Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial

Objective: In a double-blind placebo-controlled trial, human immunodeficiency virus (HIV)-seropositive patients with a CD4 lymphocyte cell count of more than 200 × 10⁶⋅l⁻¹ were randomised to receive either 800 mg N-acetylcysteine (NAC) or placebo for 4 months. Before treatment low plasma cysteine levels, high free radical activity in neutrophils in the presence of autologous plasma – measured by the nitroblue tetrazolium (NBT) test – and increased tumor necrosis factor (TNF)-α levels were found in the HIV positive patients. Results: After treatment the low plasma cysteine level in the NAC group increased to normal, and the decline of the CD4+ lymphocyte count before the study start, was less steep in the NAC group than in the placebo group after treatment. There was also a reduction in TNF-α level. However, NAC had no effect on the radical production by neutrophils, and although it did not increase the CD4+ cell count, it may have decreased the decline in CD4+ cells. Conclusion: Further controlled trials with NAC are needed to devermine whether it has a beneficial effect in the treatment of asymptomatic HIV-infected individuals. Received: 25 October 1995/Accepted in revised form: 15 February 1996     

N-Acetylcysteine ameliorates lithium-induced renal failure in rats.

BACKGROUND: Prolonged lithium treatment may induce progressive deterioration of renal function in humans and experimental animals. N-Acetylcysteine (NAC) has been shown to be effective in the prevention of hypoperfusion and toxin-induced renal failure, but its effect on lithium nephrotoxicity has not been evaluated yet. The purpose of this study was to examine a possible renoprotective effect of NAC against lithium-induced renal failure in a rat model. METHODS: Moderate renal failure was induced in 40 Sprague-Dawley rats using a 5 week protocol including 3 weeks of lithium chloride administration in the drinking water. The animals were divided randomly into two equal groups receiving either 10 mg/kg NAC or saline by two daily intraperitoneal injections. In week 6, the glomerular filtration rate (GFR) was assessed by 99mTechnetium diethylene triaminepentaacetic acid, and serum creatinine, blood urea nitrogen (BUN) and 24 h urinary protein and osmolarity were measured. Kidneys were excised for pathological evaluation. RESULTS: At the end of the lithium protocol, the GFR was significantly higher in the NAC-treated group compared with the control group, 0.92+/-0.35 vs 0.56+/-0.25 ml/min/100 g, respectively, P = 0.002. Serum creatinine and BUN were also significantly lower in the NAC-treated group 1.009+/-0.107 vs 1.143+/-0.118 mg/dl, P = 0.001, and 83.9+/-6.8 vs 88.95+/-7.1 mg/dl, P = 0.28, respectively. The percentages of tubular necrosis and tubular lumen obstruction, evaluated by light microscopy, were significantly lower in the NAC-treated group, P = 0.002 and P = 0.007, respectively. CONCLUSIONS: NAC treatment has a renoprotective effect against lithium-induced renal failure in a rat model.     

Effect of the Mucoactive Drug Nacystelyn on the Respiratory Burst of Human Blood Polymorphonuclear Neutrophils

In lung diseases such as chronic obstructive pulmonary disease (COPD) or cystic fibrosis, the activation of phagocytic cells produces high amounts of cytotoxic reactive oxygen species (ROS) that are partly implicated in the pathogenic process. In this study, the ex vivo antioxidant activity of nacystelyn (NAL), a recently developed mucoactive thiol-containing agent, was investigated using the respiratory burst of human blood polymorphonuclear neutrophils (PMNs). The ROS generation was induced by serum-opsonized zymosan and assessed with luminol- and lucigenin-enhanced chemiluminescence (ECL). The activity of NAL was compared with N-acetylcysteine (ACC) and captopril, other thiol-containing pharmacological agents having documented antioxidant properties. The three drugs significantly inhibited the ECL response of activated PMNs in the presence of luminol, a luminogenic agent which mostly reflects the production of hydroxyl and hypohalite radicals. NAL was more efficient than the other two drugs: the concentrations producing a 50% inhibition (IC₅₀) of total luminol-ECL were 290 μM, 1580 μM and 760 μM for NAL, ACC and captopril, respectively. The inhibition of the lucigenin-ECL response of activated PMNs was less marked for all compounds suggesting a poorer reactivity with superoxide radicals. These findings demonstrate that NAL, at concentrations obtainable in vivo by inhalation, impairs the PMNs chemiluminescence response related to hydroxyl and hypohalite radicals production. As those radicals are highly cytotoxic, NAL appears as a promising agent in the prevention of oxidative lung damage caused by an active inflammatory response.     

