid cysteine and reduced glutathione.[24]

Due to the presence of the acetyl substituted aminogroup, NAC is less easily oxidized to inactive cystinethan cysteine.[1] NAC is a thiol (sulfhydryl)-providingcompound; the thiol group ruptures disulfide bridges inmucoproteins and is responsible for its mucolyticactivity (section 6).[1]

5.3 Pharmacokinetic ProfileTables I and II provide a brief summary of thepharmacokinetic properties of orally administeredNAC.[25] The pharmacokinetics of oral NAC appear to bedose proportional, and NAC does not accumulate in theplasma after repeated dosing.[26]

Following oral administration, NAC is quickly andcompletely absorbed from the gastrointestinal tract. Itundergoes rapid, extensive metabolism in the gut walland liver.[27] The active NAC metabolites (cysteine andreduced glutathione), and not NAC itself, are likely to beresponsible for most of the observed pharmacologicaland clinical effects. The plasma concentration of freecysteine increases significantly after administration ofNAC. The elimination half-life of free cysteine in theplasma is ≈0.81 hours. NAC may be present in plasma and tissues as:[27]

• the parent compound or active (cysteine and reducedglutathione) or inactive metabolites

• a releasable fraction bound to proteins by disulfidelinkages

• a fraction incorporated into protein chains.

Table I Summary of the pharmacokinetic properties of oral N-acetylcysteine (NAC)[25]

Parameter Comments

Absorption

Characteristics Rapid and complete

Plasma protein binding Found in body as free NACand reversibly bound to plasma proteins through disulfide links

Bioavailability of free ≈10%NAC after hepatic first passage

Distribution

Primary spread Aqueous environment of the extracellular space

Primary location Liver, kidneys, lungs and bronchial mucous

Metabolism

Initial Rapidly deacetylized in theintestinal wall and through hepatic firstpassage to active L-cysteine

Secondary Metabolized to inactiveforms

Clearance

Renal ≈30%

Primary metabolites Cystine and cysteineexcreted

Table II Summary of the pharmacokinetic properties of N-acetylcysteine (NAC) 30mg/kg[25]

Parameter Free and Free NACbound NAC

Cmax (nmol/mL) 67 9

Time to Cmax (h) 0.75–1

Area under the curve 163 12(nmol/mL × h)

Elimination half-life (h) 1.3 0.46

Cmax = peak plasma concentration


9

6. Mucolytic Activity

NAC has two primary mechanisms of action as amucolytic (figure 5):[24]

• direct mucolytic activity. The thiol groups in NACrupture the disulfide bridges of proteins in the mucous,resulting in smaller units of the protein and, therefore,reduced viscosity and mucous that is easier toexpectorate

• activation of mucociliary clearance. The physiologicaltransport of mucous and, therefore, its removal isimproved by NAC.

The favourable effects of NAC as a mucolytic have beenshown in numerous in vitro and animal-model studiesand studies in patients (table III).[28-40] NAC reduced theviscosity of mucous, improved its transport andincreased sputum volume.NAC also had a beneficial effect on mucous induced bycigarette smoke (table III). It improved mucociliaryaction,[28] decreased the length of time necessary toreverse mucous cell hyperplasia[29] and inhibitedhypersecretion of mucous in the larynx and trachea.[30]

6.1 Clinical TrialsThe efficacy of NAC as a mucolytic in patients withrespiratory conditions, such as chronic obstructivepulmonary disease (COPD) or chronic bronchitis, is wellestablished.[7,24,41] Oral NAC has favorable effects onmucous and cough in patients, including children, withacute or chronic respiratory disorders. The focus of this monograph is the relatively short-term(10–15 days) use of oral NAC in the treatment of acuterespiratory conditions.[42-44] In these trials, the efficacy oftreatment was assessed using the differences betweenbaseline and endpoint values in various clinicalparameters.[42-44] Sputum viscosity, cough severity,difficulty of expectoration and dyspnea were eachscored on a 3- or 4-point scale, where the lowest scoresof 0 or 1 indicate ‘normal‘ function (e.g. absence ofcough) or few symptoms (e.g. very fluid sputum) and 3points indicates highly pathological conditions (e.g.very viscous sputum or intense cough during the day ornight). NAC reduces the viscosity of expectorations, whichreduces the expectoration difficulties and the severity of

Table III Summary of mucolytic effects of N-acetylcysteine in in vitro studies, animal models and studies in patients with excessrespiratory mucous

In vitro

Reduced viscosity of mucous[31-34]

Direct and immediate effect on decreasing theviscoelastic properties of bronchial secretions [35]

Inhibited Na+ absorption across human nasal epithelialcells, which may increase mucous fluidity[36]

Reduced the deleterious effect of cigarette smokeextract on mucociliary action[28]

Animal models

Increased mucous velocity and ciliary beat frequency[37]

Increased the volume of respiratory tract fluid anddecreased viscosity of sputum[38]

Reduced the time required to reverse smoke-inducedmucous cell hyperplasia[29]

Inhibited cigarette smoke-induced hypersecretion ofmucous in larynx and trachea[30]

Studies in patients

More effective than saline in reducing sputum viscosityand consistency and increasing sputum volume inpatients with chronic bronchial disease[2,39]

Improved mucociliary transport in heavy smokers withhypersecretory bronchitis and reduction in mucociliarytransport[40]

productive cough. In the short-term clinical trials, oralNAC 200mg three times daily used alone orconcomitantly with antibiotics (amoxicillin 1.5[42] or 2g/day[43,44]), decreased the consistency of sputum,facilitated its expectoration and reduced cough andthoracic physical symptoms.[42-44]

