N-AcetylCysteine, Hypertonic Saline and Mannitol in Chronic Respiratory Diseases; Efficiency and Safety Considerations

Chronic Respiratory Diseases (CRDs) are a group of long-lasting malfunctions of respiratory system. Almost all of them, are not curable and pharmacological interventions are life-time. Because of the chronic use of therapies, safety of the interventions are as important as efficacy of them. According to the guidelines of therapy, inhaled corticosteroids, inhaled beta2-agonists, methylxanthines and phosphodiesterase inhibitors are main current agents for the treatment of CRDs, while there exists a wide range of adverse reactions during long-time use of the drugs. Adding efficient agents with less side effects could be beneficial. In this article we review the efficacy and safety profile of N-AcetylCysteine, Hypertonic Saline and Mannitol on different types of CRDs, and recommend their use in the management of CRDs. Methods: All information was collected from articles of international medical journals and online Review Article Shohrati et al.; JAMPS, 11(3): 1-12, 2016; Article no.JAMPS.30622 2 databases using key words below. PubMed, Cochrane library, Scopus, Google Scholar, and Clinicaltrial.gov databases were searched for literature published between January 2000 and December 2015. Conclusion: Adding these agents to first line of therapy for CRDs could be beneficial, while more studies are needed to support their use in clinical setting.


INTRODUCTION
Chronic respiratory diseases (CRDs) are chronic diseases of the airways and other structures of the lung lasting for a long time, most of the time life-time. They are a group of diseases with some similar symptoms which affect the quality of life (QOL) of the patients. Several torturous symptoms include frequent coughs, abnormal sputum, difficulty in breathing and dyspnea, wheezing, frequent respiratory infections, shortness of breath and throat irritation [1,2].
Despite the therapeutic advances, these patients still have poor quality of lives. They are always under the influence of their disease and their lives is disturbed [3][4][5].
The pharmacotherapies being used were beneficial, but not curative enough. Also most of them have shown many different adverse effects which hurt the patients in long time.
In this article we are going to talk about three drugs which their beneficial effects in CRDs is under investigation: N-AcetylCysteine, Hypertonic Saline and Mannitol.
They have shown some significant helpful results in several studies for different CRDs, with least risk of possible adverse effects.
We recommend that these three can be added to guidelines of therapy for CRD patients, considering their much lower adverse effects.

METHODS
All information that have been used to write this review article are collected from articles of international medical journals and online databases published between January 2000 and December 2015. To access related studies, keywords such as Chronic Respiratory Disease, Lung Disease, COPD, Asthma, Chronic Bronchiolitis, Bronchiectasis, Mustard Gas, Inhaled Corticosteroids, N-AcetylCysteine, Inhaled Hypertonic Saline and Inhaled Mannitol are used in PubMed, Cochrane library, Scopus, Google Scholar, and Clinicaltrial.gov databases.

Chronic Respiratory Diseases
Chronic respiratory diseases or diseases affecting respiratory system for long periods of time are a wide range of respiratory malfunctions with different pathophysiologies. Asthma, Bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), Chronic Rhinosinusitis, Lung fibrosis and Chronic Bronchitis are the most common CRDs in the world.
They are the major causes of patient's hospitalization along with cardiovascular diseases and stroke. According to WHO statistics published on 2012, COPD is the third leading cause of death in the world [6][7][8].
The latest estimation (2004) of WHO shows that more than 235 million people have asthma, 64 million people have chronic obstructive pulmonary disease (COPD) and millions of other chronic respiratory malfunctions [1].
Nowadays tobacco smoking and air pollution are two main factors that increase the rate of respiratory diseases in the world [9][10][11].
While different CRDs have different pathophysiologies and differential symptoms, there are many common life-time symptoms. Symptoms like difficulty in breathing and dyspnea, frequent coughs, wheezing, frequent respiratory infections, abnormal sputum, shortness of breath and throat irritation are seen in most of the CRD patients and lower the quality of life [12].

Goals and objectives
There are some similar goals of therapy and managements in different CRDs [13][14][15]: -Improving health status and quality of life -Prevention and treating exacerbations -Improving exercise tolerance -Prevention from disease progression -Improving lung function parameters (FEV1, FVC and ratio of them) -Reducing the frequency of respiratory infections, coughs and shortness of breath -Improvement in sputum condition -Relieving other common symptoms

Routine pharmacologic therapies for chronic respiratory diseases
According to the guidelines of therapy of CRDs, inhaled Corticosteroids and beta2-agonists are the first choices of pharmacotherapy in approximately all types of CRD. Also antibiotics are being used to reduce and manage bacterial infections of the respiratory system because of recurrent lung infections in respiratory malfunctions. In addition methylxanthines and phosphodiesterase inhibitors are in 2 nd line of therapy [16][17][18][19].
Long term use of these therapeutic agents have shown wide range of side effects, some of them serious and more harmful.

