N-acetylcysteine improves the clinical conditions of mustard gas-exposed patients with normal pulmonary function test

Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology N-Acetylcysteine Improves the Clinical Conditions of Mustard
Gas-Exposed Patients with Normal Pulmonary Function Test
Mostafa Ghanei, Majid Shohrati, Mehrdad Jafari, Soleyman Ghaderi, Farshid Alaeddini and Jafar Aslani
Research Center of Chemical Injuries, Baqiyatallah University of Medical Sciences, Tehran, Iran (Received December 19, 2007; Accepted February 20, 2008) Abstract: Administration of N-acetylcysteine may be effective in diseases caused by oxidative–antioxidative imbalance. Weaimed to determine the effect administration for 4 months of N-acetylcysteine (1200 mg daily) on sulfur mustard-inducedbronchiolitis obliterans in patients with normal pulmonary function test. In a double-blind clinical trial, 144 patients withbronchiolitis obliterans due to sulfur mustard and bronchiolitis obliterans syndrome class 0, randomly entered to group 1(n = 72, N-acetylcysteine) and group 2 (n = 72, placebo). The changes in dyspnoea, wake-up dyspnoea, cough and sputumwere measured after 4 months using a ‘delta value’ (i.e. symptom score after 4 months – symptom score before the trial).
Spirometric findings were measured at the beginning of the trial, 2 months later and 4 months later. Dyspnoea (delta value:–0.78 (0.61), P < 0.001), wake-up dyspnoea (delta value: –0.57 (0.64), P < 0.001), and cough (delta value: –0.86 (0.63),P < 0.001) improved after 4 months of N-acetylcysteine administration compared to the control group. N-acetylcysteinereduced sputum from 76.9% (n = 40) of cases before the trial to 9.6% (n = 5) of cases after the trial. Spirometric componentswere significantly improved in N-acetylcysteine group compared to the placebo group: FEV1 (P < 0.0001), FVC(P = 0.014) and FEV1/FVC (P = 0.003). A 4-month trial with 1200 mg oral N-acetylcysteine per day can be used for treat-ing bronchitis, but is also effective in treating bronchiolitis. It also prevents sulfur mustard-induced oxidative stress, and canbe used in the treatment of sulfur mustard-induced pulmonary disease.
More than 40,000 people suffer from pulmonary diseases adverse effects [1]. In parallel, these patients do not respond due to sulfur mustard [1]. There is no common consensus well to bronchodilators due to the non-obstructive nature of about the pathophysiological basis of chronic pulmonary their disease. Hence, it is reasonable to look for new drugs disease caused by mustard gas [2,3], but bronchiolitis obliterans and protocols in order to substitute the old ones.
has been proposed as the underlying cause [4 –7].
By considering the oxidative–antioxidative imbalance in Some studies have shown that sulfur mustard-induced the pathophysiology of sulfur mustard-induced pulmonary pulmonary disease is a neutrophil and/or lymphocyte dominant lesions, it is useful to consider antioxidant as a treatment disorder (e.g. neutrophil-dominated inflammatory process).
option [7]. N-Acetylcysteine is a mucolytic drug but can Neutrophil dominant disorders, such as chronic obstructive improve clinical conditions in COPD [9–11], fibrosing pulmonary disease (COPD), bronchitis, bronchiectasis and alveolitis [12] and idiopathic pulmonary fibrosis [13] through emphysema, are characterized by increased inflammation and tissue injuries due to neutrophil-secreted enzymes and N-Acetylcysteine can also alter the inflammatory processes, cytokines. Among the theories that have tried to explain these which are the main cause of disease progression in chronic disorders, one formulates that neutrophils and lymphocytes pulmonary diseases. This alteration is evident in changes in secret proteases which themselves produce oxygen species [8].
the amount of some cytokines, different gene expression and These patients suffer from respiratory symptoms although different pattern of receptor activation [14]. It has been a majority of them have normal pulmonary function tests.
shown that N-acetylcysteine reduces the number of neutrophils Patients with sulfur mustard-induced pulmonary disorder in lung injuries in mice exposed to sulfur mustard [15].
often receive bronchodilators, corticosteroids, immuno- We conducted a double-blind, placebo-controlled clinical suppressive agents, antibiotics, mucolytics, long-term oxygen trial to investigate if administration of N-acetylcysteine over therapy and physiotherapy. But these different treatments 4 months would ameliorate the clinical conditions of sulfur are not as effective as predicted and also have known mustard-exposed patients who have normal pulmonaryfunction tests.
Author for correspondence: Mostafa Ghanei, Research Center ofChemical Injuries, Baqiyatallah University of Medical Sciences,Mollasadra Street, P.O. Box 19945-546, Tehran, Iran (fax Materials and Methods
+98 (21) 88040106, e-mail [email protected]; [email protected]).
