The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review.

CONTEXT: Sulfur mustard exposure, as the most widely used chemical weapon, can lead to acute and long-term pulmonary complications via various pathways, such as triggering an imbalance between the oxidant and antioxidant system. Currently, there is no validated antidote, chemoprophylaxis and curative modality for pulmonary toxicities secondary to sulfur mustard exposure. OBJECTIVE: The aim of this literature review is to collect available experimental and clinical data on the efficacy of N-acetylcysteine (NAC), as a prominent antioxidant agent, in the prevention and/or treatment of sulfur mustard-induced acute and chronic pulmonary toxicities. METHODS: A literature search was performed by the relevant keywords like "N-acetyl cysteine", "Sulfur mustard" and "Lung injury" in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. No time limitation was considered. Nineteen articles were selected for review. RESULTS: A number of in vitro and experimental studies concluded that oral, intravenous, intraperitoneal and intra-tracheal administration of NAC is effective in the management of sulfur mustard-induced acute lung injury, in a time-dependent manner, via direct scavenging, inhibition of oxidative stress, inflammatory responses and apoptosis. In addition, oral NAC alone (1200 or 1800 mg/day for 4 months) or at a dose 600 mg/day for 6 months in combination with clarithromycin (500 mg/day) have led to improvements of clinical and paraclinical pulmonary parameters of patients with bronchiolitis obliterans due to sulfur mustard, through undetermined mechanisms. CONCLUSION: Despite limitations of relevant experimental and clinical studies, NAC can be considered as a candidate agent for prevention and/or treatment of sulfur mustard-induced acute lung injuries, as well as its long-term pulmonary toxicities, especially bronchiolitis obliterans.

Evaluation of Aggregometery Parameters and Efficacy of Plavix versus Clopidex in Patients Suffering from Ischemic Heart Disease: A Randomized Double Blind Clinical Trial.

BACKGROUND: Ischemic heart disease is the leading cause of death in most societies. In a pathophysiologic point of view, it chiefly results from the formation of thrombus in coronary arteries which could not be only prevented by aspirin. Many of clinical trials have shown the long-term benefits of antiplatelet drugs in reducing the risk of thrombotic accidents. OBJECTIVES: Clopidogrel is a thienopyridine derivative used to prevent platelets from adhering together by direct inhibition of Adenosine diphosphate (ADP), the major factor behind platelets aggregation. Sanofi-Aventis and Bristol-Myers are companies that produce Clopidogrel by the name of Clopidogrel bisulfate. Its trade name is Plavix, nonetheless in Iran it is distributed under the name of Clopidex by Exir Company. In this study we are to compare Plavix and Clopidex in terms of efficacy as well as aggregometry parameters like ADP and PRP (Platelet Rich Plasma). PATIENTS AND METHODS: This is a double blind clinical trial in which we had two groups of patients suffering from Ischemic heart disease who were selected by inclusion criteria. Group A (36 patients) took Plavix (75 mg/d) and group B (36 patients) used clopidex (75 mg/d) both for 30 days. The aggregometry parameters also consisted of PRP and ADP that were run on the patients before and after the study. Finally, a comparison of aforementioned tests, quality of life, lab parameters and compliance in both groups was provided. RESULTS: In groups A and B, the mean levels of PRP before the study were 348000 and 340000/µL respectively. The ADPs were also 73/76 and 68/07 µM that showed no significant difference (P > 0.05).The Means of ADP5 in group A before and after the study were 66.40 and 43.84 µM respectively that there was significant difference (P = 0.001). The Means of ADP5 in group B before and after the study were 58.04 and 40.16 µM respectively that there was significant difference (P < 0.001).The Means of ADP20 in group A before and after the study were 73.76 and 54.97 µM respectively which showed significant difference (P < 0.001). The Means of ADP20 in group B before and after the study were 68.07 and 52.49 µM respectively which showed significant difference (P = 0.001). Difference of ADP5 between group A and B was not significant (P = 0.495). Difference of ADP20 between group A and B was not significant (P = 0.721). The Means of PRP in group A before and after the study were 348000 and 335000/ µL respectively that there was no significant difference (P = 0.66). The Means of PRP in group B before and after the study were 340000 and 336000/ µL respectively that indicated no significant difference (P = 0.81). Difference of PRP between group A and B was not significant (P = 0.563). CONCLUSIONS: Our findings suggested that both drugs significantly lessen the ADP level; even so there was no significant difference between two groups in PRP and ADP factors.

