N-acetylcysteine (NAC) - NutraHacker Journal Club
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Purpose: The study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and to determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied through an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 48 (likely) pathogenic TRMU variants, of which, 18 were novel. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals, 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF is a transient, reversible disease and cysteine supplementation improved survival.
GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage
Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.
Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial
Background: Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. Methods: A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition. Results: GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks. Conclusions: GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.
A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage
Glycine and cysteine are non-essential amino acids that are required to generate glutathione, an intracellular tripeptide that neutralizes reactive oxygen species and prevents tissue damage. During aging glutathione demand is thought to increase, but whether additional dietary intake of glycine and cysteine contributes towards the generation of glutathione in healthy older adults is not well understood. We investigated supplementation with glycine and n-acetylcysteine (GlyNAC) at three different daily doses for 2 weeks (low dose: 2.4 g, medium dose: 4.8 g, or high dose: 7.2 g/day, 1:1 ratio) in a randomized, controlled clinical trial in 114 healthy volunteers. Despite representing a cohort of healthy older adults (age mean = 65 years), we found significantly higher baseline levels of markers of oxidative stress, including that of malondialdehyde (MDA, 0.158 vs. 0.136 µmol/L, p < 0.0001), total cysteine (Cysteine-T, 314.8 vs. 276 µM, p < 0.0001), oxidized glutathione (GSSG, 174.5 vs. 132.3 µmol/L, p < 0.0001), and a lower ratio of reduced to oxidized glutathione (GSH-F:GSSG) (11.78 vs. 15.26, p = 0.0018) compared to a young reference group (age mean = 31.7 years, n = 20). GlyNAC supplementation was safe and well tolerated by the subjects, but did not increase levels of GSH-F:GSSG (end of study, placebo = 12.49 vs. 7.2 g = 12.65, p-value = 0.739) or that of total glutathione (GSH-T) (end of study, placebo = 903.5 vs. 7.2 g = 959.6 mg/L, p-value = 0.278), the primary endpoint of the study. Post-hoc analyses revealed that a subset of subjects characterized by high oxidative stress (above the median for MDA) and low baseline GSH-T status (below the median), who received the medium and high doses of GlyNAC, presented increased glutathione generation (end of study, placebo = 819.7 vs. 4.8g/7.2 g = 905.4 mg/L, p-value = 0.016). In summary GlyNAC supplementation is safe, well tolerated, and may increase glutathione levels in older adults with high glutathione demand. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05041179, NCT05041179.
Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine
Objective: Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on GSH synthesis rate and oxidative stress. Research design and methods: We infused 12 diabetic patients and 12 nondiabetic control subjects with [²H₂]-glycine to measure GSH synthesis. We also measured intracellular GSH concentrations, reactive oxygen metabolites, and lipid peroxides. Diabetic patients were restudied after 2 weeks of dietary supplementation with the GSH precursors cysteine and glycine. Results: Compared with control subjects, diabetic subjects had significantly higher fasting glucose (5.0 ± 0.1 vs. 10.7 ± 0.5 mmol/l; P < 0.001), lower erythrocyte concentrations of glycine (514.7 ± 33.1 vs. 403.2 ± 18.2 μmol/l; P < 0.01), and cysteine (25.2 ± 1.5 vs. 17.8 ± 1.5 μmol/l; P < 0.01); lower concentrations of GSH (6.75 ± 0.47 vs. 1.65 ± 0.16 μmol/g Hb; P < 0.001); diminished fractional (79.21 ± 5.75 vs. 44.86 ± 2.87%/day; P < 0.001) and absolute (5.26 ± 0.61 vs. 0.74 ± 0.10 μmol/g Hb/day; P < 0.001) GSH synthesis rates; and higher reactive oxygen metabolites (286 ± 10 vs. 403 ± 11 Carratelli units [UCarr]; P < 0.001) and lipid peroxides (2.6 ± 0.4 vs. 10.8 ± 1.2 pg/ml; P < 0.001). Following dietary supplementation in diabetic subjects, GSH synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly. Conclusions: Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia.
GlyNAC Supplementation Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Aging Hallmarks, Metabolic Defects, Muscle Strength, Cognitive Decline, and Body Composition: Implications for Healthy Aging
Cellular increases in oxidative stress (OxS) and decline in mitochondrial function are identified as key defects in aging, but underlying mechanisms are poorly understood and interventions are lacking. Defects linked to OxS and impaired mitochondrial fuel oxidation, such as inflammation, insulin resistance, endothelial dysfunction, and aging hallmarks, are present in older humans and are associated with declining strength and cognition, as well as the development of sarcopenic obesity. Investigations on the origins of elevated OxS and mitochondrial dysfunction in older humans led to the discovery that deficiencies of the antioxidant tripeptide glutathione (GSH) and its precursor amino acids glycine and cysteine may be contributory. Supplementation with GlyNAC (combination of glycine and N-acetylcysteine as a cysteine precursor) was found to improve/correct cellular glycine, cysteine, and GSH deficiencies; lower OxS; and improve mitochondrial function, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, and multiple aging hallmarks; and improve muscle strength, exercise capacity, cognition, and body composition. This review discusses evidence from published rodent studies and human clinical trials to provide a detailed summary of available knowledge regarding the effects of GlyNAC supplementation on age-associated defects and aging hallmarks, as well as discussing why GlyNAC supplementation could be effective in promoting healthy aging. It is particularly exciting that GlyNAC supplementation appears to reverse multiple aging hallmarks, and if confirmed in a randomized clinical trial, it could introduce a transformative paradigm shift in aging and geriatrics. GlyNAC supplementation could be a novel nutritional approach to improve age-associated defects and promote healthy aging, and existing data strongly support the need for additional studies to explore the role and impact of GlyNAC supplementation in aging.
Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial
Background: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial. Methods: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. Results: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects. Conclusion: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.
GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study
Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA (free-fatty acid) concentrations in humans with T2D remains unknown. This manuscript reports the effect of supplementing GlyNAC for 14-days on MFO, MGO, IR and FFA in 10 adults with T2D and 10 unsupplemented non-diabetic controls. Fasted T2D participants had 36% lower MFO (p < 0.001), 106% higher MGO (p < 0.01), 425% higher IR (p < 0.001) and 76% higher plasma FFA (p < 0.05). GlyNAC supplementation significantly improved fasted MFO by 30% (p < 0.001), lowered MGO by 47% (p < 0.01), decreased IR by 22% (p < 0.01) and lowered FFA by 25% (p < 0.01). These results provide proof-of-concept that GlyNAC supplementation could improve mitochondrial dysfunction and IR in patients with T2D, and warrant additional research.
