N-Acetylcysteine amide (NACA) and diNACA inhibit H2O2-induced cataract formation ex vivo in pig and rat lenses.

Oxidative stress plays a central role in cataract formation suggesting that antioxidants might slow cataract progression. The anticataract activity of N-acetylcysteine amide (NACA) and (2 R, 2 R')-3,3'-disulfanediyl bis(2-acetamidopropanamide) (diNACA) and/or N-acetylcysteine (NAC), were evaluated in porcine and rat lens models. Cataractogenesis via oxidation was induced with H2O2 and/or glucose oxidase (GO). Porcine lenses were incubated in 0.1 mM, 1 mM, or 10 mM NAC, NACA or diNACA for 24 h. Lenses were then transferred to media containing 0.75 mM H2O2 and 4.63U of GO in order to maintain a constant H2O2 level for an additional 8 h. At the end of incubation, lenses were imaged under darkfield microscopy. Separately, rat lenses were extracted from 3-week-old Wistar rats and incubated with either 10 mM NACA or 10 mM diNACA for 24 h prior to treatment with 0.2U GO to generate a steady source of ∼0.6 mM H2O2. Rat lenses were analyzed by LC-MS/MS to quantify changes in cysteine, cystine, glutathione (GSH) or oxidised glutathione (GSSG) levels in the lens epithelium, cortex or core. Pre-treatment with NACA or diNACA followed by oxidation with H2O2 and/or GO to stimulate cataract formation afforded rapid assessment in ex vivo porcine (32 h) and rat (48 h) lens models. Pre-treatment of isolated porcine lenses with 0.1 mM, 1 mM or 10 mM of either NAC, NACA or diNACA followed by H2O2/GO treatment resulted in reduced lens opacity relative to the lenses exposed to H2O2/GO, with NACA and diNACA reducing opacities to a greater extent than NAC. Rat lenses incubated with 10 mM NACA or 10 mM diNACA without exposure to H2O2 showed no signs of opacities. Pre-treatment of rat lenses with 10 mM NACA or 10 mM diNACA, followed by GO cataract induction resulted in reduced opacities compared to control (GO alone). LC-MS/MS analyses revealed that NACA, but not diNACA, increased cysteine, cystine and GSH levels in rat lens epithelium and cortex regions. Taken together, both NACA and diNACA inhibited cataract formation to a greater extent than NAC (all at 1-10 mM) in an ex vivo porcine lens model. Both NACA and diNACA (both at 10 mM) reduced cataract formation in rat lenses. Based on LC-MS/MS analyses, NACA-induced reduction in opacity observed in rat lenses was attributed to enhanced cysteine and GSH levels while the diNACA-induced reduction in opacity induced did not consistently increase cysteine, cystine and GSH levels and, therefore, appears to involve a different antioxidant mechanism. These screening studies warrant further testing of NACA and diNACA as anticataract agents.

Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS.

Weight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03).

PURPOSE: Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS: A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. RESULTS: There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). CONCLUSION: This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. TRIAL REGISTRATION: UMIN000024784.

A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders.

BACKGROUND: This study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD). METHOD: Forty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200 mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked. RESULTS: The mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect. CONCLUSIONS: Risperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well. TRIAL REGISTRATION: This trial was registered at http://www.irct.ir. The registration number of this trial was IRCT201106103930N6.

Placebo-controlled trial of cytisine for smoking cessation.

BACKGROUND: Cytisine, a partial agonist that binds with high affinity to the α(4)ß(2) nicotinic acetylcholine receptor, is a low-cost treatment that may be effective in aiding smoking cessation. This study assessed the efficacy and safety of cytisine as compared with placebo. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive cytisine or matching placebo for 25 days; participants in both groups received a minimal amount of counseling during the study. The primary outcome measure was sustained, biochemically verified smoking abstinence for 12 months after the end of treatment. Of 1542 adult smokers screened, 740 were enrolled and 370 were randomly assigned to each study group. RESULTS: The rate of sustained 12-month abstinence was 8.4% (31 participants) in the cytisine group as compared with 2.4% (9 participants) in the placebo group (difference, 6.0 percentage points; 95% confidence interval [CI], 2.7 to 9.2; P=0.001). The 7-day point prevalence for abstinence at the 12-month follow-up was 13.2% in the cytisine group versus 7.3% in the placebo group (P=0.01). Gastrointestinal adverse events were reported more frequently in the cytisine group (difference, 5.7 percentage points; 95% CI, 1.2 to 10.2). CONCLUSIONS: In this single-center study, cytisine was more effective than placebo for smoking cessation. The lower price of cytisine as compared with that of other pharmacotherapies for smoking cessation may make it an affordable treatment to advance smoking cessation globally.

Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study.