Conflict of interest statement: The authors had conflict of interest Patients. The study was designed as a parallel group trial of because the drugs (Fluimicil) were provided by Zambon Co. Since 1200 mg daily oral N-acetylcysteine versus placebo. We enrolled all the stages of this study were done in a double blind fashion, the 144 patients in this study who were randomly allocated to the conflict of interest did not affect the results.
placebo or the N-acetylcysteine group with random number table.
Each group consisted of 72 patients. Patients were free to leave the clinical conditions during the course of the trial in placebo and N- study. The trial was approved by the ethical committee of the acetylcysteine groups and the differences between these two groups.
research centre of chemical injuries, and informed consent was High-resolution computed tomography (HRCT) was obtained from the participants before administration of the medications.
The participants were patients suffering from pulmonary disorders Chest HRCT scanning was performed by High Speed Advantage due to previous exposure to a single high dose of sulfur mustard gas Scanner (General Electric Medical System, Milwaukee, WI, USA).
during the Iran–Iraq conflict in 1988. They were all from Sardasht, It consisted of five 1.0-mm collimation images obtained during deep inspiration and full expiration, while the patients were in Inclusion criteria were as follows: documented exposure to sulfur supine position. All chest HRCT scans were reviewed by a radiolo- mustard; documented diagnosis of chronic pulmonary disease due gist familiar with bronchiolitis obliterans cases. The expiratory to mustard gas (histological evidence from previous biopsies) and images were assessed for the presence of air trapping and its lobar no history of tuberculosis or resection of one or more lobes of lung.
distribution, defined as alteration of normal anterior–posterior Exclusion criteria were pneumonia and/or acute bronchitis, smok- lobar attenuation gradients and/or lack of homogenous increase in ing cigarettes or being a substance abuser, any illness in which the pulmonary attenuation, resulting in persistent areas of decreased medications could not be stopped, occurrence of any severe side attenuation. The presence of air trapping was quantified and was effects of N-acetylcysteine (stomatitis, nausea and rhinorrhoea), considered to be an indication of bronchiolitis obliterans only if it use of any kind of antioxidant drugs, and deterioration of clinical exceeded 25% of the cross sectional areas of an affected lung, in at conditions during the course of the study.
All patients received 1200 mg of N-acetylcysteine or placebo All participants underwent spirometry (by a HI-801 Chest M.I.
daily in two divided doses for 4 months. Patients were not allowed Spirometer, Tokyo, Japan) at a screening visit and afterwards at 2 to use any other treatments for at least 1 month before and during the and 4 months. The Spirometer was calibrated using the device course of the trial, but inhalatory salmeterol (50 μg, twice a day) provided by the manufacturer company. To assess the pulmonary and fluticason(250 μg, twice a day) was taken by all the patients.
function, we measured forced expiratory volume in 1 second (FEV1), In this study, we only enrolled participants in class 0 of bronchi- forced vital capacity (FVC) and FEV1/FVC ratio. Firstly, we assessed these variables at the beginning of the trial. Afterwards, to The study was done under double-blind conditions (i.e. neither reveal the effect of N-acetylcysteine, we subtracted FEV1 measured the investigator nor the patient knew to which group they were at the second month from the initial FEV1 (2, 0); subtracted assigned). N-Acetylcysteine tablets and placebo tablets looked spirometry variables measured at the fourth month from the initial identical, and were packaged and labelled, so they could not be ones (4, 0); and subtracted spirometry variables measured at the identified. The steering committee and data management unit were fourth month from the variables measured at the second month (4, masked to the treatment allocations during the study.
2) and compared these variables between the two groups.
The patients were compliant if they took at least 80% of tablets.
Drugs were delivered to them every 14 days, and they were Statistical analysis. In order to find out whether or not N-acetyl- instructed to bring their tablets with them to every visit, so that cysteine was more effective than placebo on cough, dyspnoea and compliance was assessed at every visit by counting the returned wake-up dyspnoea after 4 months, we compared ‘delta value’ (i.e.
boxes. The compliance check did not take place in the presence of symptom score after 4 months – symptom score before the trial) the patient, and the number of returned tablets was recorded in the between the two groups. Negative values indicated improvement in each symptom. For sputum, as mentioned above, negative values All patients were visited by a general practitioner before and indicated improvement, positive values indicated worsening and after the trial in order to assess the clinical condition of each zero indicated no change in the condition. All analyses were done patient and presence and severity of dyspnoea, wake-up dyspnoea, with SPSS for windows version 13.0 (SPSS Inc., Chicago, IL, USA).
cough and sputum. These symptoms (except for sputum) were Clinical data and delta values were analysed by applying t-test and quantified by a scale of 1–5 in which 1 denoted ‘no problem’ and Mann–Whitney U-test. Sputum was analysed by applying chi-square 4 or 5 denoted ‘the worst condition’. The questionnaire is depicted test. The changes of Spirometry parameters in both groups were in detail in table 1. Sputum was reported as 0 for absence and 1 for compared applying repeated measure anova (General Linear presence. By this method, we were able to analyse the changes in Model). Alpha less than 0.05 was considered statistically significant.
