Mucinac book-New Final_6x9.indd - CiplaMed

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Preface

Oxygen is one of the most abundant elements in our world, constituting 21% of the air we breathe. It is essential for the oxidation of organic

compounds, which is the process by which mammalian cells generate energy to sustain life. However, oxygen may also damage the lungs. Increasing evidence shows that oxidants play a major role in the development of pulmonary diseases. However, we must remember that the resulting free radicals because of complex chemical reactions are not “harmful”; it is only the excessive uncontrolled production that is “harmful”.

Additionally, atmospheric pollutants largely arising from the primary or secondary sources of combustion are important agents of lung injury. Among the many causes of chronic respiratory ailments, smoking is the leading cause of chronic respiratory diseases. It is said that with every puff of cigarette smoke, 1017 oxidants/1014 reactive oxygen species enter into our lungs.

This oxidant/antioxidant imbalance leads to oxidative stress — a common cause of lung damage. Studies say that oxidative stress in the lungs contributes to the pathogenesis of several infl ammatory lung diseases.

N-acetylcysteine has been traditionally used in clinical practice since the mid-1950s. N-acetylcysteine has been used for the treatment of obstructive lung diseases, primarily those associated with the hypersecretion of mucus. N-acetylcysteine has also been used since the mid-1970s as the drug of choice in treating paracetamol poisoning.

In more recent times, the drug has enjoyed a renaissance. Studies demonstrate that N-acetylcysteine is an effi cacious and well-tolerated drug in humans. In addition to mucolytic activity, N-acetylcysteine has been shown to be a potent antioxidant and free radical scavenger. N-acetylcysteine, when given orally, has been shown to protect the lungs from the damage of air pollution and cigarette smoking. This booklet gives an overview on the diverse role of N-acetylcysteine.

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What is oxidative stress?

Our body constantly reacts with the oxygen we breathe, which helps the cells to produce energy. As a consequence of this activity, highly reactive molecules, known as free radicals (oxidants), are produced.

Free radicals are chemical species that have the ability to donate or abstract electrons to or from otherwise electronically stable chemical species. Free radicals interact with other molecules within the cells. This can cause oxidative damage to proteins, membranes and genes.

On the other hand, to counteract the harmful eff ects of these oxidants, the body produces an armoury of antioxidants (endogenous scavengers) to defend itself. It is the job of the antioxidants to neutralize or “mop up” free radicals that can harm our cells.

Fig.1: Process through which oxidative stress occurs and damages the biological targets (GSH = glutathione; SOD = superoxide dismutase; ROS = reactive oxygen species; RNS = reactive nitrogen species; O● = oxygen radical)

The body’s ability to produce antioxidants is controlled by our genetic make-up and infl uenced by our exposure to environmental factors such as smoking.

When the balance between the oxidants and the antioxidants shifts in favour of the former, i.e., an excess of oxidants and/or depletion of antioxidants — oxidative stress occurs.

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What are the sources of oxidants in the lungs?

The most important reactive oxygen species (ROS) of physiological importance are the superoxide anion (O2

•), hydroxyl radical (OH·), nitric oxide (NO·) and hydrogen peroxide (H2O2).

The generation of ROS in the lungs is enhanced by cigarette smoking, which is a highly complex mixture of over 4,700 chemical compounds. The smoke comprises of high concentrations of oxidants/free radicals (1017 oxidant molecules/puff and over 1014 reactive oxygen species/puff ).

The main cellular sources of ROS in the lungs include not only neutrophils, eosinophils and alveolar macrophages, but also alveolar epithelial cells, bronchial epithelial cells and endothelial cells.

Infl ammation in chronic obstructive pulmonary disease (COPD), especially in smokers, initiates oxidant stress. Excessive proteolysis in the lungs generates infl ammatory mediators and, hence, there is oxidative stress via infl ammation.

What are the sources of antioxidants in the lungs?

Antioxidants play a crucial role in the defence mechanisms, especially in the adaptive responses of a cell to oxidative stress. Lung cells are protected against the oxidative challenge by well-developed enzymatic and non-enzymatic antioxidants.

Non-enzymatic antioxidants: Vitamins C and E, beta-carotene, uric acid, glutathione (GSH), glucose, bilirubin, taurine, and albumin.

Enzymatic antioxidants: Superoxide dismutase (SODs), catalase (CAT) and glutathione peroxidase (GPx), haem oxygenase-1 (HO-1), thioredoxins, peroxiredoxins and glutaredoxins.

How does oxidative stress occur?

The increased oxidative stress is due to the increased burden of inhaled oxidants and increased ROS generated by infl ammatory, immune and epithelial cells of the airways.

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• GSH, the major thiol antioxidant, is depleted in the lungs of smokers.

• Neutrophils, alveolar macrophages and epithelial cells are activated in response to the aspiration of smoke and other pollutants, and release ROS and inflammatory mediators such as interleukin (IL)-8, tumour necrosis factor-alpha (TNF-alpha) and leukotriene B4; this further attracts infl ammatory cells and generate more ROS and cytokines, propagating the vicious cycle of oxidant stress and infl ammation.

What are the surrogate oxidative biomarkers of lung diseases?

A number of surrogate biomarkers of oxidative stress have been recognized in the lungs of smokers. The levels of biomarkers are found to be higher in smokers. Measurement of surrogate biomarkers have been made in the blood, urine, breath or exhaled breath condensate (EBC), or in induced or spontaneously produced sputum of smokers.

• Exhaled NO has been used as a marker of airway infl ammation and as an alternate to measure oxidative stress. However, the rapid reaction of NO with O2

• - limits the usefulness of this marker.

• The quantity of H2O2 in the EBC is a direct measurement of oxidant burden in the airspaces (Fig. 2)

• Isoprostanes are products of non-enzymatic lipid peroxidation, which are used as markers of oxidative stress (Fig. 3)

Fig. 2: Patients with unstable COPD exhaled more H2O2 than control subjects or stable COPD

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• Non-specifi c lipid peroxidation products such as thiobarbituric acid reactive substances (TBARS) have also been shown to be elevated in the lungs of patients with stable COPD.

What are the consequences of oxidative stress?

• Increased oxidative stress leads to the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kB (NF-kB) signalling pathways, culminating into increased infl ammation in the lungs.

• An important consequence of oxidative stress is airspace epithelial injury that leads to an increase in airspace epithelial permeability.

• In the case of protease/antiprotease imbalance, the function of alpha-antitrypsin (alpha-AT) in the bronchoalveolar lavage (BAL) fluid was decreased by around 40% in smokers.

• Activation of neutrophils also leads to destruction of the alveolar wall.

• Neutrophil releases tissue-degrading enzymes such as elastases, which impair mucociliary clearance and stimulate goblet cell metaplasia and mucin production.

• Increased sputum neutrophilia in smokers with chronic cough and sputum production shows a decrease in the forced expiratory volume (FEV1).

• Oxidative stress has been implicated in the remodelling of the extracellular matrix in lung injury.

Fig. 3: Isoprostane levels in the EBC in smokers with COPD

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• Alveolar epithelial lining cells undergo apoptosis is response to cigarette smoking, with progressive cell loss and the development of emphysema.

Which are the diseases associated with oxidative stress?

The major pulmonary diseases in which oxidants are known to be involvedeither as direct aetiologic factors or as cofactors are as follows:

• Chronic obstructive pulmonary disease (COPD)

• Asthma

• Emphysema

• Cystic fi brosis

• Acute distress respiratory syndrome

• Idiopathic pulmonary fi brosis (IPF)

• Pulmonary reperfusion-induced injury

• Silicosis/Asbestosis

• Fibrosis from xenobiotics (e.g., bleomycin, nitrofurantoin and paraquat)

What are the sources of lung antioxidants to tackle the increased

burden of oxidants?