Effects of reduced glutathione and n-acetylcysteine on lidocaine metabolism in cimetidine treated rats

Summary— The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N-acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (ip) (1 mmol/kg) 1 hour before treatment with cimetidine (0.5 mmol/kg) or saline, and 1 hr later all rats were injected ip with lidocaine (1 mg/kg). Blood samples were drawn 30 min after the lidocaine injection. MEGX and lidocaine serum concentrations were determined by means of fluorescence polarization immuno-assay using the TDX system. Cimetidine produced a decrease in MEGX levels (from 210 ± 18 to 164 ± 13 ng/mL) and a parallel increase in lidocaine levels (from 73 ± 22 to 172 ± 47 ng/mL), consistent with cytochrome P-450 3A inhibition. Both GSH and NAC produced a significant decrease in MEGX levels (151 ± 16 and 139 ± 14 ng/mL, respectively), but no significant increase in lidocaine levels were found. As compared to the cimetidine group, pre-treatment using either GSH or NAC with Cimetidine produced a marked decrease in lidocaine levels (37 ± 27 and 63 ± 28 ng/mL, respectively) and no modification of MEGX levels (155 ± 12 and 165 ± 22 ng/mL, respectively). These results suggest that GSH and NAC might accelerate the lidocaine metabolism while counteracting the inhibitory effect of Cimetidine.     

N-乙酰半胱氨酸对AGEs诱导的微血管内皮细胞VCAM-1表达的抑制作用

用流式细胞仪测定晚期糖基化终末产物(advanced glycation end products，AGEs)刺激及N—乙酰半胱氨酸(NAC)干预前后小鼠心脏微血管内皮细胞血管细胞黏附分子1(VCAM—1)的表达，同时用放免法测定培养上清中TNF—α水平。结果发现AGEs刺激后微血管内皮细胞VCAM—1表达增加，TNF—α水平升高；NAC干预组VCAM—1表达降低，TNF—α水平下降并具有剂量依赖性。提示NAC能抑制AGEs诱导的微血管内皮细胞VCAM—1的表达，TNF—α的介导是可能的机制之一。     

小剂量强地松、红霉素和富露施联用对大鼠肺纤维化及其转化生长因子β1干预的实验观察

目的 提供更合理的肺纤维化治疗方案。方法 100只wistar大鼠，随机抽出20只作为正常组，气管内注入生理盐水(作为阴性对照)，剩余80只经气管内注入博莱霉素造模成功后随机分为模型组20只(作为阳性对照)，大剂量强地松组20只，红霉素和富露施组20只，小剂量强地松、红霉素和富露施组20只，分别给予相应药物治疗。以上各组动物在第七，十四，三十，六十天每组随机抽出5只处死进行病理切片观察，电子计算机图像分析仅进行组织形态学、胶原和转化生长因子(TGF)β1定量分析。结果 小剂量强地松、红霉素和富露施组对模型动物干预最强。结论 小剂量强地松、红霉素和富露施联合应用治疗大鼠肺纤维化伏于经典方法。     

Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis.

