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    Topic review

    Medical Uses of N-Acetylcysteine

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    Submitted by: Irina Milisav

    Definition

    N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.

    1. Introduction

    N-acetylcysteine (also known as N-acetyl-cysteine, NAC) is a precursor to the amino acid L-cysteine and consequently the antioxidant glutathione (GSH) [1]. It is most notably found in plants of the Allium species, especially in the onion (Allium cepa, 45 mg NAC/kg) [2][3]. The sulfhydryl group (–SH) within the NAC molecule directly scavenges reactive oxygen species (ROS) [4], modulates the redox state of the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (neurotransmitter effect) [5], and inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) to modulate cytokine synthesis (anti/pro-inflammatory effect) [6]. Unlike GSH itself, NAC has better oral and topical bioavailability [7][8]. Even though it has been used for more than 50 years, there are still many controversies surrounding it as a medicine as well as a dietary supplement.

    2. Medical Use of NAC

    NAC has been an established drug since the 1960s; it is on the World Health Organization’s List of 40 Essential Medicines [9] and is available as an inexpensive generic drug. It has been classically used in paracetamol overdose [10] and as a mucolytic [11], as well as to combat the toxicity of various substances that can cause generation of free radicals, such as carbon monoxide and x-ray contrasts [12]. The NAC products currently approved by Food and Drug Administration (FDA) are listed in Table 1. NAC is also used in the complementary treatment of neurological and neuropsychiatric disorders [5][11]. One death due to an anaphylactic reaction was described following an intravenous (IV) injection of 150 mg/kg of NAC in a 40 year old asthmatic woman in 2002. At comparable IV doses, vomiting was also reported in 11% of patients [13]. However, oral NAC seems to be associated with very few side effects and is considered to have an excellent safety profile [11]. One case of angioedema after oral NAC administration was described in 1997 [14]. Clinical studies have revealed benefits of NAC also in non-alcoholic steatohepatitis [15], arterial hypertension of diabetic etiology [16], chronic obstructive pulmonary disease (COPD) [17][18] and chronic bronchitis [19], substance abuse disorders [20], recurrent unexplained pregnancy loss [21], male infertility [22], polycystic ovary syndrome [23], diabetic retinopathy, age-related macular degeneration, and cataract and dry eye syndrome [4]. In total, 300 clinical studies (291 clinical trials) of NAC are listed in ClinicalTrials.gov [24] in April 2019 (Table 2). The most common disorders that were investigated by listed interventional trials with NAC (without the currently active studies) included renal disorders (48 trials) with an emphasis on radiocontrast nephropathy prevention, chronic kidney disease, and renoprotection during surgery; and neurological and psychiatric disorders (36 trials), leading with Parkinson’s disease, schizophrenia, bipolar, autistic, and behavioral disorders. Schizophrenia, for instance, has been linked to mitochondrial abnormalities, glutathione deficiency, and increased oxidative stress in the brain. Negative and general symptoms in schizophrenia may be reduced after 8–24 weeks of adjunctive treatment with NAC [25] in neuropsychiatric disorders and are discussed in greater detail in a recent review [26]. Addictive disorders (23 trials) are also a common target, with alcohol, tobacco, cocaine, cannabis, and other types of dependence. The NMDA receptors that NAC modulates may be involved in addiction [27], and at least three reviews discuss the use of NAC in addictive disorders [20][28][29] and emphasize the reduction of cravings for the substance in question. Among other commonly investigated uses of NAC were applications in gastrointestinal and pulmonary diseases. The majority of the 54 currently active interventional studies are investigating the role of NAC in addictive disorders, mental health, and neurodegenerative diseases, followed by cancer/cancer treatment side-effects, cardiovascular diseases, and surgery complications/trauma.
