lactoferrin and Hepatitis-C--Chronic

Chronic hepatitis C virus (HCV) infection is a significant public health problem, with a worldwide prevalence of approximately 170 million. The standard of care for chronic HCV, a combination of alpha-interferon (IFN) and ribavirin, is only 50% effective, has serious side effects, and can be prohibitively expensive for low-income countries with a high prevalence of HCV. Many patients use natural products, including those who are not eligible for IFN/ribavirin, cannot afford treatment, or fail to respond to IFN.. Extensive literature searches were conducted in order to identify clinical trials and reviews of natural products used for treatment of chronic HCV. This review focuses on the composition, pharmacology and results of clinical trials of three natural products: Oxymatrine, TJ-108/schisandra/Gomisin A and lactoferrin.. Several laboratory and human studies have been performed to evalaute these alternative treatments, but many of these studies are small, uncontrolled and have other important design flaws. While they do offer some safety and efficacy data, none of these studies is conclusive.. Further research is needed on the effectiveness of these natural products for treatment of chronic HCV, including their preparation and standardization.

Topics: Animals; Antiviral Agents; Biological Products; Clinical Trials as Topic; Hepatitis C, Chronic; Humans; Lactoferrin

Topics: Hepatitis C, Chronic; Humans; Iron, Dietary; Lactoferrin; Oxidative Stress; Phlebotomy

In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2), which is preferentially induced by carcinogenic heterocyclic amines. Enhancement of the activities of their phase II counterparts, such as glutathione S-transferase might have also played a critical role in post-initiation suppression in a study of tongue carcinogenesis. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis.

Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Colonic Neoplasms; Hepatitis C, Chronic; Humans; Immunity, Mucosal; Lactoferrin; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Pilot Projects

Hepatitis C virus(HCV), discovered in 1989, is the major causative agent of chronic viral hepatitis. Most patients progress to liver cirrhosis and hepatocellular carcinoma. In the therapy of hepatitis C, only interferon has been used effectively as an anti-HCV reagent in Japan, but its effectiveness is limited to about 30% of cases. Using human hepatocyte cell line which could support efficient HCV replication, we previously found that lactoferrin inhibited HCV infection, and demonstrated that this inhibiting activity was due to the interaction of lactoferrin with HCV. Further analysis found that the carboxyl region of lactoferrin, which partially shows amino acid sequence homology to human CD81, specifically bound to the HCV E2 envelope protein, and identified a 33 amino acids as a critical binding domain of lactoferrin. On the other hand, it has been shown that bovine lactoferrin was effective in some patients with chronic hepatitis received an 8-week course of lactoferrin treatment. Further clinical trials showed that lactoferrin is a promising candidate for adjuvant therapy with interferon in patients with chronic hepatitis C.

Topics: Antigens, CD; Clinical Trials as Topic; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Interferon-alpha; Lactoferrin; Membrane Proteins; Protein Binding; Sequence Homology, Amino Acid; Tetraspanin 28; Viral Envelope Proteins

Lactoferrin has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in patients with chronic hepatitis C (CHC). The aim of this study was to evaluate the effect of combined triple therapy of lactoferrin, interferon and ribavirin in patients with CHC.. A total of 111 Japanese patients with CHC were randomly assigned to a lactoferrin group (n = 50) and a control group (n = 61). The lactoferrin group was treated with lactoferrin for 8 weeks and then with lactoferrin, interferon and ribavirin for 24 weeks; the control group was treated with interferon and ribavirin for 24 weeks. Serum anti-lactoferrin antibody, clinical and laboratory measurement were determined.. The mean HCV RNA titer significantly decreased at the end of lactoferrin monotherapy. Sustained virological response to therapy was significantly higher (P < 0.05) in the lactoferrin responder group (55%) than in the control group (18%).. The results show that the decrease in HCV RNA titer by lactoferrin monotherapy contributes to the effectiveness of the combined therapy of interferon and ribavirin in patients with CHC. Lactoferrin is a potential useful adjunct treatment for patients with CHC.

Topics: Adult; Antibodies; Antiviral Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lactoferrin; Male; Middle Aged; Recombinant Proteins; Ribavirin; RNA, Viral; Time Factors; Treatment Outcome; Viremia