Inhaled corticosteroids side effects:
-Local adverse effects: Pharyngitis, Dysphonia, Reflex cough, Bronchospasm, Oropharyngeal candidiasis -Systemic side effects: Suppressed HPA-axis function, Adrenal crisis (with insufficiency), Suppressed growth velocity in children, Decreased lower-leg length in children, Reduced bone mineral density, Suppressed HPA-axis function, Bone fractures, Osteoporosis, Skin thinning, Skin bruising, Cataracts, Glaucoma [20] Also other common therapeutic agents in CRDs have shown some clinically important adverse effects.
While muscle cramps and muscle twisting were the most frequent side effects of Inhaled beta2agonists, cardiovascular side effects, especially QT-Prolongation was the most serious.
Theophylline with a narrow therapeutic index has several possible adverse effects: Because of the wide range of adverse effects of pharmacologic agents prescribed in CRDs (three agents talked about above and also many others which are not mentioned) and the chronic lifetime use of them, developing new methods of therapy with effective and less harmful agents seem to be beneficial and helpful. Thus, we here discuss three agents that can remedy different symptoms of CRDs with much lower side effects.

N-AcetylCysteine
N-AcetylCysteine is a mucolytic drug with considerable antioxidative properties; Both can be beneficial in CRDs. Excessive and thick mucus production is one of the most common symptoms of different types of CRDs, which could be relieved by NAC because of its mucolytic effect. Excess amounts of mucus can lead to problems in breathing, frequent coughs; frequent infections (sputum can be a source of food for bacteria) and some other symptoms; thus NAC with its mucolytic property can be a remedy for most of the symptoms pharmacologically.
Also pathophysiological studies have shown that in many types of CRDs oxidative mechanisms are playing an important role, so antioxidant agent, NAC, can be helpful by reduction of oxidant toxics [26].
Almost all studies have shown good safety profile of chronic use of NAC and no major side effects were seen. Life-threating and hazardous adverse drug reactions are rare [27, 28].
Some clinical trials that have evaluated NAC's effectiveness in CRDs. As shown in Table 1, many different symptoms are relieved and QOL is improved [29-37].

Hypertonic Saline
Hypertonic saline (HTS) is a hypertonic sterile solution of salty water that can be inhaled as a nebulized medication.
Multiple mechanisms of action have been found for the beneficial effects of HTS in CRDs.
Osmotic pressure made by HTS adds water to the airway surface; Thus makes the rheological properties of the mucus more favorable for clearance. HTS also triggers cough reaction and the cough increases the amount of mucus cleared from lungs. Disrupting ionic bonds within the mucus gel by HTS reduces its viscosity and elasticity because of the reduction of crosslinkings. Also, anti-inflammatory effects have been seen by HTS. It has been shown that hypertonic saline reduces biofilm formation by micro-organisms. HTS has anti-oxidative properties by increasing the level of thiols [38,39].
According to different studies, nebulized HTS is well tolerated in patients and no severe ADR is common.
[40] Cough and chest tightness are the most common causes make patients unable to tolerate HTS. [41] Some clinical trials that have evaluated HTS's effectiveness in CRDs is shown in Table 2. As can be seen in the table, many different symptoms are relieved and QOL is improved [42-49].

Mannitol
Mannitol is a sugar alcohol with a wide range of therapeutic uses. It can be inhaled as a nebulized medication in CRDs.
The same with hypertonic saline it acts as a mucoactive agent and hydrates the airways because of the osmotic gradient, thus remedies some of the symptoms of CRDs [50][51][52].
No serious ADR is observed in different studies with inhaled Mannitol and safety of chronic use of it is shown [52,54].

DISCUSSION
Low quality of life because of frequent coughs, abnormal sputum, dyspnea, wheezing, shortness of breath, throat irritation, etc. is seen in CRDs. Patients suffer from these symptoms and their lives is disturbed.
Previous studies have shown wide range of beneficial effects of N-AcetylCysteine, Hypertonic saline and Mannitol which can significantly improve QOL. Reduction in Cough, Dyspnea, Wake-up dyspnea, Hemoptysis and exacerbation frequency, physical performance improvement, reduction in admission rates and hospitalization days, reduced respiratory infections frequency and many other helpful effects have been seen by NAC. HTS and Mannitol decreased exacerbation frequency, admission rates and hospitalization days. Sputum condition was improved and expectoration was eased by them. Also improved quality of life (QOL) is reported by NAC, HTS and Mannitol according to the improved St. George's Respiratory Questionnaire (SGRQ) index.
The importance of safety and low rates of adverse drug reactions in therapy of chronic and long-lasting diseases like CRDs is obvious; because of the lifetime interventions. Reduction in frequency and doses of agents with more side effects by replacing them by agents with lower side effects could be beneficial. NAC, HTS and Mannitol seem to have less ADRs than routine pharmacotherapies for CRDs. Knowledge of chronic use of these agents as inhaled formulations is lacking and more studies are needed to explore these agents as a first line of therapy for CRDs. Large-scale clinical trials could evaluate the possibility of replacing routine pharmacologic agents of guidelines by them.

CONCLUSION
In summation, increasing data support the use of NAC, HTS and Mannitol in CRDs considering their efficiency and safety. Further studies are needed to evaluate the long-term efficiency and safety of them as an adjuvant or monotherapy. Also, studying on novel formulations and different particle shapes and particle sizes of these agents and comparison of them with standard therapies seems to be advantageous.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.