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Pronunciation | /əˌsiːtəlˈsɪstiiːn/ and similar (/əˌsɛtəl-, ˌæsɪtəl-, -tiːn/) |
Trade names | Acetadote, Fluimucil, Mucomyst, others |
Synonyms | N-acetylcysteine; N-acetyl-L-cysteine; NALC; NAC |
AHFS/Drugs.com | Monograph |
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Routes of administration | By mouth, injection, inhalation |
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Bioavailability | 10% (Oral)[2] |
Protein binding | 50 to 83%[1] |
Metabolism | Liver[1] |
Elimination half-life | 5.6 hours[3] |
Excretion | Renal (30%),[1] faecal (3%) |
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Chemical and physical data | |
Formula | C5H9NO3S |
Molar mass | 163.195 g·mol−1 |
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Specific rotation | +5° (c = 3% in water)[5] |
Melting point | 109 to 110 °C (228 to 230 °F) [5] |
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Acetylcysteine, also known as N-acetylcysteine (NAC), is a medication that is used to treat paracetamol (acetaminophen) overdose, and to loosen thick mucus in individuals with cystic fibrosis or chronic obstructive pulmonary disease.[1] It can be taken intravenously, by mouth, or inhaled as a mist.[1] Some people use it as a dietary supplement.[6][7]
N-Acetylcysteine NAC: Find the most comprehensive real-world treatment. 342 patients have reported taking N-Acetylcysteine NAC. Category: Supplements.
Common side effects include nausea and vomiting when taken by mouth.[1] The skin may occasionally become red and itchy with either form.[1] A non-immune type of anaphylaxis may also occur.[1] It appears to be safe in pregnancy.[1] For paracetamol overdose, it works by increasing the level of glutathione, an antioxidant that can neutralise the toxic breakdown products of paracetamol.[1] When inhaled, it acts as a mucolytic by decreasing the thickness of mucus.[8]
Acetylcysteine was initially patented in 1960 and came into medical use in 1968.[9] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[10] It is available as a generic medication and is inexpensive.[11]
- 1Uses
- 3Pharmacology
Uses[edit]
Paracetamol overdose[edit]
Intravenous and oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose.[12] When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to deactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, thereby damaging liver cells. This may lead to severe liver damage and even death by acute liver failure.
In the treatment of acetaminophen overdose, acetylcysteine acts to maintain or replenish depleted glutathione reserves in the liver and enhance non-toxic metabolism of acetaminophen.[13] These actions serve to protect liver cells from NAPQI toxicity. It is most effective in preventing or lessening hepatic injury when administered within 8–10 hours after overdose.[13] Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose.[12]
Although both IV and oral acetylcysteine are equally effective for this indication, oral administration is poorly tolerated because high oral doses are required due to low oral bioavailability,[14] because of its very unpleasant taste and odour, and because of adverse effects, particularly nausea and vomiting. Prior pharmacokinetic studies of acetylcysteine did not consider acetylation as a reason for the low bioavailability of acetylcysteine.[15] Oral acetylcysteine is identical in bioavailability to cysteine precursors.[15] However, 3% to 6% of people given intravenous acetylcysteine show a severe, anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due to bronchospasm), a decrease in blood pressure, rash, angioedema, and sometimes also nausea and vomiting.[16] Repeated doses of intravenous acetylcysteine will cause these allergic reactions to progressively worsen in these people.