INTRODUCTION: Since its introduction in 1977, intravenous N-acetylcysteine has become the treatment of choice for paracetamol overdose. The aim of our study was to investigate the existence of predictive factors in the likelihood of developing anaphylactoid reactions to N-acetylcysteine. METHODS: Prospective case-controlled study of all patients who presented to our emergency department (ED) between January 1997 and June 1999, and who were treated with intravenous N-acetylcysteine on the short stay observation ward. RESULTS: Sixty-four patients received N-acetylcysteine infusions; thirty-one (48.4%) developed an anaphylactoid reaction. Nineteen patients who reacted were commenced on N-acetylcysteine prior to receipt of paracetamol concentrations and fifteen (48.4%) were categorised as high-risk. Seventy-one percent of reactions occurred within the first 15 min. Thirteen patients who developed a reaction, had levels which fell below the treatment lines. The levels of a further nine reactors lay above the high-risk but below the normal-risk lines. Only five patients who reacted had levels above the normal-risk line. Two of the patients who reacted to intravenous N-acetylcysteine presented at a later date with a further paracetamol overdose. Both required treatment with intravenous N-acetylcysteine, the first bag being infused over one hour. Neither developed a reaction. CONCLUSION: We report a substantially higher incidence of anaphylactoid reactions to intravenous N-acetylcysteine than has previously been documented. It appears that these reactions are more likely to occur in high-risk patients, when plasma paracetamol concentrations were found to be below the treatment lines and in late presenters. Perhaps, giving the loading dose of N-acetylcysteine over 60 min could reduce the incidence of adverse reactions.

Cardiac teratogenicity of trichloroethylene metabolites.

OBJECTIVES: The hypothesis of this study was that metabolites of trichloroethylene (TCE), dichloroethylene (DCE) and related compounds were responsible for fetal cardiac teratogenic effects seen when TCE or DCE is consumed by pregnant rats during organogenesis. Identification of teratogenic metabolites would allow more accurate assessment of environmental contaminants and public health risks from contaminated water or possibly municipal water supplies which, when chlorinated, may produce these potentially dangerous chemicals. BACKGROUND: Human epidemiologic studies and previous teratogenic studies using chick embryos and fetal rats have shown an increased incidence of congenital cardiac lesions in animals exposed to TCE and DCE. METHODS: Metabolites and compounds studied in drinking water exposure included: trichloroacetic acid (TCAA), monochloroacetic acid (MCAA), trichloroethanol (TCEth), carboxy methylcystine (CMC), trichloroacetaldehyde (TCAld), dichloroacetaldehyde (DCAld), and dichlorovinyl cystine (DCVC). Compounds were administered to pregnant rats during fetal heart development. RESULTS: Fetuses of rats receiving 2,730 ppm TCAA in drinking water were the only group that demonstrated a significant increase in cardiac defects (10.53%) compared with controls (2.15%) on a per fetus basis (p = 0.0001, Fischer's exact test), and a per litter basis (p = 0.0004, Wilcoxon and p = 0.0015, exact permutation tests). Trichloroacetic acid also demonstrated an increased number of implantation and resorption sites (p < 0.05) over controls. Other maternal and fetal variables showed no statistically significant differences between treated and untreated groups. CONCLUSIONS: Of the metabolites tested, only TCAA appeared to be a specific cardiac teratogen in the fetus when imbibed by the maternal rat.

Hypercholesterolemia induced by cholesterol- or cystine-enriched diets is characterized by different plasma lipoprotein and apolipoprotein concentrations in rats.

This study examined the effects of diet-induced hypercholesterolemia on plasma apolipoprotein (apo) concentrations and hepatic apolipoprotein mRNA levels in rats. Hypercholesterolemia was induced by feeding rats diets containing an excess of either cholesterol or cystine. After cholesterol feeding, plasma apo E and apo B concentrations were lower (-65%, P < 0.001) and greater (+39%, P < 0.01), respectively, compared with control diet-fed rats. After cystine feeding, plasma apo B and apo E concentrations were greater (+46%, P < 0.01 and +75%, P < 0.001, respectively) and plasma apo A-IV concentration was lower (-29%, P < 0.001) than in rats fed control diet. After cholesterol or cystine feeding, a tendency (one-way ANOVA, P = 0.08) for greater apo B mRNA level (+42% and +47%, respectively) was observed compared with control diet-fed rats. No difference emerged between groups for apo E and apo A-I mRNA levels. An opposite effect of cholesterol and cystine feeding was shown for apo A-IV mRNA level, i.e., higher after cholesterol feeding (+47%, P < 0.05) and lower after cystine feeding (-65%, P < 0.01). From this work, it seems that hypercholesterolemia induced by dietary cholesterol or by increased cholesterogenesis in cystine-fed rats is characterized by different plasma lipoprotein and apolipoprotein concentrations and is associated with different apolipoprotein gene expression in the liver.

[Drug-induced oesophageal ulcers (author's transl)]. / Medikamentös induzierte Osophagusulzera.

Within a one-year period seven patients were observed who had developed ulcers of the upper and mid oesophagus after treatment with doxycycline hydrochloride (n = 3), emepronium bromide (n = 3) or Pantogar (n = 1). In each instance the drug had apparently been swallowed dry. The typical symptoms were a sudden onset of retrosternal chest pain and odynophagia during bed rest. Once the drug had been discontinued and treatment with antacid combined with topical anaesthetics and/or alginic acid instituted the symptoms disappeared within a few days. The authors stress that drugs should be swallowed only with good amounts of fluid and generally not immediately before bed rest.