It is now evident that a variety of oxidants are implicated in the pathogenesis of pulmonary diseases and, therefore, it is likely that by supplementing the

Fig. 4: Consequences of oxidative stress

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antioxidants, it should be possible to limit oxidative damage and reduce disease progression.

Potential therapeutic interventions could include natural antioxidants or synthetic pharmacological agents with antioxidant activity.

• Thiol compounds: N-acetylcysteine (NAC), N-acetyln, erdosteine, etc., are interesting as antioxidant drugs because of their ability to enhance GSH in the epithelial cells.

• Combination of dietary supplementation of vitamin C, vitamin E and beta-carotene.

• SODs and GPx mimetics.

What is NAC?

NAC is an antioxidant that is an acetylated precursor of both the amino acids, L-cysteine and reduced GSH. It is mainly indicated for the purpose of reducing the symptoms, exacerbations and decline in accelerated lung function. NAC is also used as a mucolytic agent in chronic respiratory illness as well as an antidote for hepatotoxicity due to acetaminophen overdose.

Fig. 5: Chemical Structure of glutathione andN-acetylcysteine

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How does NAC (MUCINAC) act against oxidative stress?

NAC exhibits direct and indirect antioxidant properties.

• Cigarette smoke entering directly into the lungs through the trachea causes a dose-dependent reduction in total pulmonary GSH.

• The free thiol (-SH) group in NAC interacts with ROS; this leads to the intermediate formation of NAC thiol, with NAC disulphide as major end product.

• Additionally, NAC exerts an indirect eff ect as a GSH precursor. GSH is a tripeptide made up of glutamic acid, glycine and cysteine. It protects against the internal and external toxic agents. The thiol (-SH) group of cysteine neutralizes these agents. Cellular levels of glutamic acid and glycine are plentiful, but not cysteine. NAC penetrates the cells and is deacetylated to cysteine and used for the synthesis of GSH, thereby maintaining adequate levels in the lungs.

Studies have shown that oral NAC increases the reduced GSH levels and, thus, enhances the antioxidant defence mechanism of the lungs.

A study was conducted on 27 patients, undergoing routine diagnostic bronchoscopy for the investigation of lung tumour, to determine the eff ect of NAC on BAL.

Group 1 received no NAC and underwent BAL; Group 2 and Group 3 received 600 mg NAC for 5 days and underwent BAL, 1–3 hours and 16–20 hours, respectively, after the last dose.

Fig. 6: Cysteine and reduced glutathione concentrations with respect to albumin in the bronchoalveolar lavage fl uid of three groups of patients

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Fig. 6 illustrate that plasma levels of cysteine and GSH were higher in the groups that received NAC.

Salvi and co-workers performed a randomized, double-blind study on 71 male bus drivers (aged 18–60 years) from Pune city, India. Placebo, NAC 600 mg once daily, and NAC 1,200 mg (600 mg twice daily) was administered for 4 weeks, after which there was a follow-up visit. Breath-exhaled carbon monoxide (eCO) levels and lung function parameters were measured.

The graph (Fig. 7) illustrates that NAC reduced lung oxidative stress at both doses. Lung function parameters; i.e., FEV1 and forced vital capacity (FVC) improved by 84 (p = 0.02) and 123 (p = 0.03) ml, respectively.

Fig. 7: Reduction in lung oxidative stress at both doses of NAC (p <0.0001)

How does NAC (MUCINAC) act as a mucolytic agent?

The mucus produced by goblet cells is composed of glycoproteins, sulphomucins and water, and contains many sulphydryl (-SH) groups that are able to bind to each other to form a 3-D mucoid structure. This binding, known as the “disulphide bridge”, is very strong and can be broken down only with reducing substances.

In pathological conditions, more disulphide bridges form, increasing viscosity and bronchial elasticity. The increase in viscosity in turn promotes bronchial mucus secretion, raising the risk of infection in the accumulated secretions. Purulent mucus is then formed.