Several studies have found this anaphylaxis-like reaction to occur more often in people given IV acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic.[17][18][19][20]
Mucolytic therapy[edit]
Inhaled acetylcysteine has been used for mucolytic ('mucus-dissolving') therapy in addition to other therapies in respiratory conditions with excessive and/or thick mucus production. It is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It may be considered ineffective in cystic fibrosis.[21] A 2013 Cochrane review in cystic fibrosis found no evidence of benefit.[22]
Kidney disease[edit]
Some reviews found that prior administration of acetylcysteine decreases radiocontrast induced kidney disease,[23][24] whereas another found questionable effects.[25]
Despite the conflicting research outcomes, the 2012 Kidney Disease: Improving Global Outcomes Guidelines suggest the use of oral acetylcysteine for the prevention of contrast-induced nephropathy in high-risk individuals, given its potential for benefit, low likelihood of adverse effects, and low cost.[26]
Haemorrhagic cystitis[edit]
Acetylcysteine has been used for cyclophosphamide-induced haemorrhagic cystitis, although mesna is generally preferred due to the ability of acetylcysteine to diminish the effectiveness of cyclophosphamide.[27][28]
Obstructive lung disease[edit]
Acetylcysteine is used in the treatment of obstructive lung disease as an adjuvant treatment.[29][30][31]
Psychiatry[edit]
Acetylcysteine has been successfully tried as a treatment for a number of psychiatric disorders.[32][33][34] A systematic review from 2015, and several earlier medical reviews, indicated that there is favorable evidence for N-acetylcysteine efficacy in the treatment of Alzheimer's disease, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, specific drug addictions (cocaine), and a certain form of epilepsy (progressive myoclonic).[32][33][35][36][37][38] Tentative evidence also supports use in cannabis use disorder.[39]
Evidence to date does not support the efficacy for N-acetylcysteine in treating addictions to gambling, methamphetamine, or nicotine, although pilot controlled data are encouraging.[35] Based upon preclinical evidence and limited clinical evidence, NAC appears to normalize glutamateneurotransmission into the nucleus accumbens and other brain structures, in part by upregulating the expression of excitatory amino acid transporter 2 (EAAT2), a.k.a. glutamate transporter 1 (GLT1), in individuals with addiction.[40] While NAC has been demonstrated to modulate glutamate neurotransmission in adult humans who are addicted to cocaine, NAC does not appear to modulate glutamate neurotransmission in healthy adult humans.[40]
NAC has been hypothesized to exert beneficial effects through its modulation of glutamate and dopamine neurotransmission as well as its antioxidant properties.[33]
Microbiological use[edit]
Acetylcysteine can be used in Petroff's method i.e. liquefaction and decontamination of sputum, in preparation for recovery of mycobacterium.[41] It also displays significant antiviral activity against the influenza A viruses.[42]
Acetylcysteine has bactericidal properties and breaks down bacterial biofilms of clinically relevant pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Enterobacter cloacae, Staphylococcus epidermidis, and Klebsiella pneumoniae.[43]
Other uses[edit]
Acetylcysteine has been used to complexpalladium, to help it dissolve in water. This helps to remove palladium from drugs or precursors synthesized by palladium-catalyzed coupling reactions.[44] N-actelylcysteine can be used to protect the liver.[45]
Side effects[edit]
The most commonly reported adverse effects for IV formulations of acetylcysteine are rash, urticaria, and itchiness.[13] Up to 18% of patients have been reported to experience anaphylaxis reaction, which are defined as rash, hypotension, wheezing, and/or shortness of breath. Lower rates of anaphylactoid reactions have been reported with slower rates of infusion.
Adverse effects for inhalational formulations of acetylcysteine include nausea, vomiting, stomatitis, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. Although infrequent, bronchospasm has been reported to occur unpredictably in some patients.[46]
Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever.[46]
Large doses in a mouse model showed that acetylcysteine could potentially cause damage to the heart and lungs.[47] They found that acetylcysteine was metabolized to S-nitroso-N-acetylcysteine (SNOAC), which increased blood pressure in the lungs and right ventricle of the heart (pulmonary artery hypertension) in mice treated with acetylcysteine. The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronic hypoxia). The authors also found that SNOAC induced a hypoxia-like response in the expression of several important genes both in vitro and in vivo.
The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans, the equivalent of about 20 grams per day.[47][48] Nonetheless, positive effects on age-diminished control of respiration (the hypoxic ventilatory response) have been observed previously in human subjects at more moderate doses.[49]
Although N-acetylcysteine prevented liver damage when taken before alcohol, when taken four hours after alcohol it made liver damage worse in a dose-dependent fashion.[50]
Pharmacology[edit]
Pharmacodynamics[edit]
Acetylcysteine serves as a prodrug to L-cysteine.
L-cysteine is a precursor to the biologic antioxidant glutathione. Hence administration of acetylcysteine replenishes glutathione stores.[51]
– Glutathione, along with oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO), have been found to bind to the glutamate recognition site of the NMDA and AMPA receptors (via their γ-glutamyl moieties), and may be endogenousneuromodulators.[52][53] At millimolar concentrations, they may also modulate the redox state of the NMDA receptor complex.[53] In addition, glutathione has been found to bind to and activate ionotropic receptors that are different from any other excitatory amino acid receptor, and which may constitute glutathione receptors, potentially making it a neurotransmitter.[54] As such, since N-acetylcysteine is a prodrug of glutathione, it may modulate all of the aforementioned receptors as well.