Several studies have suggested that lactoferrin administration may decrease the serum level of hepatitis C virus (HCV) RNA in patients with chronic hepatitis C. The aim of the present study was to confirm the efficacy of orally administered bovine lactoferrin (bLF) in patients with chronic hepatitis C. The patients with chronic hepatitis C randomly received either oral bLF at a dose of 1.8 g daily for 12 weeks, or an oral placebo. The primary endpoint was the virologic response, defined as a 50% or greater decrease in serum HCV RNA level at 12 weeks compared with the baseline. The secondary endpoint was the biochemical response, which was defined as a 50% or greater decrease in the serum alanine aminotransferase (ALT) level at 12 weeks compared with the baseline. One hundred and ninety-eight of 199 patients were evaluable for efficacy and safety. bLF treatment was well tolerated and no serious toxicities were observed. A virologic response was achieved in 14 of 97 patients (14.4%) in the bLF group, and 19 of 101 (18.8%) in the placebo group. There was no significant difference in virologic response rates between the two groups (-4.4%, 95% confidence interval -14.8, 6.1). In addition, bLF intake did not have any favorable effect on the serum ALT level. The virologic responses were not different between two groups in any subgroup analysis. In conclusion, orally administered bLF does not demonstrate any significant efficacy in patients with chronic hepatitis C.

Topics: Administration, Oral; Adult; Aged; Alanine Transaminase; Animals; Cattle; Double-Blind Method; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Lactoferrin; Male; Middle Aged; Placebos; RNA, Viral; Treatment Failure

To assess efficacy of cyclopheron (Polysan production) as opisthorchiasis pretreatment in patients with chronic viral hepatitis C (CHC).. Fifteen CHC patients received cyclopheron by 6 month scheme before dehelminthization. The effect was evaluated by dynamics of clinical symptoms, results of functional hepatic tests, levels of autoantibodies to antigens of native and denaturated DNA, CIC and lactoferrin. Fourteen control patients did not receive pretreatment with cyclopheron.. The study group patients exhibited a relief of asthenovegetative and pain syndromes, aminotranspherases lowered to normal in 11 patients, minimal activity of cytolytic syndrome--in 4 patients. Lactoferrin normalized in all the patients, coefficient of autoantibodies to antigens of native and denaturated DNA fell two-fold. No significant improvement in the clinical and laboratory picture was seen in the controls.. Cyclopheron in patients with CHC combination with chronic opisthorchiasis is recommended as pretreatment before dehelminthization.

Topics: Acridines; Adult; Animals; Antibodies, Helminth; Antigens, Helminth; DNA, Helminth; Female; Hepatitis C, Chronic; Humans; Interferon Inducers; Lactoferrin; Male; Opisthorchiasis; Opisthorchis; Treatment Outcome

Hepatitis C virus (HCV) is one of the most common causes of chronic hepatitis. Interferon is presently the only effective treatment for chronic hepatitis C (CH-C), though its effectiveness is limited. Lactoferrin (LF), which is an 80-kDa, iron-binding glycoprotein, has several biological activities including anti-viral activity, and it was recently reported to inhibit HCV infection in cultured human hepatocytes. The present trial was designed to assess the relationship between the dose of bovine LF (bLF) and the effect of bLF on serum alanine aminotransaminase (ALT) and HCV RNA levels in patients with CH-C. Forty-five patients entered at each of the three dose levels (bLF of 1.8, 3.6, and 7.2 g/day) received orally an 8-week course of bLF. There was no significant relation between the dose of bLF and the effect of bLF on serum ALT or HCV RNA levels. Biochemical (a 50% or greater decrease in the serum ALT level) and virological (a 50% or greater decrease in HCV RNA level) responses were observed in two and four patients, respectively, but all responders relapsed during the follow-up period after bLF treatment. The bLF treatment was generally well tolerated, and no patient had any serious adverse event. In conclusion, the excellent tolerance and potential anti-HCV activity of bLF shown in this trial suggest that further trials using a large number of patients are mandatory. We are currently conducting a double-blind randomized controlled trial comparing bLF with placebo to clarify the anti-HCV activity of bLF in patients with CH-C.

Topics: Adult; Aged; Alanine Transaminase; Dose-Response Relationship, Drug; Female; Hepatitis C, Chronic; Humans; Interferons; Lactoferrin; Male; Middle Aged; RNA, Viral

Hepatitis C virus (HCV) is associated with the development of cirrhosis and hepatocellular carcinoma. We recently found that bovine lactoferrin, a milk protein belonging to the iron transporter family, effectively prevented HCV infection in cultured human hepatocytes (PH5CH8). We tested the hypothesis that lactoferrin inhibits HCV viremia in patients with chronic hepatitis C. Eleven patients with chronic hepatitis C received an 8-week course of bovine lactoferrin (1.8 or 3.6 g/day). At the end of lactoferrin treatment, a decrease in serum alanine transaminase and HCV RNA concentrations was apparent in 3 (75%) of 4 patients with low pretreatment serum concentrations of HCV RNA. However, 7 patients with high pretreatment concentrations showed no significant changes in these indices. This pilot study suggests that lactoferrin is one potential candidate as an anti-HCV reagent that may be effective for the treatment of patients with chronic hepatitis.

Topics: Adult; Aged; Female; Hepatitis C, Chronic; Humans; Lactoferrin; Male; Middle Aged; Pilot Projects; Treatment Outcome; Viremia

Immunofluorescence is a laboratory technique commonly used to study many aspects of biology. It is typically used to visualize the distribution and/or localization of a target molecule in cells and tissues. Immunofluorescence relies on the specificity of fluorescent-labelled antibodies against their corresponding antigens within a cell. Both direct and indirect immunofluorescence approaches can be used which rely on the use of antibodies linked with a fluorochrome. Direct immunofluorescence is less frequently used because it provides lower signal, involves higher cost and less flexibility. In contrast, indirect immunofluorescence is more commonly used because of its high sensitivity and provides an amplified signal since more than one secondary antibody can attach to each primary antibody. In this manuscript, both epifluorescence microscopy and confocal microscopy were used to monitor the internalization of human lactoferrin, an important component of the immune system, into hepatic cells. Moreover, we monitored the inhibitory potential of hLF on the intracellular replication of the Hepatitis C virus using immunofluorescence. Both the advantages and disadvantages associated with these approaches are discussed.

Topics: Antiviral Agents; Cell Line, Tumor; Fluorescent Antibody Technique, Direct; Fluorescent Antibody Technique, Indirect; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Humans; Lactoferrin; Liver; Microscopy, Confocal; Microscopy, Fluorescence; Virus Replication

Topics: Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactoferrin; Male; Viral Load; Viremia

Antilactoferrin antibodies have been reported in patients with several autoimmune disorders, including primary biliary cirrhosis, autoimmune hepatitis and autoimmune cholangitis. We investigated the prevalence and the clinical significance of such autoreactivity in patients with autoimmune and viral chronic liver disease. Sera from 39 patients with autoimmune hepatitis, 51 with primary biliary cirrhosis, 17 with autoimmune cholangitis, 24 with primary sclerosing cholangitis and 28 with HCV-related chronic hepatitis were studied. Positivity for antilactoferrin antibodies was evaluated by Western immunoblotting with purified human lactoferrin. Antilactoferrin antibodies were detected more often in autoimmune liver disorders (25% autoimmune hepatitis, 25% primary biliary cirrhosis, 35% autoimmune cholangitis, 29% primary sclerosing cholangitis) than in HCV-related chronic hepatitis (3.5%, P < 0.02 versus all). Positivity for antilactoferrin antibodies was not associated with a particular clinical or biochemical profile of the underlying liver disease. No correlation was observed between antilactoferrin reactivity and perinuclear antineutrophil cytoplasmic antibodies. Antilactoferrin antibodies are present significantly more often in autoimmune than in viral liver disorders, but they cannot be considered the serological marker of a specific autoimmune liver disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Child; Child, Preschool; Cholangitis; Cholangitis, Sclerosing; Female; Hepatitis C, Chronic; Hepatitis, Autoimmune; Humans; Lactoferrin; Liver Cirrhosis, Biliary; Male; Middle Aged

High mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2 have been identified as novel antigens of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs), and the existence of anti-HMG1 and anti-HMG2 antibodies in a population of patients with ulcerative colitis has been reported.. To investigate whether HMG1 and HMG2 are target antigens for p-ANCAs in autoimmune hepatitis (AIH).. Serum samples from 28 patients with AIH, 44 patients with primary biliary cirrhosis (PBC), 27 patients with chronic hepatitis C, and 23 patients with chronic hepatitis B were tested.. ANCAs were detected by routine indirect immunofluorescence (IIF). Anti-HMG1 and anti-HMG2 antibodies were assayed by enzyme linked immunosorbent assay.. p-ANCAs were detected in 89% (25/28) of patients with AIH, 36% (16/44) of patients with PBC, 11% (3/27) of patients with chronic hepatitis C, and 13% (3/23) of patients with chronic hepatitis B. Anti-HMG1 and/or anti-HMG2 antibodies were detected in 89% (25/28) of patients with AIH, 70% (31/44) with PBC, 26% (7/27) with chronic hepatitis C, and 9% (2/23) with chronic hepatitis B. In AIH, anti-HMG1 and/or anti-HMG2 antibodies were detected in 96% (24/25) of p-ANCA positive patients. The p-ANCA staining pattern detected by IIF using sera from patients with AIH disappeared or decreased in titre after preincubation with a mixture of HMG1/HMG2. The presence and titres of those antibodies in AIH correlated significantly with those of p-ANCA, but not with those of anti-nuclear antibody or anti-smooth muscle antibody.. HMG1 and HMG2 are significant target antigens of p-ANCA in AIH.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Cathepsin G; Cathepsins; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; High Mobility Group Proteins; Humans; Lactoferrin; Liver Cirrhosis, Biliary; Male; Middle Aged; Serine Endopeptidases; Statistics, Nonparametric