    Table 1. Overview of Food and Drug Administration FDA-approved N-acetyl-cysteine (NAC) drugs and their indications.
    Route Administration Strength No.* Medical Condition/
    Therapy Type
    Indication
    Injectable Intravenous 200 mg/mL
    (6 g/30 mL)
    7 Poisoning/
    antidote
    Acetaminophen overdose reduction;
    Prevention of acute hepatic injury;
    Hepatic injury from repeated supratherapeutic ingestion.
    Effervescent tablet Oral 500 mg
    2.5 g
    1
    Solution Oral 10%
    20%
    3 Bronchopulmonary disorders/
    Adjuvant therapy
    Abnormal, viscid, inspissated mucous secretions in chronic** and acute*** bronchopulmonary disease;
    Pulmonary complications of cystic fibrosis;
    Tracheostomy care;
    Pulmonary complications associated with surgery;
    Use during anesthesia;
    Post-traumatic chest conditions;
    Atelectasis due to mucous obstruction and diagnostic bronchial studies****.
    Solution Inhalation 10%
    20%
    3
    *: Number of drugs, currently on the market. **: Chronic bronchopulmonary disease: chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis, and primary amyloidosis of the lung. ***: Acute bronchopulmonary disease: pneumonia, bronchitis, and tracheobronchitis. ****: Diagnostic bronchial studies: bronchograms, bronchospirometry, and bronchial wedge catheterization.
    Table 2. NAC clinical trials registered at ClinicalTrials.gov [24]. The number of studies is displayed according to the study status, tested medical conditions of currently active studies, tested medical conditions in completed studies, study phase and tested medical conditions of currently active studies, study phase, and tested medical conditions of completed studies.
    Status Count
    Completed 159
    Not yet recruiting 14
    Active 54
    Withdrawn/terminated/suspended 24
    Unknown status 40
    Grand Total 291
    Medical Conditions (Active Studies) Count
    Addiction 12
    Cancer/chemotherapy side effects 5
    Cardiovascular diseases 5
    Gastrointestinal diseases 4
    Genetic disorders 1
    Graft/stem cell complications/trauma 4
    Infectious diseases 1
    Metabolic diseases 1
    Neuro/psychiatric disorders 12
    Obstetrics 2
    Poisoning antidote 1
    Pulmonary diseases 1
    Surgery complications/trauma 5
    Grand Total 54
    Medical Conditions (Completed Studies) Count
    Addiction 17
    Blood disorders 4
    Cancer/chemotherapy side effects 2
    Cardiovascular diseases 10
    Dermatologic disorders 2
    Gastrointestinal diseases 15
    Genetic disorders 1
    Infectious diseases 3
    Metabolic diseases 8
    Muscle disorders 1
    Neuro/psychiatric disorders 24
    Obstetrics 11
    Ophthalmological diseases 5
    ORL 5
    Other 4
    Poisoning antidote 2
    Pulmonary diseases 13
    Renal disorders 31
    Surgery complications/trauma 1
    Grand Total 159
    Phase/Medical Conditions (Active Studies) Count
    Early Phase 1 5
    Addiction 2
    Metabolic diseases 1
    Neuro/psychiatric disorders 1
    Pulmonary diseases 1
    Not Applicable 10
    Cardiovascular diseases 2
    Gastrointestinal diseases 1
    Graft/stem cell complications/trauma 1
    Neuro/psychiatric disorders 4
    Obstetrics 1
    Surgery complications/trauma 1
    Phase 1 4
    Addiction 1
    Cancer/chemotherapy side effects 1
    Neuro/psychiatric disorders 1
    Poisoning antidote 1
    Phase 1|Phase 2 3
    Cancer/chemotherapy side effects 2
    Gastrointestinal diseases 1
    Phase 2 13
    Addiction 6
    Cancer/chemotherapy side effects 1
    Gastrointestinal diseases 1
    Genetic disorders 1
    Graft/stem cell complications/trauma 1
    Infectious diseases 1
    Neuro/psychiatric disorders 2
    Phase 2|Phase 3 3
    Addiction 1
    Graft/stem cell complications/trauma 1
    Obstetrics 1
    Phase 3 8
    Cancer/chemotherapy side effects 1
    Cardiovascular diseases 3
    Neuro/psychiatric disorders 2
    Surgery complications/trauma 2
    Phase 4 8
    Addiction 2
    Gastrointestinal diseases 1
    Graft/stem cell complications/trauma 1
    Neuro/psychiatric disorders 2