NAC is a direct mucolytic agent that acts on the formation of mucus by destroying the disulphide bridges and mucoprotein macromolecules present in

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the bronchial secretions. The pharmacological action is due to the presence of a free sulphydryl (-SH) group in the NAC molecule, which gives it its biological activity. The action determines the formation of molecules with a lower molecular weight and makes the mucus more fl uid because it reduces viscosity.

How is NAC (MUCINAC) beneficial as a mucolytic in chronic

bronchitis?

Improvement in clinical symptoms

A clinical trial with 1,392 patients demonstrated the effi cacy of NAC at a dose of 600 mg/day in reducing the viscosity of expectorations, promoting expectoration and reducing the severity of cough. After 2 months of treatment with NAC (Fig. 8), the viscosity of expectorations improved in 80% of cases, the nature of the expectorations improved in 59%, diffi culty in expectorating improved in 74%, and the severity of cough improved in 71%.

Reduction in exacerbations

A systematic review of all the published studies of NAC in chronic bronchitis concludes that with treatment periods of 12–24 weeks, oral NAC reduces the risk of exacerbations (Fig. 9) and improves symptoms in patients with chronic bronchitis compared with placebo, without increasing the risk of adverse eff ects.

Two meta-analyses have been performed on the trials with NAC and both have shown a statistically signifi cant eff ect of NAC in reducing exacerbation rates in patients with chronic bronchitis.

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Fig. 9: NAC reduces the risk of exacerbations

Study Results

GrandjeanClin Ther 2000; 22:209–21

23% reduction in the exacerbations rate with NAC compared with placebo

SteyEur Respir J 2000; 16:253–62

48.5% of patients on NAC free of exacerbations 31.2% patients on placebo free of exacerbations NNT = 5.8

NNT: Number needed to treat, i.e., the number of patients required to be on active treatment in order to avoid an exacerbation

Fig. 8: Improvement in the severity of chronic bronchitis after NAC treatment

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How is NAC (MUCINAC) benefi cial in patients with COPD?

Patients with stable COPD exhale signifi cantly more H2O2, a stable ROS, than healthy controls. The intracellular and extracellular antioxidant defence systems, which protect the lungs against ROS, are not suffi cient in COPD.

Reduction in exacerbations

An open, randomized, controlled study was conducted on 169 patients attending fi ve Italian centres. Patients received standard therapy (beta2-agonists, anticholinergics, theophylline, and inhaled/oral corticosteroids) plus NAC 600 mg once daily or standard therapy alone over a 6-month period.

The results (Fig. 10) show a decrease in the number of exacerbations (by 41%) in the group of patients having moderate to severe COPD who received the antioxidant, NAC plus standard therapy.

Fig. 10: Total number of exacerbations *p <0.05

Slower decline in lung function in patients not receiving inhaled corticosteroids (Bronchitis Randomized on NAC Cost-Utility Study [BRONCUS])

In this study, 523 patients with COPD participated in a double-blind, randomized, placebo-controlled parallel group trial of NAC 600 mg per day in 50 centres.

This study found that the treatment with 600 mg oral NAC did not aff ect the rate of decline in FEV1, yearly exacerbations, or deterioration in health status.

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Fig. 11: Reduction in lung function in the two groups

However, in patients NOT taking inhaled corticosteroids, the NAC eff ect was as follows:

– Produced slower decline in lung function.– Risk of exacerbations was lower (Fig. 12).– NAC greater than 600 mg may produce further improvement in lung

function; a dose of 1,800 mg/day improved lung function in a study of interstitial lung disease (ILD) and was well tolerated.

Fig. 12: Lower number of exacerbations in COPD patients on NAC

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Fig. 13: Lower risk of re-hospitalization in COPD patients on NAC

Lower risk of re-hospitalization

A study was conducted on 1,219 COPD patients hospitalized during the years, 1986 to 1998. It was observed (Fig. 13) that the use of NAC in patients who were ≥55 years of age reduced the risk of re-hospitalization for COPD exacerbations by 30%. Also, the risk of readmission gradually decreased with the increasing average dose of NAC.