Definition of scales which were used to quantify cough, dyspnoea After 4 months of treatment, 14 patients in the placebo group and wake-up dyspnoea in the patients.
and 20 in the N-acetylcysteine group refused to continue the Cough1 I did not have cough2 I have cough, but it is not a serious problem 3 I have cough, sometimes disturbs my work Clinical characteristics of both N-acetylcysteine (NAC) and 4 I have disturbing cough, usually disturbs my work placebo groups at the beginning of the trial before drug 5 I have disturbing cough, always disturbs my work 2 Dyspnoea only in extraordinary exercises The difference between the two groups for each clinical condition was analysed separately. The test applied and the significance level are depicted in the rightmost column.
2Data are depicted as percent (number) of patients with sputum.
Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology N-ACETYLCYSTEINE IN BRONCHIOLITIS OBLITERANS The effect of N-acetylcysteine (NAC) and placebo on clinical symptoms.
follow-up. None of these patients met our exclusion criteria.
revealed this symptom (chi-square test, P = 0.01). After 4 Patients who left the study were excluded from all analysis.
months, N-acetylcysteine reduced sputum production from Age did not differ significantly between the two groups 76.9% (n = 40) of cases before the trial to 9.6% (n = 5) of (mean ± S.D. = 44.94 ± 11.39 years in N-acetylcysteine, 46.68 ± cases after the trial (McNemar’s test, P < 0.001). Placebo 11.29 years in placebo, P = 0.422). The height and weight of also reduced sputum production after the trial [94.8% these two groups did not differ significantly (P = 0.69 and (n = 55) before the trial, 63.7% (n = 37) after the trial, 0.20, respectively). The number of men and women in both groups did not differ either [37 (71.1%) men in the placebogroup; 32 (61.5%) men in the N-acetylcysteine group, FEV1. Although FEV1 increased significantly over time inthe N-acetylcysteine group (P < 0.0001), and decreased in the placebo group (P = 0.007), there was no significant Clinical characteristics of both the N-acetylcysteine and the difference between these changes during the trial placebo groups at the beginning of the trial are shown in (P = 0.728). Considering the differences of FEV1 in both table 2. The effects of N-acetylcysteine and placebo on the groups at the beginning of the trial in the regression model, cough, dyspnoea and wake-up dyspnoea is shown in table 3.
N-acetylcysteine significantly improved FEV1 compared to Sputum production was slightly higher in the placebo group placebo after 4 months (P < 0.0001; fig. 1).
at the beginning of the trial, as 76.9% (n = 40) in the N-acetylcysteine group and 94.8% (n = 55) in the placebo group FVC. There were not any significant differences betweenthe changes in both groups over the course of trial(P = 0.664). But FVC changed significantly with time in theN-acetylcysteine group (P = 0.010), but not in the placebogroup (P = 0.283). Considering the differences of FVC inboth groups at the beginning of the trial in the regressionmodel, N-acetylcysteine significantly improved FVC overplacebo after 4 months (P = 0.014; fig. 2).
Fig. 1. The upper part represents the mean of FEV1 in the N-acetylcysteine (NAC) group (grey, continuous line) and the placebogroup (black, continuous line) at the beginning (month 0), after 2 Fig. 2. The upper part represents the mean of FVC in the N- months of the beginning of the trial (month 2) and after 4 months acetylcysteine (NAC) group (grey, continuous line) and the placebo of the beginning of the trial (month 4). The table in the lower part group (black, continuous line) at the beginning (month 0), after 2 reports the mean (S.D.) of FEV1 in both groups over time.
months of the beginning of the trial (month 2) and after 4 monthsof the beginning of the trial (month 4).
Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology N-Acetylcysteine is a potent antioxidant agent that acts as a pro-drug for cysteine and glutathione. This mechanism ofaction has been proposed as a possible basis for its use inbronchopulmonary disease [25]. N-Acetylcysteine may pro-duce effects by preventing the release of many inflammatorymediators in different pathological conditions [9,10]. Severalstudies have shown that it can prevent bronchiolitis in miceexposed to cigarette smoke [26], reduce the level of tumournecrosis factor-α in lung-transplanted persons [27], protectbronchial epithelial cells against sulfur mustard in vitro[28,29], and also treat acute lung injuries induced by mustardgas in a rat model [30]. This is in line with the evidence thatshows the effectiveness of antioxidants in preventing sulfurmustard-induced oxidative stress [31,32].