– Glutathione also modulates the NMDA receptor by acting at the redox site.[33][55]
L-cysteine also serves as a precursor to cystine which in turn serves as a substrate for the cystine-glutamate antiporter on astrocytes hence increasing glutamate release into the extracellular space. This glutamate in turn acts on mGluR2/3 receptors, and at higher doses of acetylcysteine, mGluR5.[56][57]
Acetylcysteine also possesses some anti-inflammatory effects possibly via inhibiting NF-κB and modulating cytokine synthesis.[33]
Pharmacokinetics[edit]
Acetylcysteine is extensively liver metabolized, CYP450 minimal, urine excretion is 22-30% with a half-life of 5.6 hours in adults and 11 hours in neonates.
Chemistry[edit]
Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reducefree radicals.
N-acetyl-L-cysteine is soluble in water and alcohol, and practically insoluble in chloroform and ether.[58]
It is a white to white with light yellow cast powder, and has a pKa of 9.5 at 30 °C.[5]
Dosage forms[edit]
Acetylcysteine is available in different dosage forms for different indications:
- Solution for inhalation (Assist, Mucomyst, Mucosil) – inhaled for mucolytic therapy or ingested for nephroprotective effect (kidney protection)
- Intravenous injection (Assist, Parvolex, Acetadote) – treatment of paracetamol/acetaminophen overdose
- Oral solution – various indications.
- Effervescent tablets
- Ocular solution - for mucolytic therapy
- Tablets - sometimes in a sustained release formula sold as a nutritional supplement
- Capsules
The IV injection and inhalation preparations are, in general, prescription only, whereas the oral solution and the effervescent tablets are available over the counter in many countries. Acetylcysteine is available as a health supplement in the United States, typically in capsule form.
Research[edit]
While many antioxidants have been researched to treat a large number of diseases by reducing the negative effect of oxidative stress, acetylcysteine is one of the few that has yielded promising results, and is currently already approved for the treatment of paracetamol overdose.[59]
- In mouse mdx models of Duchenne's muscular dystrophy, treatment with 1-2% acetylcysteine in drinking water significantly reduces muscle damage and improves strength.[59]
- It is being studied in conditions, such as autism, where cysteine and related sulfur amino acids may be depleted due to multifactorial dysfunction of methylation pathways involved in methionine catabolism.[60]
- Acetylcysteine in a double-blind placebo-controlled trial appears to reduce the effects of blast induced mild traumatic brain and neurological injury in soldiers.[61] Animal studies have also demonstrated its efficacy in reducing the damage associated with moderate traumatic brain or spinal injury, and also ischaemia-induced brain injury. In particular, it has been demonstrated to reduce neuronal losses and to improve cognitive and neurological outcomes associated with these traumatic events.[34]
- It has been suggested that acetylcysteine may help people with Samter's triad by increasing levels of glutathione allowing faster breakdown of salicylates, although there is no evidence that it is of benefit.[62]
- It has been shown to help women with PCOS (polycystic ovary syndrome) to reduce insulin problems and possibly improve fertility.[63]
- Small studies have shown acetylcysteine to be of benefit to people with blepharitis,[64] and it has been shown to reduce ocular soreness caused by Sjögren's syndrome.[65]
- It has been shown effective in the treatment of Unverricht-Lundborg disease in an open trial in four patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with acetylcysteine treatment has been documented.[66][67]
- Addiction to certain addictive drugs (e.g., cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of excitatory amino acid transporter 2 (EAAT2) in the nucleus accumbens (NAcc);[40] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.[40] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.[40] Drugs that help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[40]
- It has been tested for the reduction of hangover symptoms, but one clinical trial found no significant change between those receiving the drug and placebo.[68]
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Abstract
N-acetyl cysteine (NAC), as a nutritional supplement, is a greatly applied antioxidant invivo and in vitro. NAC is a precursor of L-cysteine that results in glutathione elevationbiosynthesis. It acts directly as a scavenger of free radicals, especially oxygen radicals.NAC is a powerful antioxidant. It is also recommended as a potential treatment option fordifferent disorders resulted from generation of free oxygen radicals. Additionally, it is aprotected and endured mucolytic drug that mellows tenacious mucous discharges. It hasbeen used for treatment of various diseases in a direct action or in a combination withsome other medications. This paper presents a review on various applications of NAC intreatment of several diseases.
Introduction
N-acetyl cysteine (NAC), as a safe and inexpensive medication, is commercially accessible since long-time ago (1). This drug is not found in natural sources, although cysteine is present in some meals like chicken and turkey meats, garlic, yogurt, and eggs (). NAC is a well-tolerated mucolytic drug that moderates clinging mucous secretions and enhances glutathione S-transferase activity. During oral administration, deacetylation reaction of NAC happens while passing along the small intestine as well as liver, thus its bioavailability is decreased to 4-10%. NAC stimulates glutathione biosynthesis, promotes detoxification, and acts directly as a scavenger of free radicals. It is a powerful antioxidant and a potential treatment option for diseases characterized by the generation of free oxygen radicals (). Studies have shown no maternal or fetal harmful effects of NAC treatment. This nutritional supplement is an excellent source of sulphydryl groups. NAC prevents apoptosis and oxygen related genotoxicity in endothelial cells by increasing intracellular levels of glutathione and decreasing mitochondrial membrane depolarization (). The critical antioxidant power of NAC is due to its role as a precursor of glutathione, which is one of the most important naturally occurring antioxidants (). NAC combination with vitamin E, or vitamins A+E, as well as essential fatty acids considerably reduce reactive oxygen species (ROS), leading to pregnancy rate improvement (6). Studies have indicated that preserving impact of NAC against the toxicity of chemicals is due to its dual role as a nucleophile and as a -SH donor (). In this study by reviewing literatures, various applications of NAC in treatment of some diseases are highlighted.
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is one of the most common endocrine glands-related diseases affecting 5-10% of reproductive-age women (). This syndrome is considered as the most common cause of anovulatory infertility. PCOS is also associated with pregnancy complications such as recurrent pregnancy loss (RPL). Different studies report the prevalence of PCOS in women with a history of RPL in a wide range of 10-82%. Findings show that 70.7% of PCOS women with a previous RPL had thrombophilic disorders. In addition, prevalence of protein C deficiency is significantly higher in PCOS patients compared to the non-PCOS women ().
The results of a study showed that women with PCOS have a high prevalence of metabolic syndrome and its individual components (obesity, hypertension, glucose intolerance and triglycerides), particularly decreased high density lipoprotein cholesterol (). In another study, women and their relatives with PCOS had an increased prevalence of diabetes commonly in mother’s side of the family ().
As the first medication option, clomiphene citrate (CC) is applied for the induction of ovulation in PCOS women. A collection of published results for treatment with CC showed a pregnancy rate and a miscarriage rate of 36 and 20.4%, respectively. One of the frequently determined problems of this treatment is resistance to CC in up to 40% of PCOS patients. NAC is a mucolytic drug with insulin-sensitizing properties that has been used successfully as a supporting therapy in subjects with CC-resistant PCOS (). Recent studies have shown that a combination of CC and NAC considerably increased both ovulation and pregnancy rates in women with CC-resistant PCOS. NAC has multiple biological effects, two of which are potentially and directly related to pregnancy rate improvement. NAC has mucolytic action, thus it can revoke the negative effect of CC on cervical mucus. Simultaneously, it has insulin sensitizing effect that could assist in issues related to PCOS. The negative influence of CC on cervical mucus can create a 'hostile' environment for conception (1).
Researchers evaluated the effect of NAC, known to resupply stores of the antioxidant glutathione, on insulin secretion and peripheral insulin resistance in subjects in association with PCOS. Moreover, treatment of hyperinsulinemic patients by NAC was found to tailor control parameters of glucose in them and consequently, their insulin levels and peripheral insulin sensitivity were reduced and increased, respectively. Therefore, the antioxidant effects of NAC may act as a therapeutic approach to improve the level of circulating insulin as well as insulin sensitivity in PCOS patients with hyperinsulinemia (12).