NAC was more effective than placebo in the largest ofthe short-term trials.[42] In this trial in 215 patients withacute bronchitis, superinfections of chronic bronchitis,or complicated bronchitis in patients with severechronic respiratory insufficiency, patients received NAC200mg three times daily for 10 days. Compared withbaseline, patients receiving NAC showed significantimprovements in all parameters (sputum expectoration,sputum viscosity, cough and peak expiratory flow rate[PEFR]). Moreover, NAC was significantly moreeffective than placebo in decreasing sputum viscosity,


10

Direct mucolytic activityNAC breaks disulfide bonds, rendering the mucousless viscous and easier to expectorate

Activation of mucociliary clearanceNAC improves the physiological transport of mucous, facilitating its removal

Fig. 5Primary mechanisms ofaction of N-acetylcysteine(NAC) as a mucolytic.

0–0.2–0.4–0.6–0.8

–1–1.2–1.4–1.6–1.8

–2

Chan

ge fr

om b

asel

ine (

scor

e)

Sputum viscosity Cough severity

*** ***

1009080706050403020100

Chan

ge fr

om b

asel

ine (

L/m

in)

Peak expiratory flow rate

*

6

4

2

0

–2

–4

–6

–8

–10

Chan

ge fr

om b

asel

ine (

mL/

day)

Sputum volume

**

NAC PlaceboFig. 6Efficacy of oral N-acetylcysteine (NAC)in the treatment ofpatients with acutebronchitis. Mean changesfrom baseline at day 10for various clinicalparameters in patientswith acute bronchitisreceiving oral NAC200mg three times dailyor placebo in a 10-daytrial.[42]

* p < 0.01, ** p ≤ 0.005, *** p ≤ 0.0001 vs placebo.

increasing sputum expectoration, preventing cough andincreasing PEFR (all p < 0.0001). The greatest efficacy was shown in patients with acuteor chronic bronchitis. Figure 6 shows the improvements

from baseline in clinical parameters with NACcompared with placebo in patients with acutebronchitis. The increase in the volume of sputum shownin the group receiving NAC was probably due to the

NAC

NAC


11

NAC Bromhexine Placebo

0

–0.2

–0.4

–0.6

–0.8

–1

–1.2

–1.4

Chan

ge fr

om b

asel

ine (

scor

e)

Sputum viscosity Cough severityDifficulty in

expectoration

******

*

**

***

**400350300250200150100500

Chan

ge fr

om b

asel

ine (

mL)

Forced expiratoryvolume in 1 sec

Forced vitalcapacity

0

–5

–10

–15

–20

–25Chan

ge fr

om b

asel

ine (

mL/

day)

**

*

Sputum volume

*

Fig. 7Efficacy of oral N-acetylcysteine (NAC)in the treatment ofpatients with bronchitis.Mean changes frombaseline at day 10 forvarious clinicalparameters in patientsreceiving oral NAC200mg three times daily,placebo or bromhexine8mg three times daily in a10-day trial.[43]

* p < 0.05, ** p ≤ 0.01, *** p < 0.001 vs baseline.

Table IV Efficacy of oral N-acetylcysteine (NAC) in the treatment of acute respiratory diseases in children in selected clinical trials

Study (no. of children) Acute respiratory condition Treatment regimen Results

Biscatti et al.[47] (50)

Hofman[48] (49)

Nikolic & Korac [45] (20)

Ribeiro et al.[46] (67)

Acute respiratory tractinfections

Asthma, sinobronchial syndromeor severe, purulent bronchitis

Bronchitis (afebrile acuterecurrent bronchitis frequentlyaccompanied by signs ofbronchial allergy; febrilerecurrent or catarrhal bronchitis;or simple catarrhal bronchitis)

Obstructive bronchial diseases(atelectasis, bronchiolopathy,pseudobronchiectasis,bronchiectasis, cystic fibrosis,lung abscess, chronic bronchitis,combined pathology)

Oral NAC 100–300mg/day(according to age) orplacebo for 6 daysAll patients received themost suitable antibacterialagent

Not stated

Oral NAC 100 or 200mgthree times daily (according to age) for 4daysOnly patients with acutefebrile bronchitis receivedantibacterials

NAC 10–50mg/kg/day in 2 or 3 divided doses for 7–110 days (mean 26 days)All patients had previouslyreceived other treatmentswithout success or onlypartial success

Fever, cough, dyspneaand thoracic moist ratesreturned to normal in asignificantly shorter timewith NAC than withplacebo

Subjective improvementin all patientsImproved sinusitis when itwas not chronic andpurulentImproved most cases ofbronchitis

Shortened the durationof catarrhal inflammationof the throat and coughReturned vital capacityand pulmonary air flowvalues to normal inpatients with simple orrecurrent catarrhalbronchitis after 4 days oftreatment

Improvement shown inmost patientsThe majority (>80%) ofpatients had excellent-to-good clinical andradiological results (fig. 8)


12

60

50

40

30

20

10

0

% o

f pat

ient

s

Clinical results Radiological results

Excellent Good Bad

Fig. 8Efficacy of N-acetylcysteine(NAC) in the treatment ofobstructive bronchial diseases inchildren. The proportion ofpatients with clinical orradiological results classified asexcellent, good or bad followingtreatment with NAC 10–50mg/kg/day in 2 or 3 divided dosesfor 7 to 110 days (mean 26days).[46] Patients had previouslyreceived other treatments withoutsuccess or only partial success.

decrease in mucous viscosity, which facilitated drainageof bronchial secretions.NAC is more effective than bromhexine or placebo whenused together with antibacterials, whereas bromhexineand placebo have similar efficacy.[43] In a 10-day trial in 54patients with acute infections complicating COPD oracute respiratory infections, oral NAC 200mg three timesdaily significantly improved most clinical parameters ofmucous, cough and functional parameters from baseline(figure 7). Mean changes from baseline in severalparameters (sputum viscosity, cough, difficulty ofexpectoration and forced expiratory volume in 1 second[FEV1]) were significantly greater with NAC than withplacebo or bromhexine 8mg three times daily (allp < 0.05). In contrast, there were no significant differencesbetween placebo and bromhexine in changes frombaseline for any parameter.[43] Changes in functionalrespiratory parameters are secondary to the clearing ofthe airways; the combination of NAC and an antibacterialcleared the airways better than antibacterials alone orcombined with bromhexine, leading to improvements inFEV1 and forced vital capacity values (figure 7).NAC was also more effective than bromhexine in a 15-day trial in 60 patients with non-infectious chronicbronchitis or acute respiratory infections.[44] NAC reducedsputum thickness, difficulty in raising sputum, cough

and dyspnea to a significantly greater extent thanbromhexine (all p < 0.05). For example, compared withbromhexine, NAC reduced sputum viscosity morerapidly and effectively (p < 0.001). Moreover, NAC wasmore effective than bromhexine in treating patients inboth of the treatment groups (i.e. when NAC was usedconcomitantly with antibacterial treatment in patientswith acute respiratory infections and to an even greaterdegree in those with chronic non-infectious respiratoryconditions).

6.1.1 ChildrenOral NAC was also effective in treating children withacute respiratory conditions in clinical trials (table IV).[45-48]

Although it is difficult to evaluate objective parametersof mucolytic activity in children (e.g. they may not fullycooperate in spirographic testing or mucous collection),objective and/or subjective improvements in a varietyof parameters were shown with treatment with oralNAC in children with a range of diseases of therespiratory system.[45-48] For example, both clinical andradiological results were favourable with oral NAC inchildren with a variety of obstructive respiratorydiseases (figure 8 and table IV).[45-48] Oral NAC is,therefore, a useful option in the treatment of respiratorydiseases in pediatric patients.


13

7. Anti-Inflammatory and Antioxidant Activity

The mechanism of action of NAC as an anti-inflammatoryis complex and involves both antioxidant activity and re-establishment of redox equilibrium (figure 9).[7,14]

Oxidants and free radical attack cause inflammatorydamage (section 3); therefore, agents with antioxidantactivity, such as NAC, will inhibit the inflammatoryprocess. NAC not only acts directly as an antioxidant, butalso has indirect antioxidant properties as it is a precursorto biosynthesis of the antioxidant glutathione (figure10).[7,16] Pulmonary tissues have a variety of bothintracellular and extracellular antioxidant defensesystems in order to counterbalance the production of freeradicals and cope with the normal oxidative burdenwithin the lungs. Antioxidant defense systems includeantioxidant molecules and enzymatic systems, the mostimportant of which is glutathione and its related complexenzymatic systems.[7,12,24] Glutathione directly detoxifiesreactive species by conjugation and/or reduction; theenzyme systems enhance chemical detoxification bycatalyzing conjugation reactions and reductions.[16]

Glutathione has also been implicated in numerouscellular functions.[12,14] Inflammation is mediated byinducible transcription factors that switch on the genesfor inflammatory proteins. Reactive species activate thistranscription, leading to the release of proinflammatorycytokines.[7] Therefore, to neutralize reactive species andprevent activation of transcription of inflammatoryprotein genes, the cellular redox equilibrium betweenreduced glutathione and its oxidized species glutathionedisulfide must be maintained (figure 10).[7,14]

It is essential to maintain adequate intracellular levels ofglutathione to overcome the harmful effects of reactivespecies. Depletion of glutathione is caused by itsantioxidant activity and also by elimination of oxidizedglutathione from the cells. Once oxidized glutathione iseliminated from the cell, it is not available to beregenerated to reduced glutathione via the reductasepathway. The rate-limiting substrate in the synthesis ofglutathione is cysteine.[7,12,24] Cysteine is difficult toadminister as it is poorly absorbed, has low solubility in

Fig. 9Pathway showing themechanism of action of N-acetylcysteine (NAC)as an antioxidant and re-establisher of reductive-oxidative (redox)equilibrium in thepresence of oxidativestress.

NAC

Oxygen- and nitrogen-free radicals produced

Oxidative stress

Increases intracellularand extracellularantioxidant defenses

Prevents lipidperoxidation and cellmembrane damage

Re-establishes cellularredox equilibrium

Controls release ofproinflammatorycytokines

Controls activation oftranscription ofinflammatory genes

Prevents inflammationof airways and lungs


14

Fig. 10Reductive-oxidative(redox) equilibriumbetween reducedglutathione andglutathione disulfide. Inthe presence of oxidativestress, there is a lack ofsufficient reducedglutathione to neutralizethe reactive species and,therefore, redoxequilibrium is notmaintained. N-acetylcysteine (NAC)restores redox equilibriumby increasing levels ofendogenous cysteine,resulting in increasedlevels of glutathione.

water and undergoes rapid hepatic metabolism.[14]

