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CNS Drugs Mar 2023Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for... (Review)
Review
Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials.
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N-acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior, was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability, hyperactivity, and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence.
Topics: Humans; Acetylcysteine; Anti-Inflammatory Agents; Autism Spectrum Disorder; Celecoxib; Fatty Acids, Omega-3; Minocycline; Prednisolone; Randomized Controlled Trials as Topic; Immunologic Factors
PubMed: 36913130
DOI: 10.1007/s40263-023-00993-x -
Revista Brasileira de Terapia Intensiva Mar 2020To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained...
OBJECTIVE
To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained hypotension.
METHODS
Rats were subjected to sepsis induced by cecal ligation and puncture. Animals were divided into two groups: those with high and low plasma levels of interleukin-6. Following stratification, N-acetylcysteine plus deferoxamine or saline was administered to animals starting 3 and 12 hours after surgery. N-Acetylcysteine plus deferoxamine or placebo was administered within 12 hours of meeting the inclusion criteria in hypotensive patients.
RESULTS
N-Acetylcysteine plus deferoxamine increased survival in the cecal ligation and puncture model when administered 3 and 12 hours after sepsis induction. When dividing animals that received antioxidants using plasma interleukin-6 levels, the protective effect was observed only in those animals with high IL-6 levels. The antioxidant effect of N-acetylcysteine + deferoxamine was similar in the two groups, but a significant decrease in plasma interleukin-6 levels was observed in the high-interleukin-6-level group. Compared with patients treated with antioxidants in the low-interleukin-6 subgroup, those in the high-interleukin-6 subgroup had a lower incidence of acute kidney injury but were not different in terms of acute kidney injury severity or intensive care unit mortality.
CONCLUSION
Targeting antioxidant therapy to a high inflammatory phenotype would select a responsive population.
Topics: Acetylcysteine; Adult; Aged; Animals; Antioxidants; Deferoxamine; Humans; Male; Middle Aged; Prognosis; Rats; Rats, Wistar; Retrospective Studies; Sepsis; Treatment Outcome
PubMed: 32401970
DOI: 10.5935/0103-507x.20200016 -
BMC Oral Health Sep 2022This scoping review systematically summarized the available evidence about the efficacy of N-acetyl cysteine (NAC) as an intracanal antibacterial and/or... (Review)
Review
BACKGROUND
This scoping review systematically summarized the available evidence about the efficacy of N-acetyl cysteine (NAC) as an intracanal antibacterial and/or anti-inflammatory.
METHODS
PubMed, Scopus, Web of Science, and Google scholar search engines/databases were searched up to February 2022 to retrieve relevant studies. The studies were evaluated for eligibility criteria, and identifying relevant studies.
RESULTS
Out of 193 studies, 15 fulfilled the inclusion criteria and were processed for data extraction. Thirteen in vitro studies assessed antibacterial/antibiofilm efficacy of NAC, and reported good and promising efficacy: NAC was found as efficacious as the comparators (chlorhexidine, sodium hypochlorite, calcium hydroxide), or even showed higher efficacy. Regarding the anti-inflammatory efficacy of NAC, one in vitro study found it equivalent to, while one clinical trial revealed it more efficacious than calcium hydroxide.
CONCLUSIONS
There is accumulating evidence on the anti-microbial and anti-inflammatory efficacy of NAC in context of endodontics. However, further clinical trials with robust methodology and objective and reliable clinical, biological and microbial outcomes are warranted to translate its use for clinical practice on humans.