We enrolled patients in class 0 of bronchiolitis obliterans syndrome grade 0 in which FEV1 is equal to or more than FEV1/FVC (0)
FEV1/FVC (2)
FEV1/FVC (4)
80% of baseline. Although their FEV1 is in the normal range, we also found that N-acetylcysteine could improve their FEV1. The current data cannot be used to makeconclusions about the mechanism of a potential increase in Fig. 3. The upper part represents the mean of FEV1/FVC in the N- FEV1, although its effect on reducing the secretion of many acetylcysteine (NAC) group (grey, continuous line) and the placebo inflammatory modulators [33] and on prevention of respira- group (black, continuous line) at the beginning (month 0), after 2 tory airways thickening and bronchial smooth muscle months of the beginning of the trial (month 2) and after 4 monthsof the beginning of the trial (month 4). The table in the lower part hypertrophy [34] might be implicated.
reports the mean (S.D.) of FEV1/FVC in both groups over time.
We noticed a decrease in FEV1/FVC in the placebo group of this study. It might be due to the cassation of taking self-prescribed medications, which is commonly practiced amongthe patients to relieve the symptoms of their chronic disease.
Long-term studies on pulmonary function deterioration FEV1/FVC. There were not any significant differences always have several drawbacks, which might hinder data between these changes during the trial (P = 0.962). FEV1/ interpretation. The main difficulty was drop-out with an FVC did not change significantly over time in the N- overall of 21% in our study. All our drop-outs were due to acetylcysteine group (P = 0.126), but decreased significantly the patients’ refusal of follow-up. As none of the patients in the placebo group (P = 0.006). Considering the differ- who left the study met our exclusion criteria, we assume that ences of FEV1/FVC in both groups at the beginning of the their fear for worsening their symptoms due to the stoppage trial in the regression model, N-acetylcysteine significantly of the routine medications altogether with increased anxiety improved FEV1/FVC over placebo after 4 months and depression after exposure to both high-intensity warfare and chemical weapons might be the reason [35].
We administered N-acetylcysteine or placebo in combination with fluticasone and salmeterol. Because both groups received Discussion
fluticasone and salmeterol, we cannot rule out the possibility In this study, we found that N-acetylcysteine improved not of synergistic effects of N-acetylcysteine and these medica- only the clinical symptoms of the patients with sulfur mustard- tions. We suggest that this possibility is not important as induced bronchiolitis obliterans, but also the parameters of previous results in our clinic have shown that fluticasone pulmonary function test. These findings are more interesting and salmeterol had improving effects on only 27% of the when we consider the time of the exposure to sulfur mustard studied patients with the same conditions as this study [36].
and the time of the administration of N-acetylcysteine, that Hence, planning a clinical trial with N-acetylcysteine is, a gap of 18 years and treatment for only 4 months.
administration without any other types of medications Previous studies have shown that N-acetylcysteine could be effective in the treatment of and control of clinical In conclusion, we noted that not only 1200 mg oral N- conditions in COPD patients by its antioxidative properties acetylcysteine per day can be used in treating bronchitis, but [17–19], and could also reduce bronchial infections [20] also in treating bronchiolitis. It also prevents sulfur mustard- and exacerbations [21] in these patients. It seems that N- induced oxidative stress besides treating sulfur mustard- acetylcysteine interacts with inflammatory processes induced pulmonary disease. Although N-acetylcysteine underlying the pathophysiology of COPD [22–24]. Because improved lung function in non-smoking bronchiolitis N-acetylcysteine resulted in a decrease in sputum production obliterans patients in our study, the effect of this drug on non- and dyspnoea in this study, we assume that its effect is inclusive.
smoking COPD patients should be assessed in future trials.
Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology N-ACETYLCYSTEINE IN BRONCHIOLITIS OBLITERANS comparing the effects of inhaled corticosteroids and N- This work was supported and supervised by Janbazan acetylcysteine. J Physiol Pharmacol 2005;56 (Suppl 4):135– 42.
Medical and Engineering Research Center and Zambon Co.
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by Zambon Co. Because all the stages of this study were done 20 Riise GC, Larsson S, Larsson P, Jeansson S, Andersson BA.
double blind, the conflict of interest did not affect the results.
The intrabronchial microbial flora in chronic bronchitis patients: a
target for N-Acetylcysteine therapy? Eur Respir J 1994;7:94 –
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Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology

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