High-dose NAC

NAC reduces infl ammation markers like CRP and IL-8, which are known to signifi cantly elevate during exacerbations of COPD. A randomized, double-blind, double-dummy, placebo-controlled trial studied 123 patients who had experienced at least two exacerbations in the previous 2 years, with FEV1 between 40% and 70% predicted after post-bronchodilator, and were reported to be currently experiencing acute exacerbations. NAC 1,200 mg, NAC 600 mg, or placebo was administered daily for 10 days.

Compared to 600 mg, 1,200 mg NAC/day improved biomarkers (CRP and IL-8 levels) in patients with COPD exacerbations.

Reduction in air trapping

A signifi cant cause of breathlessness in COPD is hyperinfl ation of the lungs due to air trapping, which occurs largely as a result of airfl ow limitation.

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A randomized, double-blind, crossover study included 24 patients >40 years of age with a diagnosis of COPD, a FEV1 <70% of predicted, FEV1/FVC ratio <0.70, and a functional residual capacity >120% of predicted normal. Placebo or NAC 600 mg twice daily was administered for 6 weeks followed by a 2-week washout period, and then patients were crossed over to alternate therapy for an additional 6 weeks.

Fig. 14: Mean changes in CRP and IL-8 levels. T0 = screening visit; T5 = intermediate visit after 5 days of treatment; T10 = fi nal visit after 10 days of treatment. * p <0.001 vs T0, § p < 0.002 vs NAC 600 mg.

Fig. 15: Post-exercise measurements of IC and FVC

There was a signifi cant improvement in the inspiratory capacity (IC) and the FVC, especially after exercise post-NAC treatment compared with patients receiving placebo treatment (Fig. 15)

NAC signifi cantly lowered the residual volume/total lung capacity (RV/TLC) after exercise (Fig. 16) and increased exercise time (Fig. 17) with no exacerbations reported compared to placebo.

Thus, this study shows that NAC caused a signifi cant reduction in the air trapping that occurred due to dynamic hyperinfl ation after exercise.

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What is the role of NAC (MUCINAC) in attenuating muscle fatigue?

The production of ROS in skeletal muscle has been linked with muscle fatigue. Strenuous muscle contraction increases ROS production and fatiguing exercise alters biochemical indices of oxidative stress, including GSH status and markers of lipid peroxidation. NAC, given intravenously, has shown to be benefi cial in enhancing the skeletal muscle antioxidant capacity.

Fig. 16: Post-exercise measurements of RV/TLC

Fig. 17: Comparison of endurance time

Fig. 18: Increased muscle total cysteine and reduced cysteine with NAC infu-sion. *Signifi cant time main effect; greater than preinfusion (p <0.05). §Signifi -cant interaction effect; no difference at preinfusion but NAC >Con at 45 min and fatigue (p <0.05).

In a double-blind, randomized, crossover study, 8 healthy males (mean age: 27.1 ± 5.6 yrs; mean body mass: 76.7 ± 10.9 kg) received either NAC or saline (control CON) intravenous infusion at 125 mg/kg-1h-1 for 15 minutes and, then,

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25 mg/kg-1h-1 for 20 minutes prior to and throughout exercise until fatigue set in. NAC markedly increased both the total and reduced cysteine in the muscles compared with pre-infusion levels.

Thus, NAC infusion during prolonged, sub-maximal exercise increased muscle NAC, skeletal muscle cysteine and GSH availability during exercise, and substantially enhanced performance in well-trained individuals.

What is the role of NAC (MUCINAC) in idiopathic pulmonary fi brosis

(IPF)?

IPF is a chronic progressive infl ammatory ILD with an increased oxidant burden and defi ciency of GSH, in the epithelial lung fl uid (ELF).

Studies suggest that oxidative stress plays an important role in the pathogenesis of tissue fi brosis. 8-Isoprostane has been detected in the BAL fl uid of patients with ILDs (Fig. 19). Patients with cryptogenic fi brosing alveolitis (CFA) or IPF showed a 5-fold increase in 8-Isoprostane in the BAL fl uid compared to normal subjects.

Fig. 19: 8-Isoprostane levels in patients with ILDs

NAC, a precursor of the major antioxidant, GSH, given at a daily dose of 1,800 mg, has been shown to repair depleted pulmonary GSH levels and to result in a statistically signifi cant improvement in lung function in patients with fi brosing alveolitis after 12 weeks of treatment.

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A study consisting of 17 non-smoking patients with IPF (mean age: 62 ± 2 years) received 1,800 mg NAC per day (600 mg NAC every 8 hours) for 5 days. The volume of ELF recovered by BAL was determined. Pre-therapy, the total GSH level in ELF in the IPF patients were signifi cantly less than normal (187 ± 36 versus 368 ± 60 μM) (Fig. 20). After therapy with NAC, the total GSH concentration in ELF increased to 319 ± 92 μM, close to normal values (Fig. 21)

Fig. 20: Concentration of total GSH expressed relative to the volume of ELF recovered by BAL (p <0.015)

Fig. 21: Concentration of total GSH in ELF before and after NAC therapy (p >0.2)

Idiopathic Pulmonary Fibrosis International Group Exploring N-acetylcysteine I Annual (IFIGENIA) Study

IFIGENIA is the fi rst large, randomized, placebo-controlled, multicentre study conducted in Europe with a large group of patients (n = 155) with IPF. Patients were randomized to receive either 600 mg eff ervescent tablets of NAC thrice daily or a placebo for 1 year, in addition to standard treatment with corticosteroids and immunosuppressants (prednisone and azathioprine, respectively) as recommended by the American Thoracic Society/European Respiratory Society International Consensus.

The IFIGENIA study demonstrates that NAC (3 x 600 mg/day) substantially reduces the deterioration of lung function, evaluated primarily by measuring the changes in the vital capacity (VC) and the diff usion capacity of the lungs for carbon monoxide (DLCO) over 1 year.

After 1 year of treatment, NAC improved both the VC (p <0.05) and the DLCO (p <0.005) by 9% and 24%, respectively, compared to placebo. It is the fi rst study to show positive results for a pharmacological therapy in IPF patients. These

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Fig. 22: Indicates slower rate of loss of vital capacity and DLco in the group receiving NAC

results are signifi cant since a 10% decrease in the VC or a 15% decrease in the DLCO were found to be predictive of increased mortality risk in epidemiological studies. This trial also confi rms that the NAC antioxidant mechanism of action results in clinically signifi cant benefi ts.

In conclusion, the results of the IFIGENIA study demonstrate that NAC, at a dose of 600 mg three times daily, added to prednisone and azathioprine, in patients with IPF preserves the VC and the DLCO better than standard therapy alone. High-dose NAC in addition to standard therapy is, therefore, a rational treatment option for patients with IPF.

How does NAC (MUCINAC) help in preventing contrast-induced

nephropathy (CIN)?

CIN is defi ned as acute renal failure occurring within 48 hours of exposure to intravascular radiographic contrast material in various diagnostic and interventional procedures (e.g., coronary angiography and angioplasty, CT-scans, cardiac catheterization, etc.) that is not attributable to other causes.

Evidence shows that the ROS have a role in the renal damage caused by contrast agents. NAC, a thiol containing an antioxidant, is thought to act either as a free radical scavenger or a reactive sulphydryl compound that increases the reducing capacity of the cell.

A number of trials have reported a reduction in the incidence of CIN with NAC pre-treatment the day before and on the day of contrast exposure.

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What is the place of NAC (MUCINAC) in therapy?