Premature birth and recurrent pregnancy loss
Premature birth is the most common reason of perinatal mortality and long-term unhealthiness in low-income countries (). Inflammation, fetal infection, and previous preterm delivery are significant risk factors for preterm birth and neonatal brain injury (). Rising infection with bacterial vaginosis during pregnancy is related to a risk factor for preterm delivery and low birth weight. Antimicrobial medical care is, although, not adequate for the prevention of preterm birth and the inflammatory as well as anti-inflammatory responses could make problem complex (). NAC by having an anti-inflammatory outcome can affect human term and preterm labors. NAC restrains the inflammatory response with no respect whether infection is started before or after treatment initiation with the drug. Shahin et al. () concluded that in women with previous preterm birth and bacterial vaginosis, 0.6 g of NAC daily can be taken orally along with progesterone after week 16 of pregnancy to protect against preterm birth recurrence and improve neonatal outcome.
RPL is defined as the occurrence of three or more consecutive pregnancy losses in the first or early second trimester of pregnancy (less than 20 weeks of gestation). It is one of the most common clinical problems in reproduction that a certain cause can be found in only 50% of cases (). Many etiologies have been suggested for RPL (). For example, molecular genetic background for RPL is being increasingly understood, and some polymorphisms associated with RPL have been reported. According to the research directed up to now, more than 40 gene products distinctively have been distinguished to be expressed in women with RPL compared to healthy women. These genes may have regulatory roles in establishing or maintaining normal pregnancy. In this manner, any nucleotide modifications in targeted genes may result in distinct expression and activity endangering general well-being during pregnancy. A recent study showed a relationship between c.179A>C mutation in the Bax promoter and RPL and also, two polymorphisms, namely c.90G>C and c.95G>A in exon 1, found among patients that can be considered as genetic factors making people susceptible to miscarriages (). Findings of the other recent study revealed a new genetic relationship between occurrences of RPL and SULF1 gene mutation. SULFs are a protein family of arylendosulfatase. They act as post synthetic editors that can selectively release 6-O-sulfate groups from heparin sulfates, consequently changing the sulfation patterns of proteoglycans and binding site of many growth factors. With such unique regulatory activity, SULFs have an important role in many biological processes, such as angiogenesis, cell signaling and embryogenesis. In this gene family, SULF1 is expressed in the large number of embryonic and adult tissues, while it has an important role in viability and embryonic development (). In a study conducted by some researchers, high rate of mutations in D-loop of mtDNA was observed in maternal blood, a fact that may have a direct or indirect role in inducing RPL. This outcome can be utilized as part of the RPL evaluation, planning conceivable medications for enhancing the results of assisted reproduction (). Some evidence has shown that oxidative stress might be a contributory factor in RPL (). One phenomenon that is known as a common patho-physiological pathway for various etiologies of RPL, can be placental oxidative stress. Amin concluded that NAC is a well-tolerated drug that could potentially be an effective treatment in patients with unexplained RPL. Administration of a combination of NAC and folic acid, in comparison with folic acid alone, is resulted in prolongation of a living pregnancy up to 20 weeks. In addition, combination of NAC and folic acid were also associated with a significant increase in the take-home baby rate, as compared to folic acid alone ().
Acetaminophen toxicity
Acetaminophen administration is reported as the most common drug overdose in pregnancy. Acetaminophen readily crosses the placenta and in toxic doses can result in fetal hepatic necrosis, premature birth, spontaneous abortion, and fetal death (). NAC is an amino acid that contains thiol group. It has been used for the treatment of acetaminophen toxicity (). N-Acetyl-pbenzoquinonimine is a potent oxidative metabolite of acetaminophen, resulting in hepatotoxicity, if it is not reduced by glutathione. NAC is thought to affect through multiple mechanisms including replenishing glutathione, reducing N-acetyl-pbenzoquinonimine directly, and performing nonspecific hepatoprotective actions related to its antioxidant properties. This compound is used to treat acetaminophen poisoning throughout pregnancy (). It is universally effective to prevent hepatotoxicity, if it is administrated within 10 hours of acetaminophen overdose ().
In addition, acetaminophen toxicity is a common cause of drug-induced hepatotoxicity in children and adults. NAC has been used for several decades and it has been proven as a counterpoison choice in treating acetaminophen-induced hepatotoxicity. There is considerable clinical evidence to support the fact that oral and intravenous NAC are equally effective in the prevention of hepatotoxicity. An important factor in evaluating the effectiveness of NAC is the timing of therapy commencement in relation to the administration. Patients that ingest a severe overdose and have NAC therapy started within 8 hours get well and have less than a 10% rate of occurrence of hepatotoxicity. They generally do not develop liver failure or death. Those patients who have chronically taken immoderate doses of acetaminophen over many hours and/or have NAC therapy started more than 8 hours after an acute overdose are at a risk of hepatotoxicity with approximately 8-50% incidence ().
