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The Potential Use of Metformin, Dipyridamole, N-Acetylcysteine and Statins as Adjunctive Therapy for Systemic Lupus Erythematosus.
Tan, MKX, Heng, TYJ, Mak, A
Cells. 2019;(4)
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune condition that can potentially affect every single organ during the course of the disease, leading to increased morbidity and mortality, and reduced health-related quality of life. While curative treatment is currently non-existent for SLE, therapeutic agents such as glucocorticoids, mycophenolate, azathioprine, cyclosporine, cyclophosphamide and various biologics are the mainstay of treatment based on their immunomodulatory and immunosuppressive properties. As a result of global immunosuppression, the side-effect profile of the current therapeutic approach is unfavourable, with adverse effects including myelosuppression, infection and malignancies. Hydroxychloroquine, one of the very few Food and Drug Administration (FDA)-approved medications for the treatment of SLE, has been shown to offer a number of therapeutic benefits to SLE patients independent of its immunomodulatory effect. As such, it is worth exploring drugs similar to hydroxychloroquine that confer additional clinical benefits unrelated to immunosuppressive mechanisms. Indeed, apart from hydroxychloroquine, a number of studies have explored the use of a few conventionally non-immunosuppressive drugs that are potentially useful in the management of SLE. In this review, non-immunosuppressive therapeutic agents, namely metformin, dipyridamole, N-acetylcysteine and statins, will be critically discussed with regard to their mechanisms of action and efficacy pertaining to their potential therapeutic role in SLE.
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N-ACETYLCYSTEINE AND/OR URSODEOXYCHOLIC ACID ASSOCIATED WITH METFORMIN IN NON-ALCOHOLIC STEATOHEPATITIS: AN OPEN-LABEL MULTICENTER RANDOMIZED CONTROLLED TRIAL.
Oliveira, CP, Cotrim, HP, Stefano, JT, Siqueira, ACG, Salgado, ALA, Parise, ER
Arquivos de gastroenterologia. 2019;(2):184-190
Abstract
BACKGROUND Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.
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N-acetylcysteine for cessation of tobacco smoking: rationale and study protocol for a randomised controlled trial.
Arancini, L, Bortolasci, CC, Dodd, S, Dean, OM, Berk, M
Trials. 2019;(1):555
Abstract
BACKGROUND Tobacco smoking is a highly prevalent, addictive behaviour and a key public health priority. However available cessation therapies have low quit and high relapse rates, indicating an urgent need for more effective treatments. Predicated on promising preclinical and pilot clinical data, this paper presents a rationale and protocol for the trial of N-acetylcysteine (NAC) as a novel anti-craving smoking cessation aid. METHODS Current smokers (n = 120) of at least 10 cigarettes a day are recruited through online advertisements, print publications and dissemination of flyers. Participants are randomised on a 1:1 ratio to receive either 16-week treatment of 1.8 g/day of NAC or placebo with all participants receiving quit support from the online QuitCoach tool. Participants are attending visits at baseline, 8 and 16 weeks with a 42-week post-discontinuation follow-up. The primary outcome measure is sustained abstinence at six months after treatment based on self-reported rating scales and confirmed by exhaled carbon monoxide and salivary cotinine levels. Secondary outcomes are timing of the first lapse and relapse, between-group cigarette consumption, withdrawal symptoms, general wellbeing and mood/anxiety symptoms. Between-group differences in adverse events and subgroup analyses for variables including gender and Diagnostic Statistics Manual 5 diagnostics will also be investigated. DISCUSSION The planned trial addresses an issue of major importance to human health and, if an effect is shown, may result in substantial changes to the management of smoking and nicotine addiction with overt public health implications. TRIAL REGISTRATION Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303 . Registered on 19 October 2017.
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On infusion of high-dose ascorbate in treating cancer: Is it time for N-acetylcysteine pretreatment to enhance susceptibility and to lower side effects?
Valachová, K, Juránek, I, Rapta, P, Valent, I, Šoltés, L
Medical hypotheses. 2019;:8-9
Abstract
Ascorbate administered intravenously gives a high plasma concentration of this drug. Clinical trials with pancreatic carcinoma patients revealed their prolonged survival if treated with intravenous ascorbate. On the other hand, high plasma ascorbate concentration leads to severe side effects, such as nephrotoxicity. In the present paper, we advocate to lower intravenous ascorbate dosage along with monothiol N-acetylcysteine pretreatment due to anticipation of the same therapeutic effect but less or none of side effects. We describe in detail molecular mechanism of ascorbate action to be potentiated by N-acetylcysteine, as observed under in vitro conditions. Providing further arguments, we believe that the same mechanism may be employed in vivo.
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A review of N-acetylcysteine in the treatment of grooming disorders.
Braun, TL, Patel, V, DeBord, LC, Rosen, T
International journal of dermatology. 2019;(4):502-510
Abstract
BACKGROUND Pathologic grooming disorders can lead to clinically significant distress and functional impairment. Studies on treatment of these disorders with selective serotonin reuptake inhibitors (SSRIs) and anticonvulsants have led to inconsistent findings. N-acetylcysteine (NAC) has shown promise in treatment of obsessive-compulsive and related disorders. The objective of this article is to perform an updated review of NAC in the treatment of grooming disorders. METHODS PubMed was searched from inception to October 2017 to identify literature on the use of NAC in the management of trichotillomania, onychophagia, and pathological skin picking. Case reports, case series, and randomized controlled trials were included. Data on study design, dosing regimens, comorbidities, concurrent treatment, and side effects were extracted from the included articles. RESULTS Fifteen articles were included in this review, which consisted of 10 case reports, one case series, and four randomized controlled trials. Dosing of oral NAC ranged from 450 to 2,400 mg per day, and treatment periods lasted from 1 to 8 months. Side effects were uncommon, mild, and usually gastrointestinal in nature, with severe aggression reported in one child. CONCLUSIONS While there are multiple reports of the safety and efficacy of NAC in the treatment of grooming disorders, there are currently few randomized controlled trials on this topic, and more research is needed to develop a formal treatment algorithm. While current data should be considered very preliminary, case reports have demonstrated mostly positive results and a lack of significant side effects. A trial of NAC may be a viable option for pathologic grooming disorders, especially in patients who have failed prior psychologic or pharmacologic treatment.
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Prophylactic oral NAC reduced poor hematopoietic reconstitution by improving endothelial cells after haploidentical transplantation.
Kong, Y, Wang, Y, Zhang, YY, Shi, MM, Mo, XD, Sun, YQ, Chang, YJ, Xu, LP, Zhang, XH, Liu, KY, et al
Blood advances. 2019;(8):1303-1317
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Abstract
Poor graft function (PGF) and prolonged isolated thrombocytopenia (PT) remain life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Endothelial cells (ECs) play a crucial role in regulating hematopoiesis in the bone marrow (BM) microenvironment. However, whether the impaired BM ECs are responsible for defective hematopoiesis in PGF and PT patients requires clarification, and clinical management is challenging. Two prospective clinical trials were included in the current study. In the first trial (N = 68), PGF and PT patients demonstrated defective BM ECs pre-HSCT and impaired BM EC dynamic reconstitution at early time points post-HSCT, which was positively correlated with reactive oxygen species (ROS) levels. Receiver operating characteristic curves showed that BM EC < 0.1% pre-HSCT could identify high-risk patients with PGF and PT. The second trial enrolled patients (N = 35) with EC < 0.1% who accepted oral N-acetyl-l-cysteine (NAC; 400 mg 3 times per day) from -14 days pre-HSCT to +2 months post-HSCT continuously, whereas the remaining EC ≥ 0.1% patients (N = 39) received allo-HSCT only. Prophylactic NAC intervention was safe and effective in preventing the occurrence of PGF and PT in EC < 0.1% patients by promoting the dynamic reconstitution of BM ECs and CD34+ cells, along with reducing their ROS levels, which was further confirmed by in situ BM trephine biopsy analyses. These findings suggest that the impaired BM ECs pre-HSCT are responsible for the defective hematopoiesis in PGF and PT patients. Therefore, improvement of BM ECs through prophylactic NAC intervention may be a promising therapeutic approach to promote hematopoietic reconstitution post-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT03236220 and #NCT02978274.
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The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study.
Ellegaard, PK, Licht, RW, Nielsen, RE, Dean, OM, Berk, M, Poulsen, HE, Mohebbi, M, Nielsen, CT
Journal of affective disorders. 2019;:1043-1051
Abstract
OBJECTIVE To investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression. METHOD A randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3 g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome. RESULTS A total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p = 0.88). All findings regarding secondary outcomes were statistically or clinically insignificant. LIMITATIONS The study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo. CONCLUSIONS Based on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.
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Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men.