    Surgery complications/trauma 2
    Grand Total 54
    Phase/Medical Conditions (Completed Studies) Count
    Early Phase 1 3
    Addiction 1
    Blood disorders 1
    ORL 1
    Not Applicable 18
    Cardiovascular diseases 1
    Gastrointestinal diseases 3
    Metabolic diseases 3
    Neuro/psychiatric disorders 2
    Obstetrics 2
    Pulmonary diseases 2
    Renal disorders 5
    Phase 1 22
    Addiction 3
    Cancer/chemotherapy side effects 1
    Cardiovascular diseases 1
    Gastrointestinal diseases 2
    Neuro/psychiatric disorders 4
    Ophthalmological diseases 4
    ORL 1
    Other 4
    Pulmonary diseases 1
    Renal disorders 1
    Phase 1|Phase 2 12
    Addiction 2
    Blood disorders 1
    Infectious diseases 1
    Metabolic diseases 3
    Neuro/psychiatric disorders 2
    Obstetrics 2
    Renal disorders 1
    Phase 2 47
    Addiction 8
    Blood disorders 1
    Cancer/chemotherapy side effects 1
    Cardiovascular diseases 4
    Dermatologic disorders 1
    Gastrointestinal diseases 2
    Genetic disorders 1
    Infectious diseases 1
    Metabolic diseases 1
    Muscle disorders 1
    Neuro/psychiatric disorders 14
    Obstetrics 1
    Ophthalmological diseases 1
    ORL 1
    Pulmonary diseases 2
    Renal disorders 7
    Phase 2|Phase 3 8
    Gastrointestinal diseases 1
    Obstetrics 1
    ORL 1
    Renal disorders 5
    Phase 3 20
    Addiction 2
    Blood disorders 1
    Cardiovascular diseases 2
    Dermatologic disorders 1
    Gastrointestinal diseases 4
    Infectious diseases 1
    Obstetrics 2
    Pulmonary diseases 2
    Renal disorders 5
    Phase 4 29
    Addiction 1
    Cardiovascular diseases 2
    Gastrointestinal diseases 3
    Metabolic diseases 1
    Neuro/psychiatric disorders 2
    Obstetrics 3
    ORL 1
    Poisoning antidote 2
    Pulmonary diseases 6
    Renal disorders 7
    Surgery complications/trauma 1
    Grand Total 159
    ORL: Otorhinolaryngology.
    The suspended, terminated, or withdrawn studies listed in ClinicalTrals.gov are in Table 3. Termination reasons, such as no improvement and opposite results, are recorded in only 3 out of the 23 trials. Insufficient funds and insufficient recruitment are the major termination/ suspension/ withdrawal reason [24]. There are a few reports of the NAC study premature termination in the literature. High doses of NAC did not improve respiratory health in patients with COPD and chronic bronchitis; the study was prematurely terminated [30]. The decision was based on a potential safety issue, as it was reported that NAC and vitamin E, given orally, induced lung cancer in mice. This finding was reproduced in cell lines from human and mice lung tumors [31]. Additionally, there was no indication of improvement of COPD/chronic bronchitis in the 23 patients that received 1800 mg NAC twice daily for 8 weeks compared to the equal number of subjects receiving placebo [30]. Results of a 24-week oral NAC supplementation of cystic fibrosis patients revealed that NAC recipients maintained their lung function without a significant effect on the biomarkers of neutrophilic inflammation [32]. Another trial was prematurely terminated in 2018 due to the absence of between-group differences in the rates of contrast-associated acute kidney injury; there was no noticeable benefit of the oral NAC on the contrast-associated acute kidney injury prevention, no noticeable improvement on the need for dialysis, persistent kidney injury or death in subjects at high risk of renal complications because of angiography [33]. Similar conclusions were reached from the “Acetylcysteine for contrast-induced neuropathy” trial [34].
    Table 3. Medical conditions investigated by withdrawn, terminated, and suspended studies listed by ClinicalTrials.gov [24]. Listed: number of trials listed at ClinicalTrials.gov [24]; Phase: study phase; N/A: not applicable.
    Status/Medical Condition Listed Phase Termination Reason
    SUSPENDED 4    
    Autoimmune Disorders      
    Systemic Lupus Erythematosus 1 1|2 Short of funds
    Cardiovascular Diseases      
    Cardiovascular Disease|Renal Insufficiency, Acute|Cardiopulmonary Bypass 1 4 Opposite result
    Infectious Diseases      