Topics: Acetylcysteine; Anti-Bacterial Agents; Anti-Inflammatory Agents; Calcium Hydroxide; Chlorhexidine; Humans
PubMed: 36096839
DOI: 10.1186/s12903-022-02433-6 -
Urolithiasis Dec 2023To assess the effect of co-trimoxazole and N-acetylcysteine (NAC), alone and in combination, on bacterial adherence to biofilm formed on ureteral stent surfaces. This... (Randomized Controlled Trial)
Randomized Controlled Trial
To assess the effect of co-trimoxazole and N-acetylcysteine (NAC), alone and in combination, on bacterial adherence to biofilm formed on ureteral stent surfaces. This prospective randomized study was conducted on 636 patients who underwent double J ureteral stent insertion after variable urological procedures. Patients were randomized into four groups: A (n = 165), no antibiotics or mucolytics during stent indwelling; B (n = 153), oral NAC (200 mg/day for children aged < 12 years old and 600 mg/day for adults) during stent indwelling; C (n = 162), oral co-trimoxazole (2 mg TMP/kg/day) during stent indwelling; and D (n = 156), both oral NAC and co-trimoxazole during stent indwelling. Two weeks following double J stent (JJ stent) insertion, urinalysis was performed on all patients and urine culture was done for all the patients at the day of double J stent removal. The stent was removed 2 weeks postoperatively, and a stent segment sized 3-5 cm from the bladder segment of the stent was sent for culture. Positive stent cultures were found in 63.6% (105/165), 43.1% (66/153), 37% (60/162), and 19.2% (30/156) patients of groups A, B, C, and D, respectively. E. coli was the organism most commonly isolated from the stent culture in all groups. The combination of co-trimoxazole and NAC was more effective in reducing bacterial adherence on ureteral stent surfaces than either alone.
Topics: Adult; Child; Humans; Acetylcysteine; Trimethoprim, Sulfamethoxazole Drug Combination; Prospective Studies; Escherichia coli; Ureter; Stents; Bacteria
PubMed: 38079000
DOI: 10.1007/s00240-023-01508-5 -
Oxidative stress and viral Infections: rationale, experiences, and perspectives on N-acetylcysteine.European Review For Medical and... Nov 2022This article explores current evidence on the role of oxidative stress in viral infections, and on the use of antioxidant drugs as adjunctive treatment. MEDLINE/PubMed...
This article explores current evidence on the role of oxidative stress in viral infections, and on the use of antioxidant drugs as adjunctive treatment. MEDLINE/PubMed was searched for appropriate keywords, and preclinical and clinical studies with reviews were retrieved and examined by authors. Old and current evidence shows that GSH content reduction is the main mechanism of redox imbalance in viral-infected cells. Clinical studies found that GSH levels are depleted in patients with viral infections such as HIV and SARS-CoV. Viral infections activate inflammation through different pathways, and several of these mechanisms are related to oxidative stress. NAC is a precursor of GSH, and many of its intracellular effects are mediated by GSH replenishment, but it also activates some anti-inflammatory mechanisms. NAC has an excellent safety profile and better oral and topical bioavailability than GSH. These characteristics make NAC a suitable option as a repurposed drug. Adjunctive antioxidant treatment may improve the outcomes of antiviral therapies. Current evidence supports the rationale for this practice and some clinical experience showed encouraging results.
Topics: Humans; Acetylcysteine; Antioxidants; Oxidative Stress; Virus Diseases; Inflammation
PubMed: 36459039
DOI: 10.26355/eurrev_202211_30395 -
BMC Pulmonary Medicine Dec 2022Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial.
METHODS
The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC.
DISCUSSION
The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.
Topics: Humans; Acetylcysteine; Double-Blind Method; Genotype; Idiopathic Pulmonary Fibrosis; Treatment Outcome; Vital Capacity; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 36514019
DOI: 10.1186/s12890-022-02281-8 -
The European Respiratory Journal Jan 2021A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown.
METHODS
This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide ( ) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability.
RESULTS
81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in , 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups.
CONCLUSIONS
Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.
Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Japan; Pyridones; Treatment Outcome; Vital Capacity
PubMed: 32703779
DOI: 10.1183/13993003.00348-2020 -
Experimental Biology and Medicine... Aug 2022Oxidative stress is involved in the deterioration of bone quality and mechanical strength in both diabetic and aging adults. Therefore, we studied the ability of the...