Combination therapy for airflow limitation in COPD.

UNLABELLED: Background and the purpose of the study Existing evidence confirms that no pharmacologic agent ameliorates the decline in the lung function or changes the prognosis of chronic obstructive pulmonary disease (COPD). We tried a critical combination therapy for management of COPD. METHODS: Current or past smoker (passive or active) COPD patients with moderate to severe COPD who did not respond to primitive therapy (i.e., oral prednisolone (50 mg in the morning) for 5 days; with Beclomethasone Fort (3 puff q12h, totally 1500 micrograms/day), Salmeterol (2 puffs q12h, 50 micrograms/puff) and ipratropium bromide (4 puffs q8h) for two months, enrolled to study. Furthermore they were received N-Acetylcysteine (1200 mg/daily), Azithromycin (tablet 250 mg/every other day) and Theophylline (100 mg BD). RESULTS: The study group consisted of 44 men and 4 women, with a mean age and standard deviation of 63.6 ± 12.7 years (range 22-86 years). Thirteen of 48 patients (27.0%) was responder based on 15% increasing in FEV 1 (27.7 ± 7.9) after 6.7 ± 6.1 months (57.9 ± 12.9 year old). There were statistically significant differences in age and smoking between responders and non-responders (P value was 0.05 and 0.04 respectively). There was no difference in emphysema and air trapping between two groups (p = 0.13). CONCLUSION: Interestingly considerable proportion of patients with COPD can be reversible using combination drug therapy and patients will greatly benefit from different and synergic action of the drugs. The treatment was more effective in younger patients who smoke less.

Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: a double-blind randomized clinical trial study.

Background. Dyspnea is one of the main complaints in a group of COPD patients due to exposure to sulfur mustard (SM) and is refractory to conventional therapies. We designed this study to evaluate effectiveness of nebulized morphine in such patients. Materials and Methods. In a double-blind clinical trial study, 40 patients with documented history of exposure to SM were allocated to two groups: group 1 who received 1 mg morphine sulfate diluted by 4 cc normal saline 0.5% using nebulizer once daily for 5 days and group 2 serving as control who received normal saline as placebo. They were visited by pulmonologist 7 times per day to check symptoms and signs and adverse events. Different parameters including patient-scored peak expiratory flow using pick flow meter, visual analogue scale (VAS) for dyspnea, global quality of life and cough, and number of respiratory rate, night time awaking for dyspnea and cough have been assessed. Results. The scores of VAS for dyspnea, cough and quality of life and also respiratory rate, heart rate, and night time awaking due to dyspnea and night time awaking due to cough improved significantly after morphine nebulization without any major adverse events. Also pick expiratory flow has been improved significantly after nebulization in each day. Conclusion. Our results showed the clinical benefit of nebulized morphine on respiratory complaints of patients due to exposure to SM without significant side effects.

Loss of expression of TGF-ßs and their receptors in chronic skin lesions induced by sulfur mustard as compared with chronic contact dermatitis patients.