Aim: There is no proven medical therapy for the treatment of non-alcoholic steatohepatitis (NASH). Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. The aim of our study was to evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) in improving the aminotransferases and histological parameters (steatosis, inflammation, hepatocellular ballooning, and fibrosis) after 12 months of treatment. Methods: Twenty consecutive patients (mean age 53 +/- 2 years [36-68] and body mass index [BMI] 29 [25-35]) with biopsy-proven NASH were enrolled in the study. NAC (1.2 g/day) and MTF (850-1000 mg/day) were given orally for 12 months. All patients underwent evaluation of serum aminotransferases, fasting lipid profile and serum glucose, anthropometric parameters, and nutritional status at 0 and 12 months. A low calorie diet was prescribed for all patients. Results: Serum alanine aminotransferase, high-density lipoprotein, insulin, and glucose concentrations and thehomeostasis model assessment-insulin resistance (HOMA-IR) index were reduced significantly at the end of study (P < 0.05). The BMI declined, but without statistical significance. Aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, cholesterol, and triglycerides levels were not altered with the treatment. Liver steatosis and fibrosis decreased (P < 0.05), but no improvement was noted in lobular inflammation or hepatocellular ballooning. The NASH activity score was significantly improved after treatment. Conclusion: Based on the biochemical and histological evidence in this pilot study, NAC in combination with MTF appears to ameliorate several aspects of NASH, including fibrosis. Further studies of this form of combination therapy are warranted to assess its potential efficacy.     

The effect of N-acetylcysteine on the in vitro growth of normal rabbit middle ear fibroblasts

In the present study the effect of N-acetylcysteine on the growth pattern and collagen synthesis of cultures of rabbit middle ear fibroblasts was determined. The growth pattern was evaluated by cell counting, measurements of the total content of cell protein and mitotic activity by incorporation of ³H-thymidine. Collagen synthesis was estimated by incorporation of ³H-proline. The results demonstrate a dose-dependent reduction in both normal cell proliferation and collagen production. Thus, N-acetylcysteine seems to possess properties desirable and useful in the treatment of secretory otitis media.     

The effects of N-acetylcysteine on antioxidant enzyme activities in experimental testicular torsion

Testicular torsion is a serious problem in male children and, if not treated at the right time, can lead to subfertility and infertility. The main reason for testicular damage is ischemia-reperfusion injury. A number of chemical substances have been used to protect testes against ischemia-reperfusion injury in experimental animals. The possible protective effect of N-acetylcysteine on testicular tissue after testicular detorsion was examined in the current study. Twenty-four rats were divided into four groups: sham operation, torsion, detorsion, and NAC + detorsion groups (n = 6 for each group). Excluding sham operation group, the rats were subjected to unilateral torsion (720-degree rotation in clockwise direction). After torsion (5 h) and detorsion (2 h), unilateral orchidectomy was performed. Malondialdehyde levels and superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities were determined in testicular tissue. Administration of N-acetylcysteine caused a decrease in malondialdehyde levels and an increase in glutathione peroxidase levels compared to detorsion group. The results suggest that N-acetylcysteine may be a potential protective agent for preventing the negative biochemical changes related to oxidative stress in testicular injury caused by testis torsion.     

Effect of N-acetylcysteine treatment on the expression of leukocyte surface markers after burn injury

Oxidative stress and inflammatory processes generate edema in burns. Treatment of consequent hypovolemia is a challenge.The aim of study was to assess if glutathione pro-drug N-acetylcysteine (NAC) can influence inflammation and fluid requirement. We also aimed to compare organ functions scores and vasoactive drug requirement. This prospective randomised study involved 28 patients with burn injury affecting more than 20% of body surface area. Fourteen patients were on standard therapy, whereas for other 14 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Leukocyte surface marker expressions were determined, multiple organ function scores, use of vasopressor agents and fluid requirements were recorded daily.Expression of CD11a (p < 0.05), CD18 (p < 0.05) and CD97 (p < 0.01) on the granulocytes were significantly lower in the NAC treated group, similarly to lymphocyte CD 49d (p < 0.05) and monocyte CD 49d (p < 0.01) and CD 97 (p < 0.05) expression. No significant difference was found in the fluid requirement between groups but patients the NAC group required less vasopressor and inotropic drugs from day 4.NAC treatment is associated with a less pronounced inflammation reflected in lower CD marker expression and vasopressor requirement.