Oxidative stress is involved in the deterioration of bone quality and mechanical strength in both diabetic and aging adults. Therefore, we studied the ability of the antioxidant compound, -allylmercapto--acetylcysteine (ASSNAC) to protect bone marrow stromal cells (BMSCs) from advanced glycation end-products (AGEs) cytotoxicity and improve bone microarchitecture of adult healthy and obese/diabetic (db/db) female mice. ASSNAC effect on AGEs-treated cultured rat BMSCs was evaluated by Neutral Red and XTT cell survival and reactive oxygen species (ROS) level assays. Its effect on healthy (C57BL/6) and obese/diabetic (C57BLKS/J Lepr; db/db) female mice femur parameters, such as (1) number of adherent BMSCs, (2) percentage of CD73/CD45 cells in bone marrow (BM), (3) glutathione level in BM cells, and (4) femur microarchitecture parameters by microcomputed tomography, was studied. ASSNAC treatment protected BMSCs by significantly decreasing AGEs-induced ROS production and increasing their cellular resistance to the cytotoxic effect of AGEs. ASSNAC treatment of healthy female mice (50 mg/kg/day; i.p.; age 12-20 weeks) significantly increased the number of BMSCs (+60%), CD73/CD45 cells (+134%), and glutathione level (+110%) in the femur bone marrow. Furthermore, it increased the femur length (+3%), cortical diameter (+3%), and cortical areal moment of inertia (Ct.MOI; +10%) a surrogate for biomechanical strength. In db/db mice that demonstrated a compromised trabecular bone and growth plate microarchitecture, ASSNAC treatment restored the trabecular number (Tb.N, +29%), bone volume fraction (Tb.BV/TV, +130%), and growth plate primary spongiosa volumetric bone mineral density (PS-vBMD, +7%) and thickness (PS-Th, +18%). In conclusion, this study demonstrates that ASSNAC protects bone marrow cells from oxidative stress and may improve bone microarchitecture in adult healthy and diabetic female mice.
Topics: Acetylcysteine; Allyl Compounds; Animals; Antioxidants; Bone Density; Diabetes Mellitus, Experimental; Female; Femur; Glutathione; Mice; Mice, Inbred C57BL; Neutral Red; Obesity; Rats; Reactive Oxygen Species; X-Ray Microtomography
PubMed: 35658550
DOI: 10.1177/15353702221095047 -
Dental Materials Journal May 2021This study examined the effects of N-acetylcysteine (NAC) on the inflammatory reactions of murine osteoblastic cells cultured on the 4-methacryloxyethyl trimellitate...
This study examined the effects of N-acetylcysteine (NAC) on the inflammatory reactions of murine osteoblastic cells cultured on the 4-methacryloxyethyl trimellitate anhydride/methyl methacrylate (4-META/MMA)-based resin. Superbond C&B (SB) was used as the 4-META/MMA-based resin and placed in a 48-well cell culture plate. The cells were cultured in αMEM (control) as well as on SB and SB in αMEM with NAC (SB+NAC). They were examined using the WST-1 proliferation assay, real-time PCR, enzyme-linked immunosorbent assay (ELISA), intracellular reactive oxygen species (ROS) measurements, and cellular glutathione (GSH) detection. COX-2 and IL-6 gene expressions were upregulated in SB; however, they were suppressed by NAC. Furthermore, PGE production in the culture medium was increased in SB, whereas NAC decreased the PGE production. NAC lowered the ROS level in the culture medium and significantly increased the intracellular GSH level. The present in vitro study demonstrated that NAC might be effective for dental material detoxification.
Topics: Acetylcysteine; Animals; Cells, Cultured; Dinoprostone; Methacrylates; Mice; Reactive Oxygen Species
PubMed: 33642448
DOI: 10.4012/dmj.2020-275 -
Translational Psychiatry Jun 2022It remains unclear whether mitochondrial modulators (MMs) are beneficial in the treatment of obsessive-compulsive and related disorders. Thus, in an attempt to answer... (Meta-Analysis)
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.
Topics: Acetylcysteine; Adult; Double-Blind Method; Female; Humans; Inositol; Lithium; Male; Obsessive-Compulsive Disorder; Randomized Controlled Trials as Topic
PubMed: 35764619
DOI: 10.1038/s41398-022-02026-5