Several recent studies have investigated the antioxidant properties of NAC in feto-placental metabolism (,). NAC appears to attenuate placental production of inflammatory cytokine interleukin 6 involved in placenta infection and inflammation in the pregnant rat model. A murine model demonstrated benefit of NAC in a complicated pregnancy, manipulated by infection and free radical production, suggesting the ability of NAC to restore maternal and fetal oxidative balance to reduce preterm birth caused by different factors such as acetaminophen toxicity ().
In vitrostudies have shown that oxidative stress might serve as a signal to initiate and propagate the inflammatory process, resulting in apoptosis of placental tissues (6). Bloosesky et al. () showed that preventative effect of NAC could reduce fetal inflammatory cytokines in response to maternal lipopolysaccharide. Their results suggested that prophylactic NAC administered in pregnancies was associated with a risk of maternal infection/inflammation, likely protecting fetus from adverse inflammatory sequelae.
Administration of N-acetyl cysteine for infertile patients undergoing assisted reproductive
techniques Elgindy et al. () found that 1200 mg NAC (daily) supplementation, started with administration of human menopausal gonadotrophin till the day of human chorionic gonadotrophin, did not significantly increase pregnancy rate in intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol. NAC treatment was associated with insignificant decrease in granulosa cell apoptosis, as well as insignificant increase in fertilization rate and grade-one embryo formation. Larger-scale studies, possibly with higher doses and/or longer duration of NAC administration, should be performed to identify any significant effects. In addition, Cheraghi et al. () conducted a study to determine the effect of co-administration of NAC and metformin on ovulation induction in PCOS patients with ICSI cycle. They detected that co-administration of these two components has no benefit for ovulation induction in PCOS patients with ICSI cycle. In another study, Rizk et al. (27) investigated the effect of NAC on performance of CC in ovulation induction. They concluded that the combination of NAC with CC is an effective way for ovulation induction in young women undergoing ICSI cycles.
Chronic bronchitis
Chronic bronchitis is defined as the presence of chronic productive cough for more than three months in each of two sequential years. Therefore, an important goal in the treatment of chronic bronchitis is to decrease the frequency and duration of intensification, and to decrease symptoms in patients with aggravations. In some European countries, mucolytic drugs, particularly NAC may be used as an anti-inflammatory drug as well as an antioxidant (28,29). In these countries, it is believed that NAC can decrease the frequency of aggravations and improve symptoms in patients with chronic bronchitis. Recently, a comprehensive review in literature survey has concluded in the field of the effectiveness of any oral mucolytic drugs that a decline of aggravations, days of disability and days of antibiotic treatment was averagely determined in patients with chronic clogging pulmonary disease ().
Ulcerative colitis
Ulcerative colitis is a chronic inflammatory disorder which multiple casual factors can affect it. Human colitis has many similar characteristics to acetic acid (AA)-induced colitis, as a reproducible and simple model. Studies have indicated that some signaling pathways contributing in cell apoptosis and growth, angiogenesis, redoxregulated gene expression, and inflammatory response can be affected by NAC (6,). Therefore, NAC may not only protect against the direct detrimental impacts of oxidants, but also advantageously modify inflammatory events in colitis (). The beneficial influences of NAC were related to the changes including: i. Softened colonic injury, ii. Decreased oxidative stress, iii. Lowered cell apoptosis, iv. Increased recovery of the injured colon, and v. Increased formation of the tight junction (6).
Liver cancer
Liver cancer is one of the most common lifethreatening malignancies, all over the world and up to now, there is no effective drug for the treatment of liver tumors (). Although, interferon (IFN) is the most applied medication in chronic hepatitis and hepatocarcinoma, due to its immune response activation property and also regulation of differentiation and cell growth (). NAC, as an enhancer of glutathione biosynthesis (), is one of the frequently used antioxidant drugs for treatment of liver disorders (,). Cell culture and animal models have shown that NAC can preserve normal cells against toxicity of radiotherapy and chemotherapy, but not cancerous cells (). Administration of NAC may play a role in treatment of some forms of cancer, while induced damages in DNA can be completely blocked by NAC ().