BACKGROUND: Sulfur mustard (SM) is a blister-forming agent that has been used as a chemical weapon. Sulfur mustard can cause damage in various organs, especially the skin, respiratory system, and eyes. Generally, the multiple complications of mustard gas result from its alkalizing potency; it reacts with cellular components like DNA, RNA, proteins, and lipid membranes.TGF-ß is a multi-functional cytokine with multiple biological effects ranging from cell differentiation and growth inhibition to extracellular matrix stimulation, immunosuppression, and immunomodulation. TGF-ß has 3 isoforms (TGF-ß 1, 2, 3) and its signaling is mediated by its receptors: R1, R2 and intracellular Smads molecules.TGF-ß has been shown to have anti-inflammatory effects. TGF-ßs and their receptors also have an important role in modulation of skin inflammation, proliferation of epidermal cells, and wound healing, and they have been implicated in different types of skin inflammatory disorders. METHODS: Seventeen exposed SM individuals (48.47 ± 9.3 years), 17 chronic dermatitis patients (46.52 ± 14.6 years), and 5 normal controls (44.00 ± 14.6 years) were enrolled in this study.Evaluation of TGF-ßs and their receptors expressions was performed by semiquantitative RT-PCR. Only TGF1 was analyzed immunohistochemically. RESULTS: Our results showed significant decreases in the expression percentages of TGF-ß 1, 2 and R1, R2 in chemical victims in comparison with chronic dermatitis and normal subjects and significant decreases in the intensity of R1 and R2 expressions in chemical victims in comparison with chronic dermatitis and normal controls. (P value < 0.05) CONCLUSIONS: TGF-ßs and their receptors appear to have a noticeable role in chronic inflammatory skin lesions caused by sulfur mustard.

Overexpression of transforming growth factor (TGF)-beta1 and TGF-beta3 genes in lung of toxic-inhaled patients.

Iraq frequently used toxic inhalants during the war with Iran, exposing over 100,000 people to chemical reagents. Bronchiolitis obliterans (BO) is a major pulmonary disease caused by exposure to harmful gases. Recently defect in clearance of apoptotic cells (efferocytosis) has been suggested as a mechanism that leads to several lung diseases. Transforming growth factor (TGF)-beta, a cytokine produced by efferocytotic macrophages, suppresses the inflammation and enhances the regeneration of tissue. In this study, the authors compared the expression of these 3 isoforms of TGF-beta at mRNA level in lung biopsies of Iranian victims of chemical gases with lung biopsies of control healthy volunteers. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique was used to examine the expression level of TGF-beta isoforms using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene as an internal control. The results indicated that that levels of TGF-beta1 and TGF-beta3 mRNAs were significantly higher in chemical gas-injured patients than noninjured group (P < .05). Therefore, the authors speculate that TGF-beta1 and TGFbeta3, but not TGF-beta2, secretion is a result of efficient efferocytosis in chemically injured patients, playing a protective role by improving airway remodeling and lung homeostasis in this group. These properties of TGF-beta are consistent with long-time survival of chemical-injured people suffering from BO.

Evaluation of the effects of oral N-acetylcysteine and a placebo in paraclinical and oxidative stress parameters of patients with chronic hepatitis B.

BACKGROUND AND AIMS: The treatment of chronic hepatitis B (CHB) is a challenging problem today, and previous study has shown that oxidative stress causes the collective pathophysiological conditions of many hepatopathies, so other new therapeutic approaches are needed. Hence, in this study the paraclinical and oxidative stress parameters of the efficacy of N-acetyl cysteine (NAC) as an antioxidant in the treatment of CHB have been evaluated. METHODS: In this double-blind placebo-controlled clinical trial study, 43 patients with CHB were enrolled in 2008 in Tehran, Iran. The patients were randomly assigned to receive either 1200 mg/day NAC or a placebo for 45 days. Paraclinical tests and oxidative stress parameters were measured on experimental day 0 and on day 45. RESULTS: Liver function tests, i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels were not significantly different in the NAC group and in the placebo group. A reduction in catalase (CAT) activity and an increase in glutathione concentration were statistically significant in the NAC group (P < 0.05). CONCLUSIONS: According to our results, oral NAC is not an effective adjuvant treatment for patients with CHB, but further research with a larger population is needed for the evaluation of the effectiveness of NAC in these patients.

Glutathione and malondialdehyde levels in late pulmonary complications of sulfur mustard intoxication.

It has been hypothesized that antioxidant and oxidant capacities may be related to the severity of obstructive lung impairment in patients with sulfur mustard (SM)-induced lung injuries. Our study was designed to measure the level of glutathione (GSH) and malondialdehyde (MDA) activities in patients intoxicated with SM and to evaluate the relationship between their activity and the severity of pulmonary dysfunction. A total of 250 patients with a history of exposure to a single high dose of SM gas and also 60 healthy nonsmoking individuals with no history of exposure to SM were selected. All patients underwent spirometry; based on its indices they were divided into two groups: mild (n = 140) and moderate-to-severe (n = 110) pulmonary dysfunction. Also, serum GSH and MDA concentration measurements were performed for all patients and controls. The mean GSH level in controls was 29.85 +/- 3.26 micromol/ml, which was significantly higher than in patients with mild and moderate-to-severe pulmonary dysfunction (19.02 +/- 2.36 and 17.89 +/- 2.16 micromol/ml, respectively). Also, the mean MDA level in controls was 0.69 +/- 0.09 micromol/ml, which was significantly lower than in patients with mild and moderate-to-severe pulmonary dysfunction (0.74 +/- 0.05 and 0.75 +/- 0.05 micromol/ml, respectively). There was a weak linear correlation between GSH level and some of the pulmonary function indices. On the other hand, there was no significant relationship between the MDA level and pulmonary indices. Our study confirmed important alterations in the oxidative-antioxidative system in patients suffering from SM-induced lung injuries, as shown by a decreased serum level of GSH and an increased level of MDA. Individuals with moderate-to-severe SM-induced lung injuries show a greater tendency for a decreased level of GSH and an increased level of MDA than those with mild injuries; however, there is only minimal association between pulmonary function parameters and the serum level of MDA and GSH. These findings encourage us to examine therapeutic measures to correct such imbalances in future studies.

Skin hydration and transepidermal water loss in patients with a history of sulfur mustard contact: a case-control study.

BACKGROUND: Skin lesions are among the most common complications of contact with sulfur mustard. OBJECTIVE: This study was aimed to measure skin water content and transepidermal water loss (TEWL) in patients with a history of sulfur mustard contact. METHODS: Three hundred ten male participants were included in this study: 87 (28.1%) sulfur mustard-exposed patients with current skin lesions (group 1), 71 (22.9%) sulfur mustard-exposed patients without skin lesions (group 2), 78 (25.2%) patients with dermatitis (group 3) and 74 (23.8%) normal controls (group 4) The water content and TEWL of skin was measured at four different locations of the body: forehead, suprasternal, palm and dorsum of hand. Nonparametric statistical tests (Kruskal-Wallis) were used to compare the four groups, and P < 0.05 was considered statistically significant. RESULTS: The mean age of participants were 44.0 +/- 6.7, 41.9 +/- 5.9, 43.8 +/- 9.3 and 44.8 +/- 8.9 years in groups 1 to 4, respectively (P = 0.146). Xerosis, post-lesional hyperpigmentation and lichenification were significantly more common in either sulfur mustard-exposed participants or non-exposed participants with dermatitis (P < 0.05). Skin hydration was higher in subjects with sulfur mustard contact than in non-injured participants (P < 0.05) in the dorsum and palm of hands and forehead. TEWL was significantly higher in participants only in suprasternal area and dorsum of hand. CONCLUSION: Contact with sulfur mustard agent can alter biophysical properties of the skin--especially the function of stratum corneum as a barrier to water loss-several years after exposure.

Activity and function in lung injuries due to sulphur mustard.