Successful use of N-acetylcysteine to treat severe hepatic injury caused by a dietary fitness supplement
In the absence of adequate premarketing efficacy and safety evaluations, adverse events from over-the-counter supplements are emerging as a public health concern. Specifically, bodybuilding products are being identified as a frequent cause of drug-induced liver injury. We present a case of a 20-year-old Hispanic male who presented with acute nausea and vomiting accompanied by severe right upper quadrant abdominal pain, shivering, and shortness of breath. Laboratory data pointed to mixed cholestatic and hepatocellular damage, and after exclusion of known alternate etiologies, the patient was diagnosed with acute drug-induced liver injury secondary to the use of "Friction," a bodybuilding supplement. Treatment with N-acetylcysteine (NAC) 20% oral solution was initiated empirically at a dose of 4000 mg [DOSAGE ERROR CORRECTED] (70 mg/kg) every 4 hours and was continued once the diagnosis was made. Within 48 hours of admission to our hospital, the patient began to show clinical resolution of right abdominal pain and tolerance to oral diet associated with a significant decline toward normal in his liver function tests and coagulopathy. The WHO-UMC causality assessment system suggested a "certain causality" between exposure to the supplement and the acute liver injury. In the event of suspected drug-induced liver injury, treatment with NAC should be considered given its favorable risk-benefit profile.
Late extensive intravenous administration of N-acetylcysteine can reverse hepatic failure in acetaminophen overdose
Acetaminophen is a commonly used analgesic and has been shown to be a main cause of drug-induced liver failure. N-acetylcysteine (NAC) should be employed as the antidote in case of acetaminophen poisoning within the first 8-10 hours. Oral administration of NAC is universally recommended and due to the adverse effects, the intravenous administration of the agent is reserved for patients with oral intolerance and severe complications. We here report an 18-year-old man with severe liver failure due to a huge ingestion of acetaminophen, who was taken into the Loghman Hakim Hospital Poison Center 72 hours after attempted suicide. Regarding the poor prognostic clues as his level of consciousness and impaired liver functions, an extensive intravenous regimen of NAC was started. The patient survived the condition with an additional intravenous administration of NAC past the first 72 hours of treatment. We discuss that even in late phases of intoxication; high-dose intravenous NAC can serve a substantial improvement.
Paracetamol overdose: the liver unit perspective
Liver failure resulting from deliberate or accidental paracetamol overdose continues to be an important reason for referral to liver transplant centres. Severe hepatic dysfunction often appears 72-96 h after overdose. Liver injury can be prevented by timely administration of the specific antidote, N-acetylcysteine. Unfortunately, administration of N-acetylcysteine is frequently delayed due to late presentation or late administration. While N-acetylcysteine works best if given within 8 h of overdose, it is beneficial at any time period and should always be given if there is concern about significant overdose, irrespective of interval from time of ingestion. Early discussion with liver transplant unit is suggested if there is any doubt or evidence of liver failure.
Successful treatment of acetaminophen overdose associated with hepatic failure
Acetaminophen is the most widely used antipyretic and analgesic drug in the world. Acetaminophen poisoning and the following hepatic failure are not rare and are the most common indications of liver transplantation in the USA and Europe. In this case report, the patient was a 25-year old woman with hepatic failure who was brought to Loghman-Hakim Poison Centre 24 hours after attempted suicide with 100 tablets of acetaminophen, 325 mg. She was treated with N-acetylcysteine (NAC) and discharged from the hospital 12 days after admission and followed up for 1 month. In conclusion, acetaminophen poisoning should be considered in the differential diagnoses of hepatic failure. In acetaminophen-induced hepatic damage the administration of NAC must always be considered even after 24 hours of overdose.
Paracetamol self-poisoning: when oral N-acetylcysteine saves life? a case report
Paracetamol is the most widely drug involved in accidental paediatric exposures and deliberate self-poisoning cases because of its availability. N-acetyl cystein is the main treatment for this poisoning. We report a case of a 24-year-old Arab female who has deliberately ingested 100 tablets of 500 mg paracetamol each (50g). Her first examination was normal. She has received oral N-acetyl cystein (NAC) 6 hours after the ingestion. Serum paracetamol level done 18 hours post ingestion was 900 mg/l. On review the next days, she did not develop any symptoms of liver failure. However, due to the massive paracetamol ingestion associated with high serum paracetamol levels, oral NAC was continued for 3 days. The patient was discharged well on the fifth day of hospitalization. Our patient has ingested one of the highest paracetamol overdose (50g) with the highest paracetamol blood levels ever reported in medical literature. She was treated, six hours after ingestion, with oral NAC for 3 days without any side effects.
Use of N-Acetylcysteine in Amphetamine-Induced Acute Liver Failure
Acute liver failure (ALF) is a serious complication of many drugs. Amongst recreational drugs, cocaine, amphetamines and ecstasy (methylenedioxymethamphetamine) have been known to cause ALF as a complication. However, the true effects and management on the liver of such cases have not been well reported and treatment of such conditions needs prompt action. N-acetylcysteine (NAC) is a known hepatoprotective agent but remains controversial in the use of recreational drug-induced acute liver injury. We present a case of ALF secondary to amphetamine ingestion, with a rapid recovery after administration of intravenous NAC.
N-Acetylcysteine (NAC): Impacts on Human Health
N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC's relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.
N-acetylcysteine in non-acetaminophen-induced acute liver failure: a systematic review and meta-analysis of prospective studies
Introduction: There are discordant reports on N-acetylcysteine (NAC) efficacy in non-acetaminophen acute liver failure (ALF). Aim: To determine whether NAC is beneficial in non-acetaminophen ALF. Material and methods: We performed a systemic review and meta-analysis of published data to address the question. PubMed and MEDLINE were searched using the terms non-acetylcysteine and ALF due to non-acetaminophen, viral infection, drug-induced or autoimmune hepatitis. The primary outcome was overall mortality. Secondary outcomes were transplant-free survival and length of hospital stay. Risk ratios were calculated using a random model for meta-analysis. Results: A total of 672 patients were included in this meta-analysis from 5 prospective studies (NAC group: n = 334; control group: n = 338). Viral hepatitis (45.8% vs. 32.8%) followed by drug-induced liver injury (24.6% vs. 27.5%), indeterminate cause (13.2% vs. 21.6%) and autoimmune hepatitis (6.6% vs. 8.9%) were the most common etiologies of ALF in the treatment group and control group respectively. Treatment with N-acetylcysteine improved the transplant-free survival significantly (55.1% vs. 28.1%; RR = 0.56; 95% CI: 0.33-0.94) whereas the overall survival was not improved with NAC (71% vs. 59.8%; RR = 0.73; 95% CI: 0.48-1.09). The NAC treatment was associated with shorter hospital stay (standard difference in means (SMD) = -1.62; 95% CI: -1.84 to -1.40, p < 0.001). Conclusions: The treatment of patients with acute liver failure with N-acetylcysteine improved transplant-free survival and length of stay.