Muscle performance
Investigations showed no effect of NAC on nonfatigued muscle, although after three minutes of repetitive contractions, it caused a considerably enhanced force output, up to approximately 15%. This means that NAC can improve muscle performance. This result is originated from the fact that oxidative stress plays a causal role in the fatigue process, since NAC is a scavenger of free radicals causing oxidative stress. It has been wellreported that infusion of NAC can be effective on enhancing the overall redox status in vivo. It has also been shown that NAC infusion could minimize the muscle fatigue ().
Hemodialysis
Homocysteine (Hcy) is a sulphur-containing amino acid that is produced in body, by the metabolism of the methionine amino acid (). Hcy level in patients with hemodialysis is associated with kidney-related disorders. However, in the treated hemodialysis patients, some studies have shown that NAC administration could affect plasma Hcy levels. There are some reports indicating that NAC, with an antioxidant property, has declined plasma Hcy level in the end stage renal disease (ESRD) patients undergoing hemodialysis. Although, lower dosage of NAC (for example, 600 mg/day for a period of one month) could not help to decrease Hcy plasma levels in these patients (42).
Asthma
Asthma is a chronic disorder associated with inflammation and immune cell infiltration of airways (). Airway hyper-responsiveness (AHR) can be originated from consistent presence of inflammatory mediators and immune cells in airways. AHR is clinically determined with breathlessness, coughing and wheezing symptoms (). Studies showed the preventive effect of NAC antioxidant on the AHR and steroid resistant accumulation of inflammatory cells in the airways of the animal model with acute exacerbation of asthma (,).
Alzheimer
Alzheimer disease (AD) is known as a multifactorial disease with many abnormalities in physiological, biochemical, and neurochemical point of view. Aging is the major risk factor for AD that coexists with other causes of cognitive decline, particularly vascular dementia (). Some factors, such as mitochondrial dysfunction, abnormal protein aggregation, metal accumulation, inflammation and excitotoxicity play important roles in AD pathology. Although the relationship between these factors and development of AD is multidirectional, oxidative damage is considered as a common thread linking some of these factors (). Results of different studies showed that lipoic acid (LA) and NAC decreased levels of oxidative and apoptotic markers via protection of mitochondrial function (,). Combination of both LA and NAC maximizes this protective effect suggesting that this may prevent mitochondrial decay associated with aging and age-related disorders such as AD. Antioxidant therapies based on LA and NAC seem promising since they can act on mitochondria, one key source of oxidative stress in aging and neurodegeneration ().
Parkinson
Parkinson disease (PD) is a very prevalent neurodegenerative disorder caused by unknown deterioration of cells which generate dopamine in the pars compacta, a part of the substantial nigra located in the midbrain (). In terms of pathogenesis, PD appears to be multi-factorial disorder, including environmental factors, acting on genetically vulnerable individuals when they are older (,). A wide range of both genetic and environmental factors have been proposed as contributing to the initiation and progression of PD, but aging is the single most important risk factor for this disorder and undoubtedly interferes in PD progression through its accumulative oxidative damage, decrease in antioxidant ability and impairment of mitochondrial bio-energetic capacity in the brain (,). Taking into account that most of PD patients experience accumulative oxidative damage, some clinical studies have demonstrated the controversial effect of some antioxidant administrations -such as NACon treatment of PD (,). Some improvements have been reported for systemic administration of NAC in animal models, such as: i. Enhancement of brain level of glutathione, ii. Reduction of oxidative damage-markers, iii. Enhancement of brain synaptic and non-synaptic brain mitochondrial complex I activities, and iv. Protection against dopamine-induced cell death ().
Conclusion
A review on NAC literature shows that this agent is a safe and well-tolerated supplementary drug without any considerable side effects. It 16 is as an antioxidant with a free radical scavenger property, as important characteristic of this medical supplement. It has been used as a beneficial drug treatment for some disorders such as poly cystic ovary syndrome patients with CC resistance, preterm birth, acetaminophen toxicity, RPL, chronic bronchitis, ulcerative colitis, liver cancer, muscle performance, hemodialysis, asthma, Alzheimer and Parkinson. Although in some cases, such as improving pregnancy rate in ICSI cycles, NAC action is still unclear and further investigations are necessary.
Acknowledgments
The authors would like to thank Royan Institute experts for their helpful comments and suggestions. There is no conflict of interest in this study.