    Hepatitis C 1 N/A Short of funds
    Metabolic diseases      
    Insulin Resistance|Metabolic Syndrome 1 N/A N/A
    TERMINATED/ 15    
    Addiction      
    Acetaminophen Overdose 1 3 Insufficient enrollment
    Prevention of Hangover Using NAC 1 N/A Insufficient enrollment
    Cancer/Chemotherapy Side Effects      
    Bone Marrow Suppression|Brain and Central Nervous System Tumors|Drug/Agent Toxicity by Tissue/Organ|Long-term Effects Secondary to Cancer Therapy in Children 1 1 N/A
    Malignant Ovarian Endometrioid Tumor|Malignant Ovarian Serous Tumor|Recurrent Fallopian Tube Carcinoma|Recurrent Ovarian Carcinoma|Recurrent Primary Peritoneal Carcinoma 1 2 Slow accrual
    Gastrointestinal Diseases      
    Acute Liver Failure|Fulminant Hepatic Failure 1 4 Insufficient enrollment
    Drug Induced Liver Injury 1 N/A 2 sepsis cases after steroid admin.
    Genetic disorders      
    Cystic Fibrosis 1 4 Insufficient enrollment
    Infectious Diseases      
    Helicobacter pylori Infection 1 1|2 Efficacy of eradication: 2 out of 31
    Metabolic diseases      
    Type 2 Diabetes Mellitus|Hypertension 1 4 N/A
    Neuro/Psychiatric Disorders      
    Borderline Personality Disorder|Self-Injurious Behavior 1 2 Poor subject compliance
    Bulimia Nervosa 1 2|3; 3 No meaningful improvements
    Obsessive-Compulsive Disorder 1 2 Insufficient enrollment
    Pulmonary Diseases      
    COPD|Chronic Bronchitis 1 N/A PI’s discretion
    Renal Disorders      
    Chronic Kidney Failure 1 N/A N/A
    Surgery Complications/Trauma      
    Ischemic Reperfusion Injury|Insufficiency; Hepatic, Postoperative|Liver Tumour 1 2 N/A
    WITHDRAWN/ 4    
    Cancer/Chemotherapy Side Effects      
    Ovarian Carcinoma, Stage 3 or 4|Epithelial Ovarian Carcinoma|Primary Peritoneal Carcinoma 1 1 No funding for the cost of NAC
    Gastrointestinal Diseases      
    Liver Failure|Liver Failure, Acute|Drug Induced Liver Injury|Prevention and Control|Fever 1 N/A Short of funds
    Neuro/Psychiatric Disorders      
    Autistic Disorder|Seizures|Irritability 1 N/A No eligible subjects located
    Posttraumatic Stress Disorder 1 2 Cancelled research project
    Grand Total 23    
    Pre-clinical studies imply that NAC could have more uses in supportive care and preventing human disease. Examples include Alzheimer’s disease [35][36], asthma [37], inflammatory bowel disease [38], influenza [39], intrauterine growth retardation [40], obesity and insulin resistance [41][42][43][44], ischemic cardiovascular disease [45][46], heavy metal toxicity [47][48], diabetic neuropathy [49], and age-related memory impairment [50]. Due to its capacity to break down biofilms and improve antibiotic permeability, it is promising as an adjuvant antimicrobial drug [51]. Several pre-clinical studies have also demonstrated that NAC supplementation leads to life extension and diminished effects of aging, in invertebrates [52][53][54][55] as well as mammals [56] and in human breast epithelial stem cells [57]. Such findings have yet to be replicated in humans. This is likely not solely due to NAC’s radical scavenging activity but also at least in part to telomerase activation and apoptosis inhibition [58], as is evidenced also by its capacity to delay oocyte aging [59]. However, antioxidants have the potential to either lengthen or shorten lifespan, depending on the dose and redox balance [60].
    The role of NAC in the prevention and treatment of cancer is controversial, and it is discussed in more detail in the original manuscript. NAC has also attracted considerable attention as a sports supplement that can reduce muscle fatigue, improve athletic performance, and aid muscle recovery [61]. Although NAC is a well-known antioxidant and an old generic drug with several established clinical applications, more potential uses are still inadequately investigated. One of the main challenges of NAC as a medicine and a supplement is its broad range of effects and applications, far too few of which are well studied, in spite of a large effort in conducting preclinical and clinical trials.

    The entry is from 10.3390/antiox8050111

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