The Roles of Antidotes in Emergency Situations
Management of the acutely poisoned patient requires supportive care and timely administration of antidotes to minimize ongoing toxicity and mortality. New applications for old antidotes include utilization of methylene blue and hydroxocobalamin in vasoplegia. Fomepizole is also being evaluated as a potential adjunct in acetaminophen toxicity. Other advancements include individualized acetylcysteine dosing regimens for acetaminophen toxicity and carnitine supplementation in valproic acid toxicity. Additional antidote considerations include administration of lipid emulsion in lipophilic xenobiotic exposure not responsive to standard resuscitative modalities. These expert recommendations provide guidance for providers caring for the acutely poisoned patient.
Use of N-Acetylcysteine in Amphetamine-Induced Acute Liver Failure
Acute liver failure (ALF) is a serious complication of many drugs. Amongst recreational drugs, cocaine, amphetamines and ecstasy (methylenedioxymethamphetamine) have been known to cause ALF as a complication. However, the true effects and management on the liver of such cases have not been well reported and treatment of such conditions needs prompt action. N-acetylcysteine (NAC) is a known hepatoprotective agent but remains controversial in the use of recreational drug-induced acute liver injury. We present a case of ALF secondary to amphetamine ingestion, with a rapid recovery after administration of intravenous NAC.
Targeting Sirt1, AMPK, Nrf2, CK2, and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass
There is a vast pre-clinical literature suggesting that certain nutraceuticals have the potential to aid the preservation of bone mass in the context of estrogen withdrawal, glucocorticoid treatment, chronic inflammation, or aging. In an effort to bring some logical clarity to these findings, the signaling pathways regulating osteoblast, osteocyte, and osteoclast induction, activity, and survival are briefly reviewed in the present study. The focus is placed on the following factors: the mechanisms that induce and activate the RUNX2 transcription factor, a key driver of osteoblast differentiation and function; the promotion of autophagy and prevention of apoptosis in osteoblasts/osteoclasts; and the induction and activation of NFATc1, which promotes the expression of many proteins required for osteoclast-mediated osteolysis. This analysis suggests that the activation of sirtuin 1 (Sirt1), AMP-activated protein kinase (AMPK), the Nrf2 transcription factor, and soluble guanylate cyclase (sGC) can be expected to aid the maintenance of bone mass, whereas the inhibition of the serine kinase CK2 should also be protective in this regard. Fortuitously, nutraceuticals are available to address each of these targets. Sirt1 activation can be promoted with ferulic acid, N1-methylnicotinamide, melatonin, nicotinamide riboside, glucosamine, and thymoquinone. Berberine, such as the drug metformin, is a clinically useful activator of AMPK. Many agents, including lipoic acid, melatonin, thymoquinone, astaxanthin, and crucifera-derived sulforaphane, can promote Nrf2 activity. Pharmacological doses of biotin can directly stimulate sGC. Additionally, certain flavonols, notably quercetin, can inhibit CK2 in high nanomolar concentrations that may be clinically relevant. Many, though not all, of these agents have shown favorable effects on bone density and structure in rodent models of bone loss. Complex nutraceutical regimens providing a selection of these nutraceuticals in clinically meaningful doses may have an important potential for preserving bone health. Concurrent supplementation with taurine, N-acetylcysteine, vitamins D and K2, and minerals, including magnesium, zinc, and manganese, plus a diet naturally high in potassium, may also be helpful in this regard.
Use of acetylcysteine as the life-saving antidote in Amanita phalloides (death cap) poisoning. Case report on 11 patients
alpha-Amanitin is an amatoxin known to produce deleterious effects on the liver and the kidneys, when circulating in the blood. It is produced by a particular kind of mushroom called amanita phalloides. Therapeutic options employed to treat mushroom intoxication, such as haemodiaperfusion on activated charcoal, high dosages of penicillin G, oral charcoal, etc., very often failed to act properly and liver transplantation (when a graft is available) appeared to be the only solution. In recent years, as suggest by some authors, it has been postulated that the oxidant effects of alpha-amanitin could be counteracted by the use of antioxidants such as silibinin. High dosages of N-acetyl-cysteine (CAS 616-91-1, NAC), already used as antioxidant in paracetamol poisoning, were successfully used in our Intensive Care Unit (ICU) in the treatment of Amanita phalloides poisoning. In the last two years, 11 patients (mean age of 5-72 = 38.5) were treated for Amanita phalloides poisoning of various degrees, with a protocol (haemodiaperfusion on activated charcoal, high dosages of penicillin G, etc.) further comprehending NAC (fluimucil). All the patients recovered successfully but one (bearing precedent liver disease) needed liver transplantation. Daily monitoring of liver enzymes, creatinine, coagulation, LDH, blood and urinary alpha-amanitin were used to screen the progresses of the patients.
N-acetylcysteine as a treatment for amatoxin poisoning: a systematic review
Introduction: Amatoxin leads to the majority of deaths by mushroom poisoning around the world. Amatoxin causes gastrointestinal disturbances and multiple organ dysfunction, including liver and renal failure. As a potential treatment for amatoxin poisoning, N-acetylcysteine (NAC) has been used for decades but its benefit is still unproven.Objectives: We undertook a systematic review to evaluate the performance and safety of N-acetylcysteine on patients suffering amatoxin intoxication.Methods: We searched Pubmed, EMBASE, CENTRAL and SinoMed databases, from inception to August 31, 2019. Articles were eligible if there were five or more patients with amatoxin poisoning and N-acetylcysteine was included in the therapeutic regimen. Mortality rate including liver transplant cases (MRLTi) was the primary outcome. Mortality rate not including liver transplant cases, liver and renal function, clinical complications, as well as any adverse reactions to intravenous NAC were secondary outcomes.Results: Thirteen studies with a total of 506 patients were included. The MRLTi of amatoxin-poisoning patients with NAC treatment was 11% (57/506), and a MRLTe of 7.9% (40/506) and a liver transplantation rate of 4.3% (22/506). Transaminase concentrations generally peaked around 3 days after ingestion, prothrombin time/International Normalized Ratio (PT/INR) generally worsened during the first 3-4 days after ingestion before returning to normal four to 7 days after ingestion, and Factor V levels normalized in about 4-5 days after ingestion in patients treated with NAC. Renal failure was reported in 3% (3/101) and acute kidney injury was reported in 19% (5/27). Gastrointestinal bleeding occurred in 21% (15/71). Anaphylactoid reactions were the principle adverse reaction to NAC treatment in amatoxin-poisoning patients with an incidence of 5% (4/73).Conclusions: NAC treatment combined with other therapies appears to be beneficial and safe in patients with amatoxin poisoning. Until further data emerge, it is reasonable to use NAC in addition to other treatments for amatoxin poisoning.
Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits
N-acetyl-l-cysteine (NAC) has long been used therapeutically for the treatment of acetaminophen (paracetamol) overdose, acting as a precursor for the substrate (l-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in the protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting. This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an "antioxidant". Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in the interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.
A minireview on N-acetylcysteine: An old drug with new approaches
N-acetylcysteine (NAC), a cysteine pro-drug and glutathione precursor has been used in therapeutic practices for several decades, as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication. There is a growing interest concerning the beneficial effects of NAC against the early stages of toxicity-induced by pesticides. Nevertheless, the mechanisms underlying the therapeutic and clinical applications of NAC are not fully understood. In this review we aimed to focus on the protective effects of NAC against oxidative stress caused by pesticide in many organs. The possible mechanisms of action may be associated to its antioxidant properties. The anti-oxidative activity of NAC has been attributed to the fast reaction with free radicals as well as the restitution of reduced glutathione (GSH).
Evaluation of the antioxidant properties of N-acetylcysteine in human platelets: prerequisite for bioconversion to glutathione for antioxidant and antiplatelet activity
N-Acetylcysteine (NAC) is a frequently used "antioxidant" in vitro, but the concentrations applied rarely correlate with those encountered with oral dosing in vivo. Here, we investigated the in vitro antioxidant and antiplatelet properties of NAC at concentrations (10-100 microM) that are achievable in plasma with tolerable oral dosing. The impact of NAC pretreatment (2 hours) on aggregation of platelets from healthy volunteers in response to thrombin and adenosine diphosphate and on platelet-derived nitric oxide (NO) was examined. NAC was found to be a weak reducing agent and a poor antioxidant compared with glutathione (reduced form) (GSH). However, platelets treated with NAC showed enhanced antioxidant activity and depression of reactive oxygen species generation associated with increases in intraplatelet GSH levels. An approximately 2-fold increase in NO synthase-derived nitrite was observed with 10 microM NAC treatment, but the effect was not concentration dependent. Finally, NAC significantly reduced both thrombin-induced and adenosine diphosphate-induced platelet aggregation. NAC should be considered a weak antioxidant that requires prior conversion to GSH to convey antioxidant and antithrombotic benefit at therapeutically relevant concentrations. Our results suggest that NAC might be an effective antiplatelet agent in conditions where increased oxidative stress contributes to heightened risk of thrombosis but only if the intraplatelet machinery to convert it to GSH is functional.
N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why
The main molecular mechanisms explaining the well-established antioxidant and reducing activity of N-acetylcysteine (NAC), the N-acetyl derivative of the natural amino acid l-cysteine, are summarised and critically reviewed. The antioxidant effect is due to the ability of NAC to act as a reduced glutathione (GSH) precursor; GSH is a well-known direct antioxidant and a substrate of several antioxidant enzymes. Moreover, in some conditions where a significant depletion of endogenous Cys and GSH occurs, NAC can act as a direct antioxidant for some oxidant species such as NO2 and HOX. The antioxidant activity of NAC could also be due to its effect in breaking thiolated proteins, thus releasing free thiols as well as reduced proteins, which in some cases, such as for mercaptoalbumin, have important direct antioxidant activity. As well as being involved in the antioxidant mechanism, the disulphide breaking activity of NAC also explains its mucolytic activity which is due to its effect in reducing heavily cross-linked mucus glycoproteins. Chemical features explaining the efficient disulphide breaking activity of NAC are also explained.
Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 19 (COVID-19) has numerous risk factors leading to severe disease with high mortality rate. Oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels seems to be a common pathway associated with the high COVID-19 mortality. GSH is a unique small but powerful molecule paramount for life. It sustains adequate redox cell signaling since a physiologic level of oxidative stress is fundamental for controlling life processes via redox signaling, but excessive oxidation causes cell and tissue damage. The water-soluble GSH tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) is present in the cytoplasm of all cells. GSH is at 1-10 mM concentrations in all mammalian tissues (highest concentration in liver) as the most abundant non-protein thiol that protects against excessive oxidative stress. Oxidative stress also activates the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 to regulate the expression of genes that control antioxidant, inflammatory and immune system responses, facilitating GSH activity. GSH exists in the thiol-reduced and disulfide-oxidized (GSSG) forms. Reduced GSH is the prevailing form accounting for >98% of total GSH. The concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell and its alteration is related to various human pathological processes including COVID-19. Oxidative stress plays a prominent role in SARS-CoV-2 infection following recognition of the viral S-protein by angiotensin converting enzyme-2 receptor and pattern recognition receptors like toll-like receptors 2 and 4, and activation of transcription factors like nuclear factor kappa B, that subsequently activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) expression succeeded by ROS production. GSH depletion may have a fundamental role in COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of COVID-19 disease and increasing GSH levels may prevent and subdue the disease. The life value of GSH makes for a paramount research field in biology and medicine and may be key against SARS-CoV-2 infection and COVID-19 disease.
Safety of N-Acetylcysteine at High Doses in Chronic Respiratory Diseases: A Review
N-Acetylcysteine (NAC) is widely used in respiratory medicine, with a maximum licensed dose in chronic use of 600 mg/day; however, some clinical trials have studied the efficacy of NAC at higher doses. The aim of this review was to evaluate the adverse effects profile of NAC at higher than the standard dose in chronic respiratory diseases to establish a risk–benefit ratio in increasing the daily dose; therefore, studies using NAC at a dose of at least 600 mg/day were selected. Forty-one articles where NAC has been used at 600 mg and above, up to 3000 mg/day, and with a specific report on safety, were considered. Most of the studies used oral NAC and were conducted on patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, chronic bronchitis and cystic fibrosis. In general, the safety profile was similar at both the high and standard doses with the oral formulation; gastrointestinal symptoms were reported but they were no more common than in the control group.
Iron, Neuroinflammation and Neurodegeneration
Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.