However, additional cysteine may be delivered by theadministration of NAC because it is a precursor tocysteine (figure 10). NAC increases the endogenoussupply of cysteine, either by deacetylation of NAC orthrough reduction by NAC of endogenous cystine intocysteine.[16] Relative to cysteine, NAC is well absorbedintestinally, has good water solubility, is stable tooxidation and is well tolerated. Administration of NAC results in increased levels ofendogenous cysteine that:• stimulate glutathione synthesis when there is an

increased demand• enhance the activity of enzymes dependent on

glutathione• promote antioxidant activity.NAC, therefore, maintains the redox-equilibriumbetween reduced glutathione and oxidized glutathioneand acts directly as an antioxidant, which leads tocomplete airway protection against oxidative stress andinflammation (figure 9). NAC inhibits the activation of some redox-sensitivesignal transduction factors.[14] Therefore, NAC preventsthe release of proinflammatory cytokines (figure 9) and, asa result, would have longer-term effects on the

inflammatory response than agents that inhibit only theinflammation mediators involved in the last steps of theinflammatory process.[7]

The anti-inflammatory and antioxidative actions of NAChave been shown in many in vitro and animal-modelstudies (table V).[49-60]

7.1 Patients with chronic obstructivepulmonary disease

The anti-inflammatory and antioxidative actions of NAChave also been demonstrated in studies in patients withCOPD (table VI).[14,16,49,50,61-68] Markers of oxidative stress andinflammation were reduced in the red blood cells,sputum and blood of these patients.[66-68]

Oral NAC decreased levels of C-reactive protein, which isa marker of inflammation, in patients with acuteexacerbations of COPD.[68] This double-blind 10-daystudy compared the efficacy of two dosage regimens oforal NAC (600 or 1200mg/day) with that of placebo inreducing the levels of C-reactive protein and otherindicators of inflammation in 122 patients with an acuteexacerbation of COPD. Levels of C-reactive protein decreased to a greater extentwith NAC than with placebo at day 5 and day 10 of thetrial (figure 11). The improvement was greater with the

NACN-acetylcysteine

Cysteine

Reduced glutathione

Glutathionereductase

Oxidized glutathione

Reactivespecies

Neutralspecies


15

2.5

2

1.5

1

0.5

0

CRP

(mg/

100m

L)

NAC 600 NAC 1200 Placebo

100

90

80

70

60

50

40

30

20

10

0

Nor

mal

ized

CRP

leve

ls (%

of p

atie

nts)

NAC 600 NAC 1200 Placebo

Baseline Day 5 Day 10

* * *

*†‡

†‡

Fig. 11Effect of oralN-acetylcysteine (NAC) 600 or 1200mg/day on levels of amarker of inflammation(C-reactive protein; CRP).Levels of CRP at baselineand at day 5 and day 10of treatment and theproportion of patients thatachieved normal CRPlevels at day 10 inpatients with an acuteexacerbation of chronicobstructive pulmonarydisease.[68]

* p < 0.001 vs baseline; † p < 0.001 vs placebo; ‡ p = 0.002 vs NAC 600mg/day.


Table V Summary of the protective function of N-acetylcysteine against cigarette smoke or air-borne pollution in in vitro studies, animalmodels and studies in cigarette smokers

In vitro

Protected against oxidant-mediated cytotoxicity induced by cigarette smoke[49]

Decreased toxicity due to tobacco smoke[50]

Improved the survival of cultured human bronchial cells exposed to tobacco smoke condensate[51]

Protected against the loss of pulmonary glutathione and cell toxicity associated with cigarette smoke[51]

Glutathione and cysteine protected macrophage cells from the effects of tobacco smoke[52]

Reduced stimuli-induced superoxide radical generation by human alveolar macrophages from smokers[53]

Animal models

Attenuated secretory cell hyperplasia induced by tobacco smoke[54]

Protected against acetaldehyde lethality; more effective on an equivalent mole basis than L-cysteine or L-ascorbicacid[55]

Protected against chloroacetaldehyde and metabolically formed acrolein[55]

Prevented thickening of the airway wall and improved distribution of ventilation in a model of cigarette smoke-induced alterations to small airways[56]

Prevented lung inflammation after short-term exposure to inhaled concentrated ambient particles[57]

Increased levels of interferon-γ and normalized interferon-γ : interleukin-4 ratios[58]

Studies in healthy smokers

Reduced the levels of some markers of inflammation[59]

Reduced the stimulated production of free oxygen radicals[53]

Exhibited defensive mechanism against aggressive agents[60]

16

NAC

Inhaled by individualOxygen- and nitrogen-free

radicals and other highly reactivecompounds

Mucous productionOxidative stress

Neutralized oxidantsand maintenance ofcellular reductive-

oxidative equilibrium

Decreased mucousviscosity and improvedmucociliary transport

Airways inflammationprevented

Eased expectorationReduction in coughand other symptoms Cigarette smoke

Air-borne pollution(e.g. particulate air pollution,

ozone, heavy metals)

Fig. 12Benefits of N-acetylcysteine (NAC)on countering theairway effects ofcigarette smoke or air-borne pollution.


1200mg/day regimen than with the 600mg/day regimen.The proportion of patients that achieved normal C-reactiveprotein levels was significantly greater with NAC 1200mg/day than with NAC 600mg/day or placebo (figure 11).NAC 1200mg/day also reduced interleukin-8 levels,another marker of inflammation, to a significantly greaterextent than NAC 600mg/day or placebo (both p = 0.01).[68]

Other parameters of disease severity (including thefrequency and severity of severe cough and difficulty inexpectoration) also improved with treatment withNAC.[68] In contrast, the group receiving placebo did notshow significant improvement from baseline in theseparameters.

