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  • Pharmacology 2003 Jun;68(2):105-14 : Urinary and Plasma Homocysteine and Cysteine Levels during Prolonged Oral N-Acetylcysteine Therapy.
    Ventura P, Panini R, Abbati G, Marchetti G, Salvioli G.
    Department of Internal Medicine, Chair of Internal Medicine II, University of Modena and Reggio Emilia, Modena, Italy.

    Acute administration of N-acetylcysteine (NAC) may induce alterations in plasma and urinary levels of homocysteine (Hcy) and cysteine (Cys). We studied the effects of continuous oral NAC therapy on different Hcy and Cys plasma and urinary forms in 40 healthy subjects assigned to three groups (groups A: n = 13, no therapy; group B: n = 14, NAC 600 mg/day, and group C: n = 14, NAC 1,800 mg/day) for 1 month (T(1)). After a 1-month washout period without therapy (T(2)), all subjects were treated with oral NAC (1,800 mg/day) for 2 months and (T(3) and T(4)) reassessed monthly for plasma and urinary thiols. The treated subjects showed a significant decrease in plasma total Hcy and a slight increase in total Cys levels; the alterations of different forms of plasma thiols suggested an NAC-induced increase in disulfide forms and an increase in urinary Hcy and Cys excretion as disulfide forms. The effects appeared to be dose dependent, being more marked in subjects treated with higher dosages. This approach may be important, as an association or alternative therapy in hyperhomocysteinemic conditions of poor responses to vitamins. Copyright 2003 S. Karger AG, Basel
  • Clin Sci (Lond) 2003 Apr 23; [epub ahead of print] : N-acetylcysteine improves the disturbed thiol redox balance after methionine loading.
    Raijmakers MT, Schilders GW, Roes EM, Van Tits LJ, Hak-Lemmers HL, Steegers EA, Peters WH.

    Methionine loading seems to be accompanied by an increased oxidative stress and damage. However, it is not exactly known how this oxidative stress is generated. We performed this crossover study to further elucidate the effect of methionine loading on oxidative stress in blood of healthy volunteers and to examine possible preventive effects of N-acetylcysteine (NAC) administration. Eighteen healthy subjects underwent two oral methionine loads of 100mg/kg bodyweight each 4 weeks apart, one without NAC (Meth-group), and one in combination with supplementation of 2 x 900mg NAC (Meth+Nac-group). Blood samples were collected before and 2, 4, 8 and 24 hours after methionine loading for measurements of thiol levels, protein carbonyls, lipid peroxidation, cellular fibronectin, and the ferric reducing ability in plasma (FRAP; i.e. antioxidant capacity). After methionine loading whole blood levels of free and oxidised cysteine and homocysteine increased in both groups. Furthermore, the total plasma levels of homocysteine were higher, whereas cysteine was lower after methionine loading in both groups. In the Meth+Nac-group lower oxidised homocysteine levels and a higher free-to-oxidised ratio as compared to the Meth-group was found. Although the antioxidant capacity decreased after methionine loading, no major changes over time were found for protein carbonyls and cellular fibronectin in both groups. Our results may indicate that methionine loading may initiate the generation of reactive oxygen species by (auto)-oxidation of homocysteine. In addition, the supplementation with NAC seems to be able to partly prevent excessive increase of homocysteine in plasma and oxidised homocysteine in whole blood and might thereby contribute to the prevention of oxidative stress.
  • Am J Kidney Dis 2003 Feb;41(2):442-6: The effect of N-acetylcysteine on plasma total homocysteine levels in hemodialysis: a randomized, controlled study.
    Friedman AN, Bostom AG, Laliberty P, Selhub J, Shemin D.
    Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA.
    allfried@iupui.edu

    BACKGROUND: The chronic hemodialysis population has an accelerated rate of cardiovascular morbidity and death. Furthermore, elevated levels of the putative atherothrombotic risk factor homocysteine are almost ubiquitous in this population. Attempts to normalize elevated plasma total homocysteine (tHcy) levels in dialysis patients using pharmacological-dose vitamin therapy or other strategies generally have been unsuccessful. Preliminary uncontrolled evidence suggests that N-acetylcysteine (NAC) may be an effective tHcy-lowering agent. We designed a randomized placebo-controlled study to determine the effect of prolonged oral NAC therapy on lowering tHcy levels in vitamin-replete chronic hemodialysis patients. METHODS: Thirty-eight subjects were treated before intervention with a standard dialysis vitamin supplement to ensure a uniform vitamin-replete state. They were then block randomized to treatment with NAC, 1.2 g twice a day, for 4 weeks or matched placebo. RESULTS: There were no significant baseline differences between the two groups, although differences in pyridoxal 5'-phosphate (active form of vitamin B(6)) levels approached significance (P = 0.06). In a paired analysis, there was no statistically significant difference between the NAC and placebo groups. NAC was very well tolerated in hemodialysis patients. CONCLUSION: This randomized placebo-controlled trial found that chronic oral NAC therapy did not significantly reduce tHcy levels in hemodialysis patients. Although a larger sample size theoretically could have increased the statistical significance between groups, implications of the potentially very modest reduction in tHcy levels are not yet known. Finally, based on this limited study, NAC appears to be a safe and well-tolerated therapy in the hemodialysis population. Copyright 2003 by the National Kidney Foundation, Inc.
  • Carcinogenesis 2002 Sep;23(9):1455-61 : Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination.
    Hecht SS, Upadhyaya P, Wang M, Bliss RL, McIntee EJ, Kenney PM.
    University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
    hecht002@umn.edu

    Isothiocyanates, their N-acetylcysteine conjugates, and myo-inositol (MI) are inhibitors of lung tumorigenesis in A/J mice. However, chemoprevention by combinations of these compounds in different temporal sequences has not been examined. This is important for developing practical approaches to lung cancer chemoprevention in smokers and ex-smokers. We used a tumor model in which A/J mice are treated with 8 weekly doses of benzo[a]pyrene (B[a]P) plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and killed 19 weeks after the final treatment. In Experiment 1, isothiocyanates or their N-acetylcysteine conjugates were added to the diet (1 or 3 micro mol/g) from 1 week before until 1 week after carcinogen treatment. The compounds were 2-phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), N-acetyl-S-(N-benzyl-thiocarbamoyl)-L-cysteine (BITC-NAC), N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC), and N-acetyl-S-(N-3-phenylpropylthiocarbamoyl)-L-cysteine (PPITC-NAC). Significant reductions in lung tumor multiplicity were observed in mice treated with PEITC, PEITC-NAC, PPITC and PPITC-NAC. PEITC-NAC was chosen for combination studies with MI (Experiment 2). Mice were treated with B[a]P plus NNK without or with PEITC-NAC (3 micro mol/g diet), MI (55.5 micro mol/g diet), or PEITC-NAC plus MI (3 micro mol plus 55.5 micro mol/g diet). Different temporal sequences of dietary additions were investigated: carcinogen treatment phase; post-carcinogen treatment phase; entire experiment; 50% of carcinogen treatment phase until termination; and 75% of carcinogen treatment phase until termination. All treatments reduced lung tumor multiplicity except PEITC-NAC post-carcinogen or from 75% of the carcinogen treatment phase. Reduction of lung tumor multiplicity by PEITC-NAC plus MI was greater than that in the mice treated with the agents alone in all temporal sequences. When all results were combined, PEITC-NAC plus MI was significantly more effective than the agents alone. There was a significant trend for reduction in lung tumor multiplicity with increased duration of treatment by the chemopreventive agents. These results provide a basis for further development of mixtures of PEITC-NAC and MI for chemoprevention of lung cancer.
  • 1: Oncol Rep 2002 Jul-Aug;9(4):887-96
    Phase II study of subcutaneously administered interleukin-2 in combination with medroxyprogesterone acetate and antioxidant agents as maintenance treatment in advanced cancer responders to previous chemotherapy.
    Mantovani G, Maccio A, Madeddu C, Mulas C, Massa E, Astara G, Ferreli L, Mudu MC, Gramignano G, Murgia V, Lusso MR, Mocci M, Cardia A, Mura L
    . Cattedra e Divisione di Oncologia Medica, Policlinico Universitario di Cagliari, Presidio di Monserrato, bivio Sestu, 09042 Monserrato, Cagliari, Italy. mantovan@pacs.unica.it
    An open, non-randomized phase II study was carried out including patients with advanced solid tumors who achieved an objective response or disease stabilization as a result of previous chemotherapy, to receive a maintenance treatment with recombinant interleukin-2 (rIL-2) plus medroxyprogesterone acetate (MPA) plus antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cysteine (NAC). The first study endpoints were to define clinical outcome and toxicity as well as the evaluation of quality of life. As secondary endpoints we measured the changes of lymphocyte absolute count, the serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin after treatment. rIL-2 was administered at a dose of 1.8 MIU subcutaneously 3 times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg/day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered continuously. Twenty-eight patients were enrolled in the study. The median duration of maintenance treatment was 10 months (6-30+). The response to maintenance treatment at September 15, 2001 was: CR 11 patients (39.3%); SD 2 patients (7.1%); PD 15 patients (53.6%). The median duration of response was 11 months (6-34+). The median follow-up duration was 11 months (6-34+). The median OS was not reached. The median PFS was 21.5 months (1-40+). The 1-year survival rate was 72.2%. At September 15, 2001, 16 patients were still surviving. No grade 3/4 toxicity and one grade 2 skin toxicity were observed. We found a significant increase of the absolute lymphocyte count and serum levels of IL-2 and a significant decrease of TNFalpha after treatment. The evaluation of patient subgroups showed the following: the patients alive at the end of study had a significant increase of lymphocyte count, IL-2 and leptin, and a significant decrease of IL-1beta, IL-6 and TNFalpha, whereas the patients who had died had only a significant increase of lymphocyte count and IL-2. Among the patients alive, those in objective clinical response (CR + PR) + those in SD had a significant increase of lymphocyte count, IL-2 and leptin and a significant decrease of IL-1beta, IL-6 and TNFalpha, whereas those with PD had no significant changes in any of the above values. We conclude that the combination of s.c. rIL-2 with oral MPA and anti-oxidant agents ALA and NAC in an intermittent schedule, repeated for a long-term period, is feasible, has a very low toxicity and results in the improvement of biological markers which are predictive for patient outcome.
  • 1: Clin Chem Lab Med 2002 May;40(5):452-5
    The effect of N-acetylcysteine supplementation upon viral load, CD4, CD8, total lymphocyte count and hematocrit in individuals undergoing antiretroviral treatment.
    Spada C, Treitinger A, Reis M, Masokawa IY, Verdi JC, Luiz MC, Silveira MV, Michelon CM, Avila-Junior S, Gil DO, Ostrowskyl S.
    UFSC Clinical Analysis Department, Centro de Ciencias da Saude, Universidade Federal de Santa Catarina, Florianopolis, Brazil. celso@ccs.ufsc.br
    Individuals infected with the human immunodeficiency virus (HIV-1) present with decreased CD4, a progressive increase in viral load, compromised cell immune defense, and hematologic alterations. The aim of this study was to assess the serum viral load, CD4, CD8, lymphocyte count and hematocrit at the beginning of antiretroviral therapy in individuals who were supplemented with N-acetylcysteine (NAC). Twenty volunteers participated in this double-blind, placebo-controlled 180-day study. Ten participants received 600 mg of NAC per day (NAC group) and the other ten serving as a control group received placebo. The above mentioned parameters were determined before treatment, and after 60, 120 and 180 days. In NAC-treated patients hematocrit remained stable and an increase in CD4 cell count took place earlier than that in the control group
  • nhibition of apoptosis and virus replication in feline immunodeficiency virus-infected cells by N-acetylcysteine and ascorbic acid. Mortola E, Okuda M, Ohno K, Watari T, Tsujimoto H, Hasegawa A. Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan. Infection of feline immunodeficiency virus (FIV) has been shown to induce apoptosis that might be associated with the lymphocyte depletion in the infected cats. To investigate the inhibitory effect of antioxidants on FIV-induced apoptosis, we examined the effect of N-acetylcysteine (NAC) and ascorbic acid (AA) on apoptosis and virus replication in feline lymphoblastoid (Fel-039) and fibroblastoid (CRFK) cell lines infected with FIV. The treatment with NAC or AA induced a significant inhibition of viral replication and apoptosis in Fel-039 cells and tumor necrosis factor alpha (TNF-alpha)-treated CRFK cells infected with FIV. Both cell lines in the presence of noncytotoxic concentrations of NAC or AA showed in increase of intracellular glutathione (GSH) level, which might protect the cells against oxidative stresses exerted by FIV infection and TNF-alpha treatment. On the basis of these in vitro results, we suggest that antioxidant therapies aimed at restoring depleted GSH level might be effective for inhibition of viral replication and cell death associated with the development of immunodeficiency. PMID: 9853298 [PubMed - indexed for MEDLINE] homevet sells Nac for animals