Mitochondrial modulators for obsessive-compulsive and related disorders: a systematic review and meta-analysis
It remains unclear whether mitochondrial modulators (MMs) are beneficial in the treatment of obsessive-compulsive and related disorders. Thus, in an attempt to answer this clinical question, we performed a systematic review and a random-effects meta-analysis of double-blind, randomized, placebo-controlled trials. The primary outcome was change in overall symptoms as measured using standardized rating scales. Other outcomes were response to treatment; improvement in anxiety-related scales scores, depression-related scale scores, Clinical Global Impression Severity Scale (CGI-S) scores, and Sheehan Disability Scale (SDS) scores; all-cause discontinuation; and individual adverse events. We calculated the standardized mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. We reviewed 17 studies (n = 629, 72.62% female; duration = 2-20 weeks; mean age = 30.47 years) of MMs: eicosapentaenoic acid (K = 1), folic acid (K = 1), lithium (K = 1), N-acetylcysteine (K = 10), inositol (K = 3), and silymarin (K = 1). MMs outperformed placebo in overall improvement in symptoms (p < 0.01) and in improving anxiety-related scale scores (p = 0.05). Subgroup analysis of individual MMs revealed that although overall symptoms were better improved by N-acetylcysteine (p < 0.01) and lithium (p = 0.04), no MMs outperformed placebo in terms of improving anxiety-related scale scores. Neither pooled nor individual MMs outperformed placebo in improving response to treatment, depression-related scale scores, CGI-S scores, SDS scores, or all-cause discontinuation. N-acetylcysteine was no more associated with a higher incidence of individual adverse events including gastrointestinal symptoms, than placebo. In conclusion, N-acetylcysteine was beneficial in the treatment of obsessive-compulsive and related disorders. However, further study with larger samples is necessary to confirm this finding.
N-Acetylcysteine in the Treatment of Excoriation Disorder: A Randomized Clinical Trial
Importance: Excoriation (skin-picking) disorder (SPD) is a disabling, underrecognized condition in which individuals repeatedly pick at their skin, leading to noticeable tissue damage. To date, there has been no clearly effective pharmacologic or psychological treatment for SPD. Objective: To determine whether N-acetylcysteine, an amino acid that appears to restore extracellular glutamate concentration in the nucleus accumbens, will be more effective than placebo in reducing compulsive picking behavior. Design, setting, and participants: A randomized, double-blind trial was conducted at ambulatory care centers at the University of Minnesota (September 12, 2011, to June 15, 2012) and the University of Chicago (December 17, 2012, to June 26, 2015) and included 66 adults with SPD. Data analysis was performed from July 16 to September 9, 2015. Interventions: N-acetylcysteine (dosing range, 1200-3000 mg/d) or placebo was administered for 12 weeks. Main outcomes and measures: Participants were assessed using measures of skin-picking severity, including the modified Yale-Brown Obsessive Compulsive Scale (NE-YBOCS); total scores range from 0 to 40, with higher scores reflective of greater symptom severity. Another measure of skin-picking severity was the Clinical Global Impression-Severity Scale; total scores range from 1 (normal) to 7 (among the most extremely ill patients), and improvement ratings range from 7 (very much worse) to 1 (very much improved). Selected cognitive tasks included the Intra-dimensional/Extra-dimensional Shift Task to examine cognitive flexibility, with the key outcome measures being the number of errors, and Stop-Signal Reaction Time task, which evaluates motor inhibition. Outcomes were examined using a linear mixed-effects model. Results: Of the 66 participants (31 randomized to placebo and 35 to N-acetylcysteine) included in the analysis, 59 (89%) were women; mean (SD) age was 34.8 (11.0) years. Compared with placebo, N-acetylcysteine treatment was associated with significant improvements in the NE-YBOCS. At baseline, NE-YBOCS scores were 18.9 and 17.9 for the treatment and placebo groups, respectively, and at 12 weeks, the scores were 11.5 and 14.1 for the treatment and placebo groups, respectively (P = .048). For the Clinical Global Impression-Severity scale, baseline scores were 3.5 and 4.0 and 12-week scores were 3.0 and 4.2, respectively (P = .003). These effects were significant both in terms of treatment by time interactions and post hoc tests at 1 or more individual time points. At the study's end point, of the 53 participants who completed the study, 15 of the 32 participants (47%) receiving N-acetylcysteine were much or very much improved compared with 4 of the 21 participants (19%) receiving placebo (P = .03). There were no significant differences between the active and placebo arms in terms of psychosocial functioning. Conclusions and relevance: N-acetylcysteine treatment resulted in significant reductions in skin-picking symptoms and was well tolerated. The glutamate system may prove a beneficial target in treating SPD and other compulsive behaviors. Trial registration: clinicaltrials.gov Identifier: NCT01063348.
N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study
Context: Trichotillomania is characterized by repetitive hair pulling that causes noticeable hair loss. Data on the pharmacologic treatment of trichotillomania are limited to conflicting studies of serotonergic medications. N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the nucleus accumbens and, therefore, offers promise in the reduction of compulsive behavior. Objective: To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania. Design: Twelve-week, double-blind, placebo-controlled trial. Setting: Ambulatory care center. Patients: Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years). Interventions: N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks. Main outcome measures: Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the Clinical Global Impression scale, the Psychiatric Institute Trichotillomania Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined using analysis of variance modeling analyses and linear regression in an intention-to-treat population. Results: Patients assigned to receive N-acetylcysteine had significantly greater reductions in hair-pulling symptoms as measured using the Massachusetts General Hospital Hair Pulling Scale (P < .001) and the Psychiatric Institute Trichotillomania Scale (P = .001). Fifty-six percent of patients "much or very much improved" with N-acetylcysteine use compared with 16% taking placebo (P = .003). Significant improvement was initially noted after 9 weeks of treatment. Conclusions: This study, the first to our knowledge that examines the efficacy of a glutamatergic agent in the treatment of trichotillomania, found that N-acetylcysteine demonstrated statistically significant reductions in trichotillomania symptoms. No adverse events occurred in the N-acetylcysteine group, and N-acetylcysteine was well tolerated. Pharmacologic modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors. Trial registration: clinicaltrials.gov Identifier: NCT00354770.
Dramatic Improvement of Trichotillomania with 6 Months of Treatment With N-Acetylcysteine
We present a case of a 17-year-old male with recurrent hair twirling resulting in patchy alopecia, who improved dramatically on N-acetylcysteine (NAC). Trichotillomania is characterized by repetitive hair pulling, twisting, or twirling and can vary from a mild habit to an impulse-control disorder. Standard treatment for pediatric trichotillomania includes cognitive behavioral therapy or medical therapy with selective serotonin reuptake inhibitors. NAC is a more recently utilized, safe, and well-tolerated over-the-counter supplement with some evidence of benefit for habitual skin and hair disorders. For this patient, we recommended 600 mg twice daily, increasing to 1200 mg twice daily as tolerated. After 6 months, our patient reported decreased desire to twirl his hair and his hair had almost completely regrown. Pediatricians who see patients with trichotillomania or other habitual disorders can consider treating these patients with NAC given its potential benefits and favorable side effect profile.