AIM: Pulmonary complications are known to occur in over half the patients exposed to sulphur mustard. Many studies have focused on the clinical complications, often ignoring the pathogenesis of sulphur mustard. Also, the reasons for the variable severity of lung injuries caused by sulphur mustard are unclear. Hence, the current study was performed to evaluate the correlation between superoxide dismutase (SOD) and catalase (CAT) activity and pulmonary function in patients exposed to sulphur mustard. METHODS: Our study was a comparative cross-sectional survey. Two hundred and fifty incident survivors were selected from the Sardasht population who were exposed to sulphur mustard in 1987. A control group from non-exposed civilians was also selected. We used a pulmonary function test, and SOD and CAT activity was measured in these groups. RESULTS: The mean SOD activity in the healthy control group (70.5+/-10.8 U ml(-1)) was higher than in the moderate-to-severe group (67.0+/-6.1 U ml(-1)) (p <0.001, one-tail ANOVA, least significant difference (LSD) post hoc). The mean activity in the mild group (72.5+/-6.9 U ml(-1)) was no higher than in the healthy control group (70.5+/-10.8 U ml(-1)) (p=0.095 one-tail ANOVA, LSD post hoc). The mean CAT activity in the healthy control group (4.9+/-1.5 U ml(-1)) was lower than in the moderate-to-severe group (8.0+/-1.8 U ml(-1)) (p <0.001, one-tail ANOVA, LSD post hoc) and in the mild group (7.5+/-1.5 U ml(-1)) (p=0.012 one-tail ANOVA, LSD post hoc). CONCLUSION: According to our findings, it is reasonable to hypothesize that re-establishment of the activation-inactivation or oxidant-antioxidant balance in favour of the activation and antioxidant balances would be useful as a therapeutic strategy to suppress pathological mechanisms underlying lung injuries.

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

Administration of N-acetylcysteine may be effective in diseases caused by oxidative-antioxidative imbalance. We aimed to determine the effect administration for 4 months of N-acetylcysteine (1200 mg daily) on sulfur mustard-induced bronchiolitis obliterans in patients with normal pulmonary function test. In a double-blind clinical trial, 144 patients with bronchiolitis 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 sputum were 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-acetylcysteine reduced sputum from 76.9% (n = 40) of cases before the trial to 9.6% (n = 5) of cases after the trial. Spirometric components were 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 treating bronchitis, but is also effective in treating bronchiolitis. It also prevents sulfur mustard-induced oxidative stress, and can be used in the treatment of sulfur mustard-induced pulmonary disease.

Therapeutics effect of N-acetyl cysteine on mustard gas exposed patients: evaluating clinical aspect in patients with impaired pulmonary function test.

AIMS: Long-term prescription of N-acetyl cysteine (NAC) may be effective in diseases caused by active radicals of oxygen species. The aim of this study was to determine the effect of 2- and 4-month administration of NAC (1800 mg daily) on mustard induced bronchiolitis obliterans. METHODS AND MATERIALS: In a double blind clinical trial, 144 patients with bronchiolitis obliterans due to sulfur mustard in bronchiolitis obliterans syndrome (BOS) classes 1 and 2, randomly entered Group 1 (n=72, NAC) and Group 2 (n=72, placebo). Dyspnea, wake-up dyspnea, cough, and sputum were measured after 4 months. Spirometric findings were measured at the beginning of the trial, 2 months after and after 4 months of prescription of 1800 mg/day in three doses of NAC or placebo. RESULTS: Dyspnea, cough, sputum, and wake-up dyspnea improved after 4 months of NAC compared to the control group. After 4 months, spirometric components were significantly improved in NAC group compared to placebo group. CONCLUSION: Fourth months administration of NAC (1800 mg daily) can improve clinical conditions and spirometric findings in mustard exposed in BOS class 1 or 2.

Cutaneous and ocular late complications of sulfur mustard in Iranian veterans.

Although sulfur mustard (SM) has been used as a chemical warfare agent since the early twentieth century, it has reemerged in the past decade as a major threat around the world. This agent injured over 100,000 Iranians and one-third is suffering from late effects until today. Mustard affects many organs such as the skin, eyes, and lungs, as well as the gastrointestinal, endocrine, and hematopoietic system. In this study we focused on review of the late Cutaneous and ocular complications caused by exposure to SM. All studies regarding long-term ocular and cutaneous effects, which have been done on Iranian population, were collected from domestic and international sources. Pruritus is the most common complain and a malignant change is the most important lesion, which has to be considered. Also this agent is causes of chronic and delayed destructive lesions in the ocular surface and cornea, leading to progressive visual deterioration and ocular irritation.