NAC is an eff ective and well-tolerated drug in the treatment of pulmonary diseases. NAC is administered as a mucolytic drug in patients with hypersecretion and accumulation of mucus. Being a GSH precursor, NAC also has antioxidant properties that protect against lung damage. NAC is indicated in the following:

• Acute and chronic airway diseases like bronchitis

• Oxidative stress in COPD patients

• IPF

• Antidote for paracetamol/acetaminophen poisoning

• Prevention of CIN

What is the recommended dose of NAC (MUCINAC)?

MUCINAC 600 Tablets

Each eff ervescent tablet contains: N-acetylcysteine …… 600 mg

The eff ervescent tablets should be dissolved in a glass of water.

Adults and adolescents (14 years and above)As a mucolytic agentOne 600 mg eff ervescent tablet daily.

As an antioxidantCOPD

One 600 mg tablet daily. However, the BRONCUS study and other recent studies indicate that higher doses (up to 1,200 mg) may be needed.

IPF

In the various studies on IPF, NAC at 1,800 mg daily in three divided doses (3 x 600 mg/day) has been used.

As an antidoteLoading dose is 140 mg/kg orally, followed by 70 mg/kg orally for every 4 hours for 17 additional doses.

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Prevention in CIN600 mg or 1,200 mg to be taken orally the day before and on the day of the procedure.

What is the safety and tolerability profi le of NAC (MUCINAC)?

Generally, NAC is safe and well tolerated even at high doses. However, mild eff ects such as nausea, vomiting and gastrointestinal disturbances may be observed with high oral doses and, therefore, NAC is contraindicated in patients with active peptic ulcers.

What are the possible adverse eff ects of NAC (MUCINAC)?

Mild effects such as nausea and vomiting may be observed. Rarely, hypersensitivity reactions like urticaria may be seen. In addition, as studies in pregnant women are inadequate, NAC administration during pregnancy should be done with caution and only if clearly indicated.

Are there any contraindications to the use of NAC (MUCINAC)?

• At high doses, NAC causes gastrointestinal disturbances and, therefore, oral administration is contraindicated in patients with active peptic ulcers.

• Patients who are hypersensitive to NAC.

• Since the eff ervescent preparation contains aspartame, it is contraindicated in patients suff ering from phenylketonuria.

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Summary

• Oxidative stress has been implicated in the pathogenesis of a variety of pulmonary diseases (COPD, asthma, IPF, lung cancer, chronic bronchitis, cystic fi brosis).

• NAC is a compound with antioxidative properties that reduces oxidative stress in the lung tissue by replenishing GSH levels.

• Studies demonstrate that NAC may alter lung oxidant/antioxidant imbalance and, consequently, reduce the symptoms, exacerbations and decline of lung function in patients with COPD.

• NAC administered orally to patients with IPF increases GSH levels, thereby improving the pulmonary antioxidant capacity and inhibiting fi brosis in IPF.

• Due to its multifaceted properties, NAC has a diverse pharmacological use. Listed below are the clinical indications of NAC along with dosing information:

MucolyticOne 600 mg oral NAC eff ervescent tablet daily is recommended for adults and adolescents above 14 years of age.

Acetaminophen poisoningLoading dose is 140 mg/kg orally, followed by 70 mg/kg orally for every 4 hours for 17 additional doses.

AntioxidantCOPDOne 600 mg oral NAC eff ervescent tablet daily is recommended for adults.

IPFIn the various studies on IPF, NAC at 1,800 mg daily in three divided dose (3 x 600 mg/day) has been used.

• NAC is well tolerated. However, mild eff ects such as nausea and vomiting may be observed.

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Further Reading

1. Stav David and Raz Meir, (2009). Eff ect of N-acetylcysteine on air trapping in COPD. Chest 136:381–386.

2. Dekhuijzen P.N.R., (2004). Antioxidant properties of N-acetylcysteine: Their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J. 23:629–636.

3. Demedts M., Behr J., Bulil R. et al, (2004). IFIGENIA: Eff ects of N-acetylcysteine on primary endpoints, VC and DLCO. Eur Respir J. 24 (suppl 48):6683 (P4078).