7.2 Protection from the Effects of CigaretteSmoke or Air-borne Pollution

NAC is useful in respiratory conditions caused byoxidative stress and inflammation in the airways that areinduced by cigarette smoke and air-borne pollution(section 3.1).[7] When excessive amounts of oxidants areinhaled from cigarette smoking or air-borne pollution,the normal oxidant burden in the lungs is increased andoxidative stress may occur, resulting in lung injury.[16]

Inadditionto itsbeneficialeffects as a mucolytic (section 6),NAChasantioxidantproperties and the ability to maintainthe glutathione redox equilibrium (figure 9). Acting as adirect antioxidant and a precursor of glutathione synthesis,NAC has a beneficial effect by increasing the antioxidant

Table VI Summary of antioxidant and anti-inflammatory effectsof N-acetylcysteine in in vitro studies and animal models

In vitro

Supported intracellular glutathione synthesis[16]

Acted as a scavenger of reactive species[16,61]

Decreased oxidant-mediated cytotoxicity[49,50]

Inhibited activation of a mitogen-activated proteinkinases resulting in reduced release of chemokines[62]

Protected cells against death induced by exposure tonoxious stimuli[63]

Protected against programmed cell death (apoptosis)associated with exposure to inadequate amounts oftrophic factors[63]

Altered lung oxidant : antioxidant imbalance[14]

Animal models

Reduced pulmonary response to endotoxin in a modelof adult respiratory disease syndrome[61]

Prevented the release of granulocyte aggregatesfollowing endotoxin-induced lung injury[64]

Improved immune function in a model of prematureageing[65]

Studies in patients with chronic obstructive pulmonarydisease (COPD)

Reduced markers of oxidative stress in red blood cellsin patients[66]

Decreased markers of inflammation in sputum andblood in patients with stable COPD[67]

Decreased levels of activated protein C, a marker ofinflammation, in patients with acute exacerbations ofCOPD[68]

17

status in patients with pulmonary inflammation induced by cigarette smoke or air-borne pollution. Exposure toparticulate matter induces transcription of manyproinflammatory genes;[57] therefore, the activity of NACin maintaining cellular redox equilibrium will also play arole in its protective effects. The various mechanisms ofaction of NAC will result in the inhibition of theinflammatory process induced by cigarette smoke or air-borne pollution and improve the clearance of mucous(figure 12).In in vitro and animal-model studies, the action of NACas an antioxidant offered protection against cigarettesmoke or air-borne pollution (table V). Oral NAC also

had beneficial effects on markers of inflammation inhealthy smokers (table V). In three studies in healthysmokers,[53,59] the effects of treatment with oral NAC200mg three times daily on bronchoalveolar lavage fluidwere assessed. NAC significantly reduced the levels ofsome markers of inflammation[59] and reduced thestimulated production of free oxygen radicals.[53]

Following NAC treatment, there was an increase inlymphocyte concentrations, improvement in thephagocytic activity of alveolar macrophages and anincrease in leukotriene B4 secretion.[60] These activitiesindicated that NAC has important defense mechanismsagainst toxic agents.


18

8. Immunomodulatory Activity

NAC

Viral infections

Oxidative stressRedox imbalance

Increase in inflammatory mediators

Decreased function of immune cells

Increased antioxidantability and restablished

cellular redoxequilibrium

Prevented cellmembrane damage and

controlled release ofproinflammatory

cytokines

Improved defensesagainst infections

Increased function ofimmune cells

Decreased frequencyand severity of

infections

Fig. 13Immunomodulatoryeffects of N-acetylcysteine (NAC).

Table VII Summary of the immunomodulatory activity of N-acetylcysteine in in vitro studies and animal models and studiesin patients

In vitro

Protected lymphocytes from the toxic activity ofreactive oxygen species[21]

Improved immune function of macrophages from micewith endotoxin-induced oxidative stress[69]

Improved immune function of lymphocytes from micewith endotoxin-induced oxidative stress[70]

Animal models

Increased the resistance to influenza virus[9]

Pretreatment reduced the virus-induced activation ofoxidase-sensitive transcription factors[20]

Pretreatment reduced the release of inflammatorycytokines[20]

Reduced the mortality of mice intranasally infectedwith influenza virus[18]

Increased the antiviral activity of ribavirin in asynergistic manner[19]

NAC has shown beneficial effects on the immune systeminmany invitrostudiesandanimalmodels (tableVII),[9,18-21,69,70]

and also in studies in patients. The antioxidant activity ofNAC appears to play a role in its efficacy in improvingimmune function.[19,69] The pathogenesis of influenza andother infections, and age-related decreases in immunefunction involves oxidative stress, redox imbalance andthe production of inflammatory cytokines (section 4). NAC may also have a direct action on immune cells; itimproves the local immune response by protecting thefunction of lymphocytes and macrophages when exposedto reactive oxygen species in vitro.[21,69,70] In addition, it isthe precursor to glutathione, which has been shown toplay a pivotal role in regulating, directly or indirectly,antimicrobial activity in immune cells (particularlymacrophages).[71] In mice models of respiratory influenza,NAC increased the resistance to the virus and reducedinfluenza-associated mortality.[9,18] Beneficial effects onimmune function were also shown in patients at risk ofinfluenza infection (section 8.1) and in postmenopausalwomen (section 8.2). Therefore, NAC can protect againstviral infection by improving the defenses against the

virus and by protecting against the development ofinflammation in the lung (figure 13).


19

60

50

40

30

20

10

0

Influ

enza

-like

episo

des (

% o

f pat

ient

s)

Total treatmentduration

1 month 2 months 3 months

Monthly assessment

4 months 5 months 6 months

NAC Placebo

***

* **

**

Fig. 14Efficacy of oral N-acetylcysteine(NAC) 600mg twice dailycompared with placebo in theattenuation of influenza-likesymptoms. Proportion ofpatients experiencing influenza-like symptoms during the totalduration of ≥ 5 monthstreatment and on a monthlybasis.[71]

* p < 0.05, ** p < 0.01, *** p = 0.0006 vs placebo.