The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders
N-acetyl-L-cysteine (NAC) is a compound of increasing interest in the treatment of psychiatric disorders. Primarily through its antioxidant, anti-inflammatory, and glutamate modulation activity, NAC has been investigated in the treatment of neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, anxiety disorders, obsessive compulsive-related disorders, substance-use disorders, neurocognitive disorders, and chronic pain. Whilst there is ample preclinical evidence and theoretical justification for the use of NAC in the treatment of multiple psychiatric disorders, clinical trials in most disorders have yielded mixed results. However, most studies have been underpowered and perhaps too brief, with some evidence of benefit only after months of treatment with NAC. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders. Future research with well-powered studies that are of sufficient length will be critical to better understand the utility of NAC in the treatment of psychiatric disorders.
N-acetylcysteine as a new prominent approach for treating psychiatric disorders
N-acetylcysteine (NAC) is a well-known and safe mucolytic agent, also used in patients with paracetamol overdose. In addition to these effects, recent preclinical and clinical studies have shown that NAC exerts beneficial effects on different psychiatric disorders. Many potential mechanisms have been proposed to underlie the therapeutic effects of NAC, including the regulation of several neurotransmitters, oxidative homeostasis, and inflammatory mediators. In this paper, we summarize the current knowledge on the ability of NAC to ameliorate symptoms and neuropathologies related to different psychiatric disorders, including attention deficit hyperactivity disorder, anxiety, bipolar disorder, depression, obsessive-compulsive disorder, obsessive-compulsive-related disorder, posttraumatic stress disorder, and schizophrenia. Although preclinical studies have shown a positive effect of NAC on animal models of psychiatric disorders, the clinical efficacy of NAC is not fully established. NAC remains a strong candidate for adjunct treatment for many psychiatric disorders, but additional preclinical and clinical studies are needed.
Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review
N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.
Subchronic N-acetylcysteine Treatment Decreases Brain Kynurenic Acid Levels and Improves Cognitive Performance in Mice
The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA's key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA's bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.
N-Acetylcysteine Inhibits Kynurenine Aminotransferase II
The tryptophan metabolite kynurenic acid (KYNA) may play an important role in normal and abnormal cognitive processes, most likely by interfering with α7 nicotinic and NMDA receptor function. KYNA is formed from its immediate precursor kynurenine either by non-enzymatic oxidation or through irreversible transamination by kynurenine aminotransferases. In the mammalian brain, kynurenine aminotransferase II (KAT II) is the principal enzyme responsible for the neosynthesis of rapidly mobilizable KYNA, and therefore constitutes an attractive target for pro-cognitive interventions. N-acetylcysteine (NAC), a brain-penetrant drug with pro-cognitive efficacy in humans, has been proposed to exert its actions by increasing the levels of the anti-oxidant glutathione (GSH) in the brain. We report here that NAC, but not GSH, inhibits KAT II activity in brain tissue homogenates from rats and humans with IC50 values in the high micromolar to low millimolar range. With similar potency, the drug interfered with the de novo formation of KYNA in rat brain slices, and NAC was a competitive inhibitor of recombinant human KAT II (Ki: 450 μM). Furthermore, GSH failed to S-glutathionylate recombinant human KAT II treated with the dithiocarbamate drug disulfiram. Shown by microdialysis in the prefrontal cortex of rats treated with kynurenine (50 mg/kg, i.p.), peripheral administration of NAC (500 mg/kg, i.p., 120 and 60 min before the application of kynurenine) reduced KYNA neosynthesis by ∼50%. Together, these results suggest that NAC exerts its neurobiological effects at least in part by reducing cerebral KYNA formation via KAT II inhibition.
Kynurenic acid and kynurenine aminotransferases in retinal aging and neurodegeneration
The kynurenine aminotransferases (KATs) KAT I and KAT II are pivotal to the synthesis of kynurenic acid (KYNA), the only known endogenous glutamate receptor antagonist and neuroprotectant. KAT I and II have been found in avian, rodent, and human retina. Expression of KAT I in Müller cell endfeet and KAT II in retinal ganglion cells has been documented. Developmental changes in KAT expression and KYNA concentration in the avian and rodent retina have also been found. Studies of retinal neurodegeneration have shown alterations in KYNA synthesis in the retina in response to retinal ganglion cell loss. In DBA/2J mice, a model of ocular hypertension, an age-dependent decrease of retinal KYNA and KATs was found. In the corpora amylacea in the human retina intensive KAT I and II immunoreactivity was demonstrated. In summary, these findings point to the potential involvement of KYNA in the mechanisms of retinal aging and neurodegeneration.
L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry
There is an urgent need for development of drugs that are able to reverse the adverse effects of opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes the effects of bolus injections of N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) on ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) and analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion of fentanyl (1 μg/kg/min, IV). Fentanyl infusion elicited pronounced disturbances in (1) ventilatory parameters (e.g., decreases in frequency of breathing, tidal volume and minute ventilation), (2) ABG chemistry (decreases in pH, pO2, sO2 with increases in pCO2), (3) A-a gradient (increases that were consistent with reduced alveolar gas exchange), and (4) sedation and analgesia. Bolus injections of L-NAC given 60 and 90 min after start of fentanyl infusion elicited rapid and sustained reversal of the deleterious effects of fentanyl infusion on ventilatory parameters and ABG chemistry, whereas they did not affect the sedative or analgesic effects of fentanyl. Systemic L-NAC is approved for human use, and thus our findings raise the possibility that this biologically active thiol may be an effective compound to combat opioid-induced respiratory depression in human subjects.
Role of kynurenines in the central and peripheral nervous systems
Kynurenine (KYN) is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. KYN is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier (BBB). In the brain, KYN can be converted to two other components of the pathway: the neurotoxic quinolinic acid (QUIN) and the neuroprotective kynurenic acid (KYNA). QUIN is probably the most widely studied metabolite of KYN, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate (NMDA) receptor complex, a type of glutamate receptor. KYNA is another metabolite of KYN; its synthesis is catalysed by KYN aminotransferases. This is the only known endogenous NMDA receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, KYNA non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid (EAA) receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the EAA receptor antagonist KYNA can exert a therapeutic effect in these neurological disorders. It has been established that KYNA has only a very limited ability to cross the BBB. Other KYNA derivatives have been synthesised (e.g. glucosamine-KYNA, 4-chloro-KYNA and 7-chloro-KYNA), which are well transported across the BBB and act on the glutamate receptors. Moreover, it has been demonstrated that probenecid, a known inhibitor of the transport of organic acids (e.g. KYNA), increases the cerebral concentration of KYNA. There is another new perspective to the maintenance of a high level of KYNA in the brain: the use of enzyme inhibitors, which can block the synthesis of the neurotoxic QUIN. These are some of the most promising possibilities as novel therapeutic strategies for the treatment of neurodegenerative diseases, in which the hyperactivation of amino acid receptors could be involved. The presence and importance of KYN derivatives in the periphery are also discussed in the light of recent publications.
Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases
N-acetylcysteine (NAC), which is an acetylated cysteine compound, has aroused scientific interest for decades due to its important medical applications. It also represents a nutritional supplement in the human diet. NAC is a glutathione precursor and shows antioxidant and anti-inflammatory activities. In addition to the uses quoted in the literature, NAC may be considered helpful in therapies to counteract neurodegenerative and mental health diseases. Furthermore, this compound has been evaluated for its neuroprotective potential in the prevention of cognitive aging dementia. NAC is inexpensive, commercially available and no relevant side effects were observed after its administration. The purpose of this paper is to give an overview on the effects and applications of NAC in Parkinson's and Alzheimer's disorders and in neuropathic pain and stroke.
Oxidative Stress in Chronic Obstructive Pulmonary Disease
There is a marked increase in oxidative stress in the lungs of patients with COPD, as measured by increased exhaled 8-isoprostane, ethane, and hydrogen peroxide in the breath. The lung may be exposed to exogenous oxidative stress from cigarette smoking and indoor or outdoor air pollution and to endogenous oxidative stress from reactive oxygen species released from activated inflammatory cells, particularly neutrophils and macrophages, in the lungs. Oxidative stress in COPD may be amplified by a reduction in endogenous antioxidants and poor intake of dietary antioxidants. Oxidative stress is a major driving mechanism of COPD through the induction of chronic inflammation, induction of cellular senescence and impaired autophagy, reduced DNA repair, increased autoimmunity, increased mucus secretion, and impaired anti-inflammatory response to corticosteroids. Oxidative stress, therefore, drives the pathology of COPD and may increase disease progression, amplify exacerbations, and increase comorbidities through systemic oxidative stress. This suggests that antioxidants may be effective as disease-modifying treatments. Unfortunately, thiol-based antioxidants, such as N-acetylcysteine, have been poorly effective, as they are inactivated by oxidative stress in the lungs, so there is a search for more effective and safer antioxidants. New antioxidants in development include mitochondria-targeted antioxidants, NOX inhibitors, and activators of the transcription factor Nrf2, which regulates several antioxidant genes.
N-acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions
Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has shown its persistent pandemic strength. This viral infectivity, kinetics, and the mechanisms of its actions in human body are still not completely understood. In addition, the infectivity and COVID-19 severity reportedly differ with patient's gender with men being more susceptible to the disease. Thus, different studies have also suggested the adverse impact of COVID-19 on male reproductive functions, mainly emphasizing on high expressions of angiotensin-converting enzyme 2 (ACE2) in the testes that allows the viral entry into the cells. Main body: The N-acetylcysteine (NAC), a potent therapeutic agent of COVID-19, may be effective in reducing the impairing impacts of this disease on male reproductive functions. NAC acts as mucolytic agent by reducing sulfide bonds in the cross-linked glycoprotein matrix in mucus owing to its free sulfhydryl group. Since NAC also breaks the viral disulfide bonds required for the host cell invasion, it may help to prevent direct SARS-CoV-2 invasion into the testicular cells as well. NAC also acts as a potent anti-inflammatory and antioxidant, directly scavenging reactive oxygen species (ROS) and regulating the redox state by maintaining the thiol pool being a precursor of cysteine (an essential substrate for glutathione synthesis). Since it is suggested that male reproductive impairment in COVID-19 patient may be caused by secondary immune responses owing to systemic inflammation and OS, the anti-inflammatory and antioxidant properties of NAC explained above may attribute in protecting the male reproduction functions from these COVID-19-mediated damages. Conclusion: This article explains the mechanisms how NAC treatment for COVID-19 may prevent the infection-mediated disruptions in male reproduction.
The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione
Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. Taken together, these data indicate that Cys-488 in spike RBD is required for SARS-CoV-2 spike functions and infectivity, and could be a target of anti-SARS-CoV-2 therapeutics.
N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis
Objective: To assess the utility of N-acetylcysteine administration for depressive symptoms in subjects with psychiatric conditions using a systematic review and meta-analysis. Data sources: A computerized literature search was conducted in MEDLINE, Embase, the Cochrane Library, SciELO, PsycINFO, Scopus, and Web of Knowledge. No year or country restrictions were used. The Boolean terms used for the electronic database search were (NAC OR N-acetylcysteine OR acetylcysteine) AND (depression OR depressive OR depressed) AND (trial). The last search was performed in November 2014. Study selection: The literature was searched for double-blind, randomized, placebo-controlled trials using N-acetylcysteine for depressive symptoms regardless of the main psychiatric condition. Using keywords and cross-referenced bibliographies, 38 studies were identified and examined in depth. Of those, 33 articles were rejected because inclusion criteria were not met. Finally, 5 studies were included. Data extraction: Data were extracted independently by 2 investigators. The primary outcome measure was change in depressive symptoms. Functionality, quality of life, and manic and anxiety symptoms were also examined. A full review and meta-analysis were performed. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% CIs were calculated. Results: Five studies fulfilled our inclusion criteria for the meta-analysis, providing data on 574 participants, of whom 291 were randomized to receive N-acetylcysteine and 283 to placebo. The follow-up varied from 12 to 24 weeks. Two studies included subjects with bipolar disorder and current depressive symptoms, 1 included subjects with MDD in a current depressive episode, and 2 included subjects with depressive symptoms in the context of other psychiatric conditions (1 trichotillomania and 1 heavy smoking). Treatment with N-acetylcysteine improved depressive symptoms as assessed by Montgomery-Asberg Depression Rating Scale and Hamilton Depression Rating Scale when compared to placebo (SMD = 0.37; 95% CI = 0.19 to 0.55; P < .001). Subjects receiving N-acetylcysteine had better depressive symptoms scores on the Clinical Global Impressions-Severity of Illness scale at follow-up than subjects on placebo (SMD = 0.22; 95% CI = 0.03 to 0.41; P < .001). In addition, global functionality was better in N-acetylcysteine than in placebo conditions. There were no changes in quality of life. With regard to adverse events, only minor adverse events were associated with N-acetylcysteine (OR = 1.61; 95% CI = 1.01 to 2.59; P = .049). Conclusions: Administration of N-acetylcysteine ameliorates depressive symptoms, improves functionality, and shows good tolerability.