Jannatifar, R, Parivar, K, Roodbari, NH, Nasr-Esfahani, MH
Reproductive biology and endocrinology : RB&E. 2019;(1):24
Abstract
BACKGROUND Infertile men have higher levels of semen reactive oxygen species (ROS) than fertile men. High levels of semen ROS can cause sperm dysfunction, sperm DNA damage and reduced male reproductive potential. This study investigated the effects of supplementation with N-acetyl-cysteine (NAC) on the sperm quality, chromatin integrity and levels of oxidative stress in infertile men. METHODS The study was carried out in the unit of ACECR Infertility Research Center, Qom, Iran. The patients consisted of 50 infertile men with asthenoteratozoospermia who received NAC (600 mg/d) orally for 3 months, after which they were compared with pre-treatment status. Semen was analyzed according to WHO (2010), followed by the assessment of protamine content [chromomycin A3 (CMA3)] and DNA integrity [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)]. Oxidative stress markers, i.e. total antioxidant capacity (TAC) and malondialdehyde (MDA), as well as hormonal profile (LH, FSH, Testosterone and Prolactin) were determined by ELISA kit. RESULTS After NAC treatment, patients' sperm count and motility increased significantly whereas abnormal morphology, DNA fragmentation and protamine deficiency showed significant decreases compared to pre-treatment levels (P < 0.05). Hormonal profile improvement was associated with lowered FSH and LH levels and increased amount of testosterone (P < 0.05). TAC significantly increased and MDA decreased with an inverse significant correlation between TAC and MDA (P < 0.05). CONCLUSION NAC oral supplementation may improve sperm parameters and oxidative/antioxidant status in infertile males.
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Differentially expressed plasma proteins of β-thalassemia/hemoglobin E patients in response to curcuminoids/vitamin E antioxidant cocktails.
Panachan, J, Chokchaichamnankit, D, Weeraphan, C, Srisomsap, C, Masaratana, P, Hatairaktham, S, Panichkul, N, Svasti, J, Kalpravidh, RW
Hematology (Amsterdam, Netherlands). 2019;(1):300-307
Abstract
OBJECTIVE Iron overload and oxidative stress are the major causes of serious complications and mortality in thalassemic patients. Our previous work supports the synergistic effects of antioxidant cocktails (curcuminoids or vitamin E, N-acetylcysteine, and deferiprone) in treatment of β-thalassemia/Hb E patients. This further 2-DE-based proteomic study aimed to identify the plasma proteins that expressed differentially in response to antioxidant cocktails. METHODS Frozen plasma samples of ten normal subjects and ten β-thalassemia/Hb E patients at three-time points (baseline, month 6, and month 12) were reduced the dynamic range of proteome using ProteoMiner kit and separated proteins by two-dimensional gel electrophoresis. Differentially expressed proteins were identified using tandem mass spectrometry. Several plasma proteins were validated by ELISA and Western blot analysis. RESULTS Thirteen and 11 proteins were identified with altered expression levels in the curcuminoids- and vitamin E cocktail groups, respectively. The associations between vitronectin (VTN) expression and total bilirubin levels, as well as between serum paraoxonase/arylesterase 1 (PON1) expression and blood reactive oxygen species were observed. Validation results were consistent with proteomics results. DISCUSSION AND CONCLUSIONS These plasma proteins may provide better understanding of the mechanisms underlying the therapeutic effects of antioxidant cocktails in thalassemic patients.
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N-Acetylcysteine Prevents Post-embolization Syndrome in Patients with Hepatocellular Carcinoma Following Transarterial Chemoembolization.
Siramolpiwat, S, Punjachaipornpon, T, Pornthisarn, B, Vilaichone, RK, Chonprasertsuk, S, Tangaroonsanti, A, Bhanthumkomol, P, Phumyen, A, Yasiri, A, Kaewmanee, M
Digestive diseases and sciences. 2019;(11):3337-3345
Abstract
BACKGROUND Post-embolization syndrome is a common complication after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). N-acetylcysteine (NAC) is known to ameliorate liver damage from several causes. AIM: To determine the efficacy of intravenous NAC in the prevention of post-embolization syndrome in HCC patients following TACE. METHODS In this study, patients with HCC admitted for TACE were prospectively enrolled. All patients were randomized stratified by Child A or B to receive NAC or placebo. The NAC group received intravenous NAC 24 h prior to TACE (150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h, then continuous infusion 6.25 mg/h for 48 h after the procedure). The placebo group received an infusion of 5% glucose solution until 48 h after procedure. The post-embolization syndrome was defined as: T ≥ 38.5 c and serum ALT > 3 times of pretreatment value. RESULTS In total, 111 HCC patients were enrolled; 57 were randomly assigned to NAC group and 54 to placebo group. The incidence of post-embolization syndrome was lower in NAC group (24.6%) compared to placebo group (48.2%); P = 0.01. On multivariate analysis, receiving IV NAC (P = 0.03) and HCC diameter (P < 0.01) were associated with developing post-embolization syndrome. Post-TACE liver decompensation was documented in 26/111 (23.4%) patients. There was no difference in the incidence of post-TACE liver decompensation between NAC and placebo group. CONCLUSIONS In this study, intravenous NAC administration reduces the incidence of post-embolization syndrome after TACE in patients with HCC. However, it does not prevent post-TACE liver decompensation. TRIAL REGISTRATION NUMBER This study was registered with Thai Clinical Trial Registry (TCTR20150313002).