8.1 Clinical Trials8.1.1 Effect on Influenza-like SymptomsNAC reduced both the frequency and severity ofinfluenza-like episodes in a randomized, double-blindtrial (table VIII).[71] Treatment with oral NAC 600mgtwice daily for 6 months attenuated influenza-likesymptomatology relative to placebo in patients withoutchronic respiratory diseases (the majority of the 190evaluable patients were aged ≥ 65 years).[72] The frequencyof influenza-like symptoms was significantly less withNAC than with placebo (figure 14). When assessed on amonthly basis, significant between-group differences in thefrequency of influenza-like episodes were shown duringthe period of greatest seasonal incidence of influenza inEurope (i.e. during the winter months of December toMarch [2–4 months after beginning treatment]).The severity of influenza-like symptoms was also less

with NAC than with placebo.[72] Of the 46 influenza-likeepisodes in the NAC-treatment group, 72% wereclassified as mild, 25% as moderate, and 2% as severe. Incomparison, of the 99 episodes within the placebo group,48%, 47%, and 6% were classified as mild, moderate, orsevere, respectively.The incidence of specific local influenza-like symptoms(coryza/rhinorrhea, sore throat, catarrh and cough) andgeneral influenza-like symptoms (headache, myalgia)was significantly lower with NAC than with placebo(all p < 0.05).[72] This indicates that NAC, in addition to its mucolytic effects, also has antioxidant andimmunomodulatory activity.Relative to placebo, NAC also significantly reduced thelength of time spent in bed due to influenza-likesymptoms.[72] Indeed, 9 of the 10 patients with influenza-like symptoms who were not bedridden were receivingNAC. Conversely, of the 25 patients who werebedridden for ≥ 6 days, only 3 patients were in the NAC-treatment group.The frequency of seroconversion towards influenza viruswas similar in the NAC and placebo-treatment groups(29% vs 24%), indicating that NAC did not preventsubclinical infections. However, significantly fewer NACrecipients developed a symptomatic form of the condition(figure 15). This indicates that NAC had a protective effectwith respect to clinically evident disease. In those patientswho did not undergo seroconversion towards the virus(71% vs 76%), the proportion of patients experiencing aninfluenza-like episode was numerically, but not

Table VIII Summary of the immunomodulatory activity of N-acetylcysteine in patients with nonrespiratory chronicdegenerative diseases[71]

Decreased the severity of influenza-like episodes

Decreased the incidence of specific local and generalinfluenza-like symptoms

Decreased the length of time spent in bed due toinfluenza-like symptoms

Protective effect with respect to clinically evidentdisease

Shift from anergy to normergy in cell-mediatedimmunity


20

60

50

40

30

20

10

0

Nor

mer

gy (%

of p

atie

nts)

NAC Placebo

Baseline 6 months

*†

Fig. 16Effect of oral N-acetylcysteine(NAC) 600mg twice dailycompared with placebo on cell-mediated immunity. Proportionof patients with cell-mediatednormergy at baseline and after 6months of treatment.[71]

* p < 0.001 vs baseline; † p < 0.05 vs placebo.

90

80

70

60

50

40

30

20

10

0

Influ

enza

-like

episo

des (

% o

f pat

ient

s)

Seroconversion No seroconversion

NAC Placebo

*

Fig. 15Efficacy of oral N-acetylcysteine(NAC) 600mg twice dailycompared with placebo inpatients with or withoutseroconversion towardsinfluenza virus. Proportion ofpatients experiencing influenza-like symptoms as related toseroconversion towardsinfluenza virus.[71]

* p < 0.0001 vs placebo.

group, but not in the placebo treatment group (figure 16).The change in the proportion of normergic patients wassignificantly greater with NAC than with placebo(p < 0.05). These changes in cell-mediated immunity confirm theimmunomodulatory properties of NAC. Patients who areelderly and/or have chronic pathological conditions areparticularly vulnerable to viral respiratory diseases, asthere is a general impairment in immune defenses, loss ofantioxidants and reduced function of immunocompetentsystems. Therefore, NAC may be of benefit in boosting theimmune response in elderly and high-risk individualsduring the influenza season.

significantly, lower with NAC than with placebo (figure 15).Following NAC treatment, there was a progressive,significant shift from anergy to normergy in anevaluation of cell-mediated immunity.[72] In general,anergy was defined as a lack of skin reactivity to any ofthe 7 tested antigens; hypoergic as skin reactivity to ≤ 2 ofthe 7 antigens; and normergy as skin reactivity to ≥ 3antigens. As is common in elderly patients, a relativelyhigh proportion of the patients in both of the treatmentgroups were anergic (≈20%) or hypoergic (≈48%) at thebeginning of the trial. Throughout the study, there wassignificant increase from the baseline in the proportion ofpatients who were normergic in the NAC treatment


21

100

90

80

70

60

50

40

30

20

10

0

Chan

ge fr

om b

asel

ine (

%)

Chan

ge fr

om b

asel

ine (

%)

Neutrophilchemotaxis

Lymphocytechemotaxis

Phagocytosis Proliferationresponse to PHA

IL-2production

NKactivity

0

–5

–10

–15

–20

–25

–30

–35

–40

Neutrophiladhesion

Lymphocyteadhesion

TNFproduction

Basal SOlevels

StimulatedSO levels

Combined groups Age 50-60y Age >70yFig. 17Effect of oral N-acetylcysteine (NAC) 600mg/day on markers ofimmune function.Percentage change frombaseline in immune functionvalues in postmenopausalwomen receiving oral NAC600mg/day for 2 months.[72]

Values are shown for thecombined treatment groupsand in groups stratified by age (50-60 years and > 70 years). IL = interleukin; NK = natural killer; PHA = phytohemagglutinin;SO = superoxide; TNF = tumour necrosisfactor-α. All changes frombaseline were significant (p ≤ 0.05).

8.1.2 Effects on Aging-Related Changes in ImmuneFunctionNAC improved age-related deterioration of immunefunction in a study in 36 postmenopausal women (18aged 50–60 years and 18 aged > 70 years).[22,23] The women,who were in overall good health, received oral NAC600mg once daily for 2 months.NAC significantly improved the immune function ofneutrophilsandoflymphocytes(tableIX),[22,23] indicating thatthere was a decrease in the oxidative stress of the cell andrejuvenation of immune function.[22,23] Improvements frombaseline were significant for all values in each of the agegroups and in the combined treatment groups (figure 17).[73]

Immune function of neutrophils and lymphocytes in theolder women was restored to that of younger women.[73]

Improvements from baseline in age-depressed immunefunction in the group aged >70 years were generallygreater than those in the group aged 50–60 years (figure 17).At the beginning of treatment, baseline values for immunefunction parameters had deteriorated in the older age group compared with values in the younger agegroup, being significantly different in the case of

lymphoproliferation in response to PHA and IL-2liberation. The immune function values at the end oftreatment in the older group were either significantlybetter or similar to baseline values in the younger group.This indicates that, in older people, NAC can restore someimmune functions.

Table IX Effects of oral N-acetylcysteine on the immune function ofneutrophils and leukocytes in postmenopausal women.

Effect on neutrophils[22] Effect on lymphocytes[23]

Reduced adhesion Reduced adhesion

Reduced superoxide levels Reduced secretion oftumour necrosis factor-α

Stimulated mobility Stimulated mobilitytowards the infectious towards the infectiouscenter center

Stimulated phagocytosis of Stimulated production ofstrange particles interleukin-2

Stimulated theproliferation response tophytohemagglutinin

Stimulated ‘natural killer’activity


22

9. Tolerability

9.1 General ProfileOral NAC has a general tolerability profile similar to thatof placebo.[41,74] Adverse events occur infrequently, aregenerally mild in severity and resolve without medicalintervention. When they do occur, adverse events includegastrointestinal effects (e.g. pyrosis, nausea, vomiting,and diarrhea), headache, fever, and hypersensitivityreactions (e.g. urticaria).[25]

In a summary of tolerability data from nine randomized,controlled clinical trials of oral NAC 300–600mg/dayadministered for 6 to 180 days in adults or children withrespiratory conditions,[74] there was no difference betweenNAC and placebo in the incidence of adverse events(based on adverse events leading to the withdrawal oftreatment). These events were generally gastrointestinalin nature (gastric pyrosis, nausea, dyspepsia, diarrhea,stypsis, and rarely vomiting). The exceptions togastrointestinal events were urticaria and itching in onepatient receiving NAC and two patients receivingplacebo.Similar results were shown in a meta-analysis of 23randomized, controlled trials of oral mucolytic drugs,primarily NAC, in patients with stable bronchitis orCOPD.[41] The frequency of adverse events was similarbetween mucolytic and placebo recipients. The frequency of adverse events suspected to beassociated with oral NAC have been estimated fromspontaneous or solicited reports from physicians inclinical practice in Europe (table X).[74]

The once-daily effervescent tablet formulation of NAC600mg is at least as effective and well tolerated as NAC200mg three times daily.[75] Higher dosages of NAC thanthose commonly used as mucolytics are also welltolerated.[72] In the study of oral NAC as an influenzaprophylactic, the proportion of patients reportingadverse events was not significantly different betweenNAC 600mg twice daily and placebo (9% vs 5%).[72]

Moreover, there were no significant differences betweentreatment groups for any of the individual adverse events. Oral NAC is also well tolerated in children.[46] In the studyin children with obstructive bronchial diseases,[46] oralNAC was well tolerated by 96% of patients (64 of 67patients reported good acceptance and safety). Only three

Table X Adverse events possibly associated with oral N-acetylcysteine(NAC) based on reports by prescribing physicians in Europe[74]

Rating Adverse event

Occasional (1–10% of Gastric events (pyrosis,patients) nausea), intestinal events

(diarrhea, stypsis) anddyspepsia

Rare (<1% of patients) Urticaria/itching, anorexia,vomiting, abdominaldistension anddizziness/malaise

Once only Asthma worsening,dyspnea and lessening ofphenprocoumon effects

Once only but causal Alopecia and menorrhagiaassociation with NACdeemed unlikely byreporting physicians

Table XI Laboratory indices that were not changed followingtreatment with oral N-acetylcysteine in clinical trials in patientswith respiratory conditions or in healthy volunteers[74]

Parameter Indices

Coagulation Prothrombin, thrombin,Factors VII and X,fibrinogen,platelet aggregation

Hematological Hematocrit, hemoglobin,red blood cells, white bloodcells, platelets, erythrocytesedimentation rate

Hepatic Aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,orthinine carbamyl transferase, bilirubin

Fecal Occult blood

Immunoglobulins Serum IgA, IgG, IgM, sputumIgA

Other blood chemistry Serum protein fractions,cholesterol, glucose

Renal Blood urea nitrogen, serumcreatinine, urinalysis

patients (4%) had minor adverse effects, and all patientsconsidered there were no safety issues.


23

9.2 Gastrointestinal EventsAlthough most adverse events are gastrointestinal in nature,therapeutic doses of oral NAC do not cause a loss of blood inthe gastrointestinal tract.[74] Moreover, oral NAC taken on afull or empty stomach does not adversely affect the stomachor duodenum as assessed by gastroduodenal endoscopy orhistological examination.[76] In a placebo-controlled end-oscopic study of therapeutic dosages of oral NAC (200mgtwo to three times daily for 14 days) in patients withbronchopneumopathies, NAC was not associated with any

gastroduodenal lesions (edema, hyperemia, erosions orulcerations) or pathological changes.[76]

9.3 Laboratory ParametersOral NAC was not associated with changes in values oflaboratory tests in clinical trials in patients withrespiratory conditions (table XI).[74] Oral NAC did notaffect hematological, coagulation, platelet aggregation,hepatic, renal, immunoglobulin, serum protein fractions,cholesterol or glucose values.


24

10. Dosage and Administration

Oral NAC is indicated in acute respiratory conditionsassociated with cough (e.g. productive cough, acutebronchitis and influenza; figure 1).[25] It reduces theviscosity and facilitates expulsion of mucous secretionsand has a protective action on the respiratory system.

NAC is available as an over-the-counter product in theform of granules or effervescent tablets for oral solution,and oral solution.[25]

A summary of product information is presented in table XII.[25]

Table XII Summary of product information for oral N-acetylcysteine (NAC)[25]

Indications for use in respiratoryconditions

Mechanism of action

Usual dosage in acute conditions Children (aged 2–12y)Adults

Adverse effects

ContraindicationsAll formulations

Granules and effervescent tablets

Granules

Ready-to-use syrup

PrecautionsAll formulations

Effervescent tablets

Potential drug interactions

AvailabilityGranules for oral solutionReady-to-use oral solutionEffervescent tablets for oral solution

StorageAll productsReady-to-use-syrup after opening

Respiratory conditions characterized by the formation of dense, difficult-to-expectorate secretions

Mucolytic, antioxidant and anti-inflammatory

300-600mg/day600mg/day divided into one or more administrations (e.g. 200mg three timesdaily or 600mg as a single dose)

Occur rarelyGastrointestinal effects: pyrosis, nausea, vomiting, diarrheaOther: urticaria, headache, fever Predisposed patients: hypersensitivity reactions (e.g. urticaria, bronchospasm) Unpleasant breath odor: probably due to the breaking of mucous disulfidebonds

Hypersensitivity to any of the ingredientsActive gastroduodenal ulcerPhenylketonuria: these formulations contain aspartame (as an excipient),which metabolizes to phenylalanineFructose intolerance: this formulation contains sorbitol (as an excipient),which metabolizes to fructoseConfirmed hypersensitivity to preservative agents E218 or E211: thisformulation contains E218 and E211

Asthma, a past history of bronchospasm or other serious respiratoryinsufficiency, as NAC may increase obstruction of the respiratory tract orinduce bronchospasmRisk of gastrointestinal bleeding (e.g. history of peptic ulceration oresophagus varices), as oral NAC may induce vomitingPregnancy: animal studies did not show any teratogenic effects, but theadministration of NAC during pregnancy must be supervised by a physicianBreast feeding: there is a lack of data on the passage of NAC into breastmilk, however discontinuation of lactation is advised when receiving NACtherapyHypertension or other conditions in which salt use is to be avoided: thisformulation contains 140mg sodium (350mg sodium chloride); therefore, useone of the salt-free formulationsConcomitant treatment with certain antibacterials or metal salts: a 2-hourinterval should separate their administration

100, 200 and 600mg sachets2% (100mg/5mL) 200 and 600mg

Away from light in a dry place at room temperature15 days at room temperature


25

11. Conclusions

The oral formulation of NAC is convenient and easy-to-use, and represents a useful option in the treatment ofpatients with acute respiratory conditions (figure 1). NACsafely and effectively reduces mucous and cough in adultsandchildrenwithacute respiratory disorders. Its mucolyticeffects in breaking disulfide bonds in mucous andenhancing mucociliary transport are useful in respiratoryconditions associated with dense difficult-to-expectorate

mucous. In addition, its antioxidant, anti-inflammatory,and immunomodulatory effects offer protection againstinhaled oxidants, are beneficial in attenuating influenza-like symptoms and rejuvenate immune function ofneutrophils and lymphocytes in older patients. An overall summary of the clinical benefits of the use ofNAC in treating acute respiratory conditions is presentedin table XIII.

Table XIII Summary of the overall clinical benefits of oral N-acetylcysteine (NAC) in the treatment of acute respiratory conditions

• Mucolytic, antioxidant, anti-inflammatory andimmunomodulatory effects

• Mucolytic effect involves decreasing mucous viscosity andimproving mucociliary transport

• Antioxidant effects are both direct and indirect

• Anti-inflammatory effects involve antioxidant properties,re-establishment of the cellular reductive-oxidativeequilibrium and preventing the release of inflammatorycytokines

• Immune effects involve antioxidant protection againstoxidative stress and improving the function of someimmune cells

• Effective in a wide range of acute respiratory disorders inadults and children

• May be used in combination withantibacterials in patients with acuterespiratory infections with mucopurulentsputum

• Confers protection against cigarettesmoking and air-borne pollution

• Decreases the severity and frequency ofinfluenza-like symptoms in high-riskpatients

• Restores age-related deterioration ofimmune function

• Very well tolerated in adults and children

• Tolerability profile similar to that ofplacebo


26

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27

41. Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronicobstructive pulmonary disease: systematic review. BMJ 2001; 322: 1271-4

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