N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas
Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as NR2a, MGLUR5, GLUR1, and GLUR2 in nucleus accumbens, and CAMK2, NR1, and GLUR2 in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.
Medical and Dietary Uses of N-Acetylcysteine
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.
Effect of dietary restriction and N-acetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats
The age-related changes of glutathione (GSH) levels and the effect of hypocaloric regimen and N-acetylcysteine (NAC) supplementation were investigated in intestinal mucosa and liver mitochondria of 28 months rats. Old rats exhibited lower proteins, GSH and protein sulphydrils (PSH) concentrations, higher GSH-peroxidase (GSH-Px) activity and protein carbonyl deposit, partial inhibition of succinate stimulated mitochondrial state III respiration and decreased mitochondrial nitrosothiols (RSNO) concentration. Lower electric potential and current intensity were found in the colonic mucosa. Old rats undergone hypocaloric regimen showed higher intestinal concentrations of GSH, lower oxidized protein accumulation and GSH-Px activity and higher mitochondrial RSNO levels. Mitochondrial state III respiration and intestinal transport were improved. NAC supplementation enhanced GSH and PSH levels in the ileal but not in the colonic mucosa, GSH and RSNO in liver mitochondria, while GSH-Px and protein carbonyls were decreased everywhere. Mitochondrial respiration ameliorated. In conclusion, ageing is characterized by a spread decrease of GSH concentrations, increased protein oxidation and decreased mitochondrial NO content. Hypocaloric diet ameliorated intestinal transport and, as well as NAC, was effective in enhancing GSH levels but at different extent according to the investigated districts. Both interventions reduced the age-associated increase of GSH-Px and protein carbonyls and improved mitochondrial respiration.
Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine
Ethanol intake depletes the mitochondrial pool of reduced glutathione (GSH) by impairing the transport of GSH from cytosol into mitochondria. S-Adenosyl-L-methionine (SAM) supplementation of ethanol-fed rats restores the mitochondrial pool of GSH. The purpose of the current study was to determine the effect of ethanol feeding on the kinetic parameters of mitochondrial GSH transport, the fluidity of mitochondria, and the effect of SAM on these changes. Male Sprague-Dawley rats were fed ethanol-liquid diet for 4 weeks supplemented with either SAM or N-acetylcysteine (NAC). SAM-supplementation of ethanol-fed rats restored the mitochondrial GSH pool but NAC administration did not. Kinetic studies of GSH transport in isolated mitochondria revealed two saturable, adenosine triphosphate (ATP)-stimulated components that were affected significantly by chronic ethanol feeding: lowering Vmax (0.22 and 1.6 in ethanol case vs. 0.44 and 2.7 nmol/15 sec/mg protein in controls) for both low and high affinity components with the latter showing an increased Km (15.5 vs. 8.9, mmol/L in ethanol vs. control). Mitochondria from SAM-supplemented ethanol-fed rats showed kinetic features of GSH transport similar to control mitochondria. Determination of membrane fluidity revealed an increased order parameter in ethanol compared with control mitochondria, which was restricted to the polar head groups of the bilayer and was prevented by SAM but not NAC supplementation of ethanol-fed rats. The changes elicited in mitochondria by ethanol were confined to the inner membrane; mitoplasts from ethanol-fed rats showed features similar to those of intact mitochondria such as impaired transport of GSH and increased order parameter. A different mitochondrial transporter, adenosine diphosphate (ADP)/ATP translocator, was unaffected by ethanol feeding. Furthermore, fluidization of mitochondria or mitoplasts from ethanol-fed rats by treatment with a fatty acid derivative restored their ability to transport GSH to control levels. Thus, ethanol-induced impaired transport of GSH into mitochondria is selective, mediated by decreased fluidity of the mitochondrial inner membrane, and prevented by SAM treatment.
Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.
The 3,4-Quinones of Estrone and Estradiol Are the Initiators of Cancer whereas Resveratrol and N-acetylcysteine Are the Preventers
This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.
N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks)
Objective: To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention. Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. This study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented. Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. These conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn's disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles. There are also a number of other conditions that may show benefit; however, the evidence is not as robust. Conclusion: The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.
Pharmacokinetics of N-acetylcysteine in man | SpringerLink
N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h. Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h. The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed. The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability.
N‐acetylcysteine replenishes glutathione in HIV infection - De Rosa - 2000 - European Journal of Clinical Investigation - Wiley Online Library
NAC treatment for 8 weeks safely replenishes whole blood GSH and T cell GSH in HIV-infected individuals. Thus, NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology, e.g. rheumatoid arthritis, Parkinson's disease, hepatitis, liver cirrhosis, septic shock and diabetes.
Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats - ScienceDirect
This study examined whether sucrose-rich diet (SRD)-induced hyperglycaemia, dyslipidemia and oxidative stress may be inhibited by N-acetylcysteine (C5H9–NO3S), an organosulfur from Allium plants. Male Wistar 40 rats were divided into four groups (n = 10): (C) given standard chow and water; (N) receiving standard chow and 2 mg/l N-acetylcysteine in its drinking water; (SRD) given standard chow and 30% sucrose in its drinking water; and (SRD-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water. After 30 days of treatment, SRD rats had obesity with increased abdominal circumference, hyperglycaemia, dyslipidemia and hepatic triacylglycerol accumulation. These adverse effects were associated with oxidative stress and depressed lipid degradation in hepatic tissue. The SRD adverse effects were not observed in SDR-N rats. N-Acetylcysteine reduced the oxidative stress, enhancing glutathione-peroxidase activity, and normalizing lipid hydroperoxyde, reduced glutathione and superoxide dismutase in hepatic tissue of SRD-N rats. The β-hydroxyacyl coenzyme-A dehydrogenase and citrate-synthase activities were increased in SRD-N rats, indicating enhanced lipid degradation in hepatic tissue as compared to SRD. SRD-N rats had reduced serum oxidative stress and diminished glucose, triacylglycerol, very-low-density lipoprotein (VLDL), oxidized low-density lipoprotein (ox-LDL) and cholesterol/high-density lipoprotein (HDL) ratio in relation to SRD. In conclusion, NAC offers promising therapeutic values in prevention of dyslipidemic profile and alleviation of hyperglycaemia in high-sucrose intake condition by improving antioxidant defences. N-Acetylcysteine had also effects preventing metabolic shifting in hepatic tissue, thus enhancing fat degradation and reducing body weight gain in conditions of excess sucrose intake. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection.
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