Nilla Hemed

Treatment of chronic hepatitis C virus infection via antioxidants : Results of a phase I clinical trial

Background: The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection. Aims: To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants. Methods: Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire. Results: In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted. Conclusions: These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.

Treatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins.

OBJECTIVES:Hepatitis B virus (HBV) is a noncytopathic virus, and hepatocellular injury is mediated by a defective host antiviral immune response. We have previously shown that antiviral immunity can be modulated through oral feeding of viral proteins. The aims of this study were to determine the safety and efficacy of treatment of patients with chronic HBV by means of p.o. administration of HBV envelope proteins.METHODS:A total of 42 chronic HBV patients were treated p.o. with HBV envelope proteins (HBsAg+preS1+preS2), three times/wk for 20–30 wk, and followed for an additional 20 wk. Patients were monitored for HBV-DNA levels, liver enzymes, and liver histology. HBV-directed T cell immune modulation was assessed in vitro by HBV specific T cell-proliferation, cytotoxicity, IFNγ, and IL10 ELISPOT assays, and reverse transcription–polymerase chain reaction cytokines assay.RESULTS:Favorable response in one of the primary endpoints was achieved in 28/42 patients (66.6%) by means of p.o. immune regulation. A significant decrease in viral load was observed in 15 patients (35.7%). HBsAg/HBcAg biopsy scores improved in 41% and 57.1% of patients, respectively. Histological improvement in liver necroinflammatory score was noted in 12/40 patients (30%). In all, 80% showed biochemical response. Five of 19 HBeAg positive patients (26.3%) became negative for HBeAg. A favorable augmentation in anti-HBV specific T cell response, with increased HbsAg specific T cell proliferation (78%), cytotoxicity (75%), and IFNγ positive T cell clones (62.9%) was noted. In addition, a decrease in the IL10 γ positive T cell clones was achieved (48.1%). Natural killer T (NKT) lymphocytes increased significantly in all treated patients.CONCLUSIONS:Immune regulation of the anti-HBV immune response via p.o. administration of HBV envelope proteins alleviated the immune-mediated liver injury while augmenting the effective antiviral immunity.

Induction of oral immune regulation towards liver-extracted proteins for treatment of chronic HBV and HCV hepatitis: results of a phase I clinical trial

Abstract: 
Background: Anti‐viral immunity can be modulated via oral feeding of viral proteins. Hepatitis B and C viral (HBV, HCV)‐associated hepatocellular injury is mediated by a defective host anti‐viral immune response.

Continuous 13C-methacetin breath test differentiates biliary atresia from other causes of neonatal cholestasis.

Background and Aim: Distinguishing biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. Continuous BreathID 13C-methacetin breath test (MBT) is a novel method that determines liver function. Methacetin is metabolized uniquely by the liver and 13CO2 is measured passively, through a nasal cannula in the exhaled breath. The aim of this study was to assess the ability of MBT to differentiate BA from other causes of NC. Methods: MBT was performed in infants with NC before any invasive procedure. Percent dose recovered (PDR) peak and time to peak (TTPP) of 13C recovered were correlated with blood test results and degree of fibrosis on liver biopsy. Results: Fifteen infants were enrolled in the study. Eight were eventually diagnosed as having BA. MBT showed that infants with NC from various causes reached the PDR peak after 44.5 ± 6.7 minutes, whereas infants with BA reached the PDR peak value after 54.7 ± 4.3 minutes (P < 0.005). This suggested low cytochrome P450 1A2 activity in the BA group. The area under the curve (AUC) was 0.95 (95% confidence interval [CI] 0.83–1), sensitivity of 88%, and specificity of 100%. Conclusions: This pilot study shows that MBT can differentiate between BA and other causes of NC by time to peak of methacetin metabolism. The results suggest that MBT may be used as part of the diagnostic algorithm in infants with liver disease. Larger-scale studies should be conducted to confirm these initial observations.

Oral mixture of autologous colon-extracted proteins for the Crohn's disease: A double-blind trial.