4. Gerrits C.M.J.M., Herings R.M.C., Leufkens H.G.M. and Lammers J.W.J., (2003). N-acetylcysteine reduces the risk of re-hospitalization among patients with chronic obstructive pulmonary disease. Eur Respir J. 21:795–798.

5. Grandjean E.M., Berthet P., Ruff mann R. and Leuenberger P., (2000). Effi cacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: A meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther. 22:209–21.

6. H. van der Vaart, Postma D.S., Timens W. and Ten Hacken N.H.T., (2004). Acute eff ects of cigarette smoke on infl ammation and oxidative stress. Thorax. 59:713–721.

7. Kasielski M. and Nowak D., (2001). Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med. 95:448–456.

8. Decramer Marc, Rutten-van Mölken Maureen, Dekhuijzen Richard P. N., et al, (2005). Eff ects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, [BRONCUS]): A randomized, placebo-controlled trial. Lancet. 365:1552–60.

9. Medved I., Brown M.J. et al, (2004). N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. J Appl Physiol. 97:1477–1485.

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10. Melpo Christofidou-Solomidou and Muzykantov Vladimir R., (2006). Antioxidant strategies in respiratory medicine. Treat Respir Med. 5(1):47–78.

11. Meyer A., Buhl R. and Magnussen H., (1994). The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fi brosis. Eur Respir J. 7:431–436.

12. Bridgeman Myrtle M. E., Marsden Mark, MacNee William, Flenley David C., Ryle Andrew P., (1991). Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fl uid after treatment with N-acetylcysteine. Thorax. 46:39–42.

13. Montuschi Paolo, Ciabattoni Giovanni, Paredi Paolo, Pantelidis Panagiotis, Du Bois Roland M., Kharitonov Sergei A. and Barnes Peter J., (1998). 8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases. Am J Respir Crit Care Med. 158:1524–27.

14. Pela R., Calcagni A.M., Subiaco S., Isidori P., Tubaldi A., and Sanguinetti C.M., (1999). N-acetylcysteine reduces the exacerbations rate in patients with moderate to severe COPD. Respiration 66:495–500.

15. Black Peter N., Morgan-Day Althea, McMillan Tracey E., Poole Phillippa J. and Young Robert P., (2004). Randomized, controlled trial of N-acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease. BMC Pulmonary Medicine. 4:13.

16. Pier Carlo Braga, (2006). Oxidative Stress: Respiratory Diseases and Thiol Compounds. Pacini Editore SpA, Pisa, Italy.

17. Rahman I. and Mac Nee W., (2000). Oxidative Stress and regulation of glutathione in lung infl ammation. Eur Respir J. 16:534–554.

18. Rahman I. and Mac Nee W., (1996). Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med. 21:669–681.

19. Salvi S., Singh M., Brashier B., Valsa S., Ghongane B., Deshpande P. and Nandal D., (2007). Bus drivers supplemented with the antioxidant, N-acetylcysteine (NAC) for 4 weeks show reduced lung oxidative stress and improved lung function. Eur Respir J. 30:Suppl. 51, 474s.

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20. Stey C., Steurer J., Bachmann S., Medici T.C. and Tramer M.R., (2000). The eff ect of oral N-acetylcysteine in chronic bronchitis: A quantitative systematic review. Eur Respir J. 16:253–62.

21. Comhair Suzy A. A. and Erzurum Serpil C., (2002). Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol. 283:L246–L255.

22. Tattersall A.B., Bridgman K.M. and Huitson A., (1983). Acetylcysteine (Fabrol) in chronic bronchitis: A study in general practice. J Int Med Res.11:279–284.

23. Zuin R., Palamides A., Negrin R., Catozzo L., Scarda A. and Balbinot M., (2005). High- dose N-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease. Clin Drug Invest. 25(6):401–408.

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Notes

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Notes

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