AIM To evaluate the safety and efficacy of oral administration of Alequel™, an autologous protein-containing colon extract. METHODS A total of 43 patients were enrolled in a randomized, placebo-controlled, double-blind trial. Patients were orally administered with autologous protein-containing colon extract three doses of autologous study drug per week for 15 wk, for a total of 45 doses. Patients were followed for safety parameters. Remission was defined as a Crohns disease activity index (CDAI) score of less than or equal to 150. All patients were followed for changes in subsets of T cells by fluorescence-activated cell sorting analysis. RESULTS Analysis was performed on a total number of evaluable patients of 14 in the study drug group and 15 in the placebo group. Treatment was well tolerated by all patients. No major treatment-related adverse events were reported or observed in any of the treated patients during the feeding or follow-up periods. Between weeks 6 and 9 of the study, six of the 14 (43%) evaluable subjects who received the study drug achieved a CDAI of 150 or lower. In contrast, five of the 15 (33%) evaluable subjects in the placebo group achieved remission. Between weeks 9 and 12, the remission rates were 50% and 33% for the drug group and placebo group, respectively. Among the drug-treated subjects who achieved remission, the effect of the drug was judged as stable in eight of the 14 subjects as measured by at least two CDAI scores indicating remission in the 15-wk treatment period. A decreased percentage of peripheral natural killer T regulatory cells (a decrease of 28% vs an increase of 16%) and an increased ratio of CD4(+)/CD8(+) T lymphocytes (an increase of 11% vs a decrease of 9%) were noted in subjects with a significant clinical response. CONCLUSION Oral administration of the autologous colonic extract could be a safe and effective for the treatment of patients with moderate to severe Crohns disease.

Activity of cytochrome P450 1A2 in relation to hepatic iron accumulation in transfusion‐dependent β‐thalassaemia major patients

Cytochrome P450 1A2 (CYP1A2) is a cytochrome enzyme with a pivotal role in hepatic drug metabolism. Data from CYP1A2(−/−) mouse suggest that CYP1A2 plays a role in aspects of hepatic iron toxicity. The aim of this study was to assess the activity of CYP1A2 in relation to hepatic iron load in patients with transfusion‐dependent β‐thalassaemia major.

T1241 Promotion of CD4+CD25+FOXP3+ Regulatory Cells by Oral Administration of Locally Acting Delayed Release Low-Dose 6MP Formulation Alleviated Crohn's Disease: Results of Phase I/II Clinical Trial

Introduction: Clinical outcomes are suboptimal in patients with ulcerative colitis (UC). Nonadherence, side effects, ineffective monitoring, limited education, and restricted access to care contribute to poor outcomes. Use of telemedicine for inflammatory bowel disease (IBD) is feasible and improves outcomes. Our goals were to evaluate the effect of a home telemanagement system for UC (UC HAT) on disease activity, quality of life (QoL), and adherence compared to best available care (BAC). Methods: Adults with UC evaluated at either the University of Maryland or the VA were invited to participate. Participants in UC HAT underwent weekly self-testing. Self-testing consisted of answering questions regarding disease activity, adherence, side effects, and measurement of weight. An educational curriculum was delivered at the end of each session. Alerts and action plans were generated based on the results. The BAC arm underwent routine follow up, received written action plans and were given educational fact sheets. Seo Index scores, IBDQ scores, and Morisky Medication Adherence scale scores were measured every 4 months for 1 year. Results: 25 patients were randomized to UC HAT and 22 to BAC. At baseline, 56% of UC HAT participants were on immune suppressants (IS) compared to 27% in BAC (p=0.05). BAC participants had higher QoL scores (191 vs. 172, p=0.02) and lower depression scores (16 vs. 21, p=0.01) than UC HAT participants at baseline. Adherence was poor at baseline (45% BAC and 40% UC HAT, p=NS). After 12 months, 11 (44%) participants withdrew in UC HAT compared to 5 (24%) in BAC. Disease activity, QoL, and adherence were not significantly different between groups at any time point post baseline. In UC HAT, decreased disease activity was seen at 8 and 12 months (-11 and -10 respectively, p=0.07) compared to baseline. Analysis of trial completers, adjusting for baseline disease activity and QoL, demonstrated improved QoL in UC HAT compared to BAC at 12 months (194 vs. 178, p=0.12). UC HAT participants experienced a 12 point increase in QoL scores compared to a 5 point decrease in BAC (p= 0.10). Conclusions: UC HAT did not improve disease activity or self-reported adherence compared to BAC after 1 year. However, significant differences in IS use, QoL, and depression scores were present at baseline between the arms which may have impacted the results. This is supported by a per-protocol analysis adjusted for baseline disease activity and QoL; UC HAT participants had a trend towards improved QoL compared to BAC. Our results suggest a potential benefit of UC HAT. Further research is indicated to determine if telemedicine improves outcomes in patients IBD.

Original contributionTreatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins

Treatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins