Unmet Needs for the Treatment of Chronic Hepatitis E Virus Infection in Immunocompromised Patients.

Hepatitis E virus (HEV) is the most prevalent hepatitis virus worldwide. Genotypes 3 (HEV3) and 4 (HEV4) as well as rat HEV can lead to chronic hepatitis E and cirrhosis in immunosuppressed patients. Within the last decade, several options for treating chronic hepatitis have been developed and have achieved a sustained virological response. However, there are still unmet needs such as optimizing immunosuppression to allow HEV clearance with or without ribavirin, as well as alternative therapies to ribavirin that are discussed in this paper.

IgG4-related Autoimmune Hepatitis with a Suspected Drug-induced Etiology.

A 69-year-old man was referred to our department with acute hepatitis. He had been newly treated with benidipine hydrochloride for two months. His blood test results were as follows: aspartate aminotransferase, 1,614 IU/L; alanine aminotransferase, 1,091 IU/L and anti-smooth muscle antibody, ×80. Needle liver biopsy specimen showed interface hepatitis with mainly lymphocytic infiltration and bridging fibrosis in the periportal area. Immunohistochemistry revealed lymphocytic infiltration positive for IgG4. We diagnosed him with IgG4-related AIH with an etiology that was suspected of being drug-induced. Oral prednisolone was started and then tapered after achieving biochemical remission. Hepatitis recurred after the cessation of steroids; however, remission was achieved with ursodeoxycholic acid.

Clarifying of the potential mechanism of Sinisan formula for treatment of chronic hepatitis by systems pharmacology method.

Chronic hepatitis is a general designation class of diseases, which results in different degrees of liver necrosis and inflammatory reaction, followed by liver fibrosis, may eventually develop into cirrhosis. However, the molecular pathogenesis of chronic hepatitis is too complex to elucidate. Herbal medicines, featured with multiple targets and compounds, have long displayed therapeutic effect in treating chronic hepatitis, though their molecular mechanisms of contribution remain indistinct. This research utilized the network pharmacology to confirm the molecular pathogenesis of chronic hepatitis through providing a comprehensive analysis of active chemicals, drug targets and pathways' interaction of Sinisan formula for treating chronic hepatitis. The outcomes showed that 80 active ingredients of Sinisan formula interacting with 91 therapeutic proteins were authenticated. Sinisan formula potentially participates in immune modulation, anti-inflammatory and antiviral activities, even has regulating effects on lipid metabolism. These mechanisms directly or indirectly are involved in curing chronic hepatitis by an interaction way. The network pharmacology based analysis demonstrated that Sinisan has multi-scale curative activity in regulating chronic hepatitis related biological processes, which provides a new potential way for modern medicine in the treatment of chronic diseases.

The use of Chinese herbal medicine as an adjuvant therapy to reduce incidence of chronic hepatitis in colon cancer patients: A Taiwanese population-based cohort study.

ETHNOPHARMACOLOGICAL RELEVANCE: There is a decided lack of in-depth studies to evaluate the effectiveness of Chinese Herbal Medicine (CHM) as an adjuvant therapy on the incidence of chronic hepatitis in patients with colon cancer. AIM OF THE STUDY: The aim of this study is to assess whether CHM treatment decreased the incidence of chronic hepatitis in colon cancer patients who received conventional Western medical treatment. MATERIALS AND METHODS: A Taiwanese nationwide population-based study of colon cancer patients receiving Western medicine treatment in conjunction with CHM treatment, using data provided by the National Health Insurance (NHI) Research Database, was conducted. A total of 61676 patients were diagnosed with colon cancer in Taiwan within the defined study period, from 1997 to 2010. After randomly equal matching for age, sex, excluding patients younger than 18 years of age, chronic hepatitis before colon cancer diagnosis date, receiving acupuncture and/or moxibustion and taking CHM for less than 30 days, data from 155 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence of CHM and the therapeutic potential of herbal products in treating patients with colon cancer. RESULTS: CHM used for patients with colon cancer exhibited significantly decreased incidence rates of chronic hepatitis [hazard ratio (HR)=0.53; 95% confidence interval (CI):0.38-0.74], with multivariate adjustment, compared to those without CHM use. The protective effect of CHM treatment with statistical significance across the stratification of age, gender, co-morbidity and treatment modality was noted. The cumulative incidence of chronic hepatitis was also reduced in patients with colon cancer receiving CHM treatment during a five-year period. In this study, we provide the ten most used single herbs and herbal formulas that were prescribed for patients with colon cancer; moreover, we identify the eight single herbs and five formulas used in CHM treatment which significantly decreased incidence of chronic hepatitis among colon cancer patients. CONCLUSIONS: This nationwide retrospective cohort study determined that therapy using CHM as an adjuvant modality may have a significant impact on liver protection in patients with colon cancer.

Curcumin, Silybin Phytosome(®) and α-R-Lipoic Acid Mitigate Chronic Hepatitis in Rat by Inhibiting Oxidative Stress and Inflammatory Cytokines Production.

Chronic hepatitis is recognized as a worldwide health problem that gradually progresses towards cirrhosis and hepatocellular carcinoma. Despite the large number of experiments using animal models for allergic hepatitis, it is still difficult to produce a picture of chronic hepatitis. Therefore, this study was conducted to introduce an animal model approximating to the mechanism of chronicity in human hepatitis. The study also aimed to examine the hepatoprotective effects of curcumin, silybin phytosome(®) and α-R-lipoic acid against thioacetamide (TAA)-induced chronic hepatitis in rat model. TAA was administered intraperitoneally at a dose of 200 mg/kg three times weekly for 4 weeks. At the end of this period, a group of rats was killed to assess the development of chronic hepatitis in comparison with their respective control group. TAA administration was then discontinued, and the remaining animals were subsequently allocated into four groups. Group 1 was left untreated, whereas groups 2-4 were allowed to receive daily oral doses of curcumin, silybin phytosome(®) or α-R-lipoic acid, respectively, for 7 weeks. Increases in hepatic levels of malondialdehyde associated with TAA administration were inhibited in groups receiving supplements. Furthermore, glutathione depletion, collagen deposition, macrophage activation and nuclear factor κappa-B expression as well as tumour necrosis factor-α and interleukin-6 levels were significantly decreased in response to supplements administration. Serological analysis of liver function and liver histopathological examination reinforced the results. The above evidence collectively indicates that the antioxidant and anti-inflammatory activities of curcumin, silybin phytosome(®) and α-R-lipoic acid may confer therapeutic efficacy against chronic hepatitis.

In Vitro and in Vivo Inhibitory Effects of Glycyrrhetinic Acid in Mice and Human Cytochrome P450 3A4.

Glycyrrhetinic acid (GA) has been used clinically in the treatment of patients with chronic hepatitis. This study evaluated the effect of GA on the activity of five P450(CYP450) cytochrome enzymes: CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, in human liver microsomes (HLMs) and recombinant cDNA-expressed enzyme systems using a HPLC-MS/MS CYP-specific probe substrate assay. With midazolam as the probe substrate, GA greatly decreased CYP3A4 activity with IC50 values of 8.195 µM in HLMs and 7.498 µM in the recombinant cDNA-expressed CYP3A4 enzyme system, respectively. It significantly decreased CYP3A4 activity in a dose- but not time-dependent manner. Results from Lineweaver-Burk plots showed that GA could inhibit CYP3A4 activity competitively, with a Ki value of 1.57 µM in HLMs. Moreover, CYP2C9 and CYP2C19 could also be inhibited significantly by GA with IC50 of 42.89 and 40.26 µM in HLMs, respectively. Other CYP450 isoforms were not markedly affected by GA. The inhibition was also confirmed by an in vivo study of mice. In addition, it was observed that mRNA expressions of the Cyps2c and 3a family decreased significantly in the livers of mice treated with GA. In conclusion, this study indicates that GA may exert herb-drug interactions by competitively inhibiting CYP3A4.

Medical management of chronic liver diseases in children (part I): focus on curable or potentially curable diseases.

The management of children with chronic liver disease (CLD) mandates a multidisciplinary approach. CLDs can be classified into 'potentially' curable, treatable non-curable, and end-stage diseases. Goals pertaining to the management of CLDs can be divided into prevention or minimization of progressive liver damage in curable CLD by treating the primary cause; prevention or control of complications in treatable CLD; and prediction of the outcome in end-stage CLD in order to deliver definitive therapy by surgical procedures, including liver transplantation. Curative, specific therapies aimed at the primary causes of CLDs are, if possible, best considered by a pediatric hepatologist. Medical management of CLDs in children will be reviewed in two parts, with part I (this article) specifically focusing on 'potentially' curable CLDs. Dietary modification is the cornerstone of management for galactosemia, hereditary fructose intolerance, and certain glycogen storage diseases, as well as non-alcoholic steatohepatitis. It is also essential in tyrosinemia, in addition to nitisinone [2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione] therapy, as well as in Wilson disease along with copper-chelating agents such as D-penicillamine, triethylenetetramine dihydrochloride, and ammonium tetrathiomolybdate. Zinc and antioxidants are adjuvant drugs in Wilson disease. New advances in chronic viral hepatitis have been made with the advent of oral antivirals. In children, currently available drugs for the treatment of chronic hepatitis B virus infection are standard interferon (IFN)-α-2, pegylated IFN-α-2 (PG-IFN), and lamivudine. In adults, adefovir and entecavir have also been licensed, whereas telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine, and thymosin α-1 are currently undergoing clinical testing. For chronic hepatitis C virus infection, the most accepted treatment is PG-IFN plus ribavirin. Corticosteroids, with or without azathioprine, remain the basic strategy for inducing remission in autoimmune hepatitis. Ciclosporin (cyclosporine) and other immune suppressants may be used for patients who do not achieve remission, or who have significant side effects, with corticosteroid/azathioprine therapy. The above therapies can prevent, or at least minimize, progression of liver damage, particularly if started early, leading to an almost normal quality of life in affected children.

Utility of nano-sized, water-in-oil emulsion as a sustained release formulation of glycyrrhizin.

The aim of this study was to determine the efficiency of nano-sized water-in-oil (w/o) emulsions that encapsulate glycyrrhizin (GZ) (Rp-I) as a sustained release formulation for subcutaneous administration. Four formulations were assessed in rats for 8-72 h: nano-sized water-in-oil (w/o) emulsion encapsulating GZ (Rp-I), GZ aqueous solution (Rp-II), oil-in-water (o/w) emulsion containing GZ (Rp-III), and w/o emulsion containing solid GZ (Rp-IV). All had a GZ concentration of 150 mg/ml. Over an 8-h period, GZ elimination in bile after subcutaneous administration of Rp-I, Rp-II, Rp-III, and Rp-IV (50 mg/kg GZ) was 10.8%, 97.0%, 81.0%, and 7.1%, respectively. The elimination of GZ into bile after the administration of Rp-IV was the lowest (30.5%) at the 72-h endpoint, dropping significantly from 48 to 72 h. On the other hand, the elimination rate of GZ after the administration of Rp-I was sustained at a constant level (1.8-2.1 mg/24 h) over 72 h. GZ concentration in liver at 72 h in Rp-I was highest (19.9 µg/g tissue) among the four formulations, suggesting that the release of GZ from the Rp-I formulation is constant, at least up to 72 h after administration. These results suggest that a nano-sized w/o emulsion is useful as a sustained release formulation for long-term therapy of chronic hepatitis.

Effect of medical ozone therapy on renal blood flow and renal function of patients with chronic severe hepatitis.

BACKGROUND: Medical ozone therapy system was reported to have certain effects on the treatment of severe hepatitis, but its mechanism is not very clear. One of the causes of death of severe hepatitis is complication of renal damage or hepatorenal syndrome. The present study aimed to observe effects of medical ozone therapy system on plasma renin activity (PRA), angiotensin II (AII), aldosterone (ALD), renal blood flow and renal function of patients with chronic severe hepatitis and explore mechanisms of medical ozone therapy in the treatment of severe hepatitis. METHODS: Eighty-five cases with chronic severe hepatitis were randomly divided into ozone therapy group (43 cases) and control group (42 cases). The patients in the ozone therapy group were treated with basic treatments plus ozone therapy system. Basic autohemotherapy was used. One hundred milliliter venous blood was drawn from each patient, and was mixed with 100 ml (35 µg/ml) medical ozone and then was returned the blood to the patient intravenously, once every other day for 20 days. Only the basic treatments were given to the control group. PRA, AII, ALD, renal blood flow and damage to renal function of the two groups before treatment and 20 days after treatment were compared. Survival rates were also compared. RESULTS: Twenty days after the treatment, in ozone therapy group, PRA was (1.31 ± 0.12) ng·ml⁻¹·h⁻¹, AII (111.25 ± 17.35) pg/ml, ALD (251.31 ± 22.60) pg/ml, which decreased significantly compared with those before treatment (PRA (2.23 ± 0.13) ng·ml⁻¹·h⁻¹, AII (155.18 ± 19.13) pg/ml, ALD (405.31 ± 29.88) pg/ml, t = 4.67 - 14.23, P < 0.01), also lower than those of control group 20 days after the treatment (PRA (2.02 ± 0.11) ng·ml⁻¹·h⁻¹, AII (162.21 ± 15.32) pg/ml, ALD (401.20 ± 35.02) pg/ml, t = 4.97 - 15.61, P < 0.01); renal blood flow was (175.15 ± 28.20) ml/min, which increased compared with that before the treatment ((125.68 ± 21.25) ml/min) and was higher than that of control group 20 days after the treatment ((128.59 ± 23.15) ml/min, t = 4.78, 4.61, P < 0.01). Renal damage occurred in 2 cases (5%) in ozone therapy group, less than that in control group (9 cases, 21%) (χ² = 5.295, P < 0.05). Thirty-three cases (77%) in ozone therapy group vs. 16 cases (38%) in control group survived (χ² = 12.993, P < 0.01). CONCLUSIONS: Basic treatment plus medical ozone therapy for patients with chronic severe hepatitis could decrease PRA, AII and ALD levels significantly increase renal blood flow, prevent renal damage to certain extent and improve survival rate of the patients.

[Rationale for using essential phospholipids in chronic diseases of the liver: the dynamics of electric and viscoelastic parameters of erythrocytes].

Under supervision there were 38 men (age from 36 till 57 years) with diffuse hepatic diseases (DHD) in stadia of hepatitis, 27--in dynamics of treatment of essential phospholipids. Is experimentally established: structure-functional erythrocyte characteristics by methods of dielectrophoresis, thin-layer chromatography correlate with lipid and phospholipid composition of red cell membranes. The low level of phospholipids in erythrocyte membranes and direction of changes in their fractional composition in the DHD is the basis for the use of essential phospholipids. Against the background of therapy noted a significant increase in amplitude of deformation, polarizability, capacity, speed of movement of red blood cells to the electrodes and lower levels of generalized indicators of viscosity, rigidity, electrical conductivity, index of aggregation and destruction.

Frequency and pattern of Chinese herbal medicine prescriptions for chronic hepatitis in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) has been commonly used in treating liver diseases in Asian countries. AIM OF STUDY: To conduct a large-scale pharmacoepidemiological study and evaluate the frequency and pattern of CHM prescriptions in treating chronic hepatitis. MATERIALS AND METHODS: We obtained the database of traditional Chinese medicine outpatient claims from the national health insurance in Taiwan for the whole 2002. Patients with chronic hepatitis were identified by the corresponding diagnosis of International Classification of Disease among claimed visiting files. Corresponding prescription files were analyzed, and association rule were applied to evaluate the co-prescription of CHM in treating chronic hepatitis. RESULTS: Among the 91,080 subjects treated by CHM for chronic hepatitis, the peak age was in the 40 s, followed by 30 s and 50 s. Male/female ratio was 2.07:1. Long-dan-xie-gan-tang and Saliva miltiorrhiza (Dan-shen) were the most commonly prescribed Chinese herbal formula and single herbal drug, respectively. The most common two-drug prescription was Jia-wei-xia-yao-san plus Saliva miltiorrhiza, and the most common three-drug prescription was Jia-wei-xia-yao-san plus Saliva miltiorrhiza and Artemisia capillaries (Yin-chen-hao). CONCLUSIONS: This study showed the utilization pattern of Chinese herbal drugs or formulae in treating chronic hepatitis. Further researches and clinical trials are needed to evaluate the efficacy of these Chinese herbs or its ingredients in treating chronic hepatitis.

[Novel formulations of a liver protection drug glycyrrhizin].

In Japan, glycyrrhizin injections have been used as a therapeutic drug for allergy inflammation since 1948 and for chronic hepatitis since 1979. A 20 ml injection of glycyrrhizin contains 53 mg of monoammonium glycyrrhizinate (40 mg as glycyrrhizin acid), 400 mg of glycine, and 20 mg of L-cysteine. Patients receiving glycyrrhizin injections two or three times per week are forced to accept a decline in quality of life. Because administering glycyrrhizin by injection has some disadvantages, many researchers have systematically searched for novel glycyrrhizin formulations that can be administered through oral, rectal, intranasal, and subcutaneous routes. There are two problems, however, in developing new formulations: (1) glycyrrhizin has low membrane permeability and is thus poorly absorbed, and (2) highly concentrated glycyrrhizin readily forms gels in aqueous solutions. Here, we describe the utility of glycyrrhizin formulations prepared in safe solubility agents and absorption-enhancing agents, as assessed in animal experiments. We also discuss pharmaceutical issues in developing various glycyrrhizin formulations. In the near future, convenient pharmaceutical preparations of glycyrrhizin will be developed for chronic hepatitis patients who require glycyrrhizin therapy.

[Clinical observation on auxiliary treatment with suanzaoren decoction for chronic severe hepatitis].

OBJECTIVE: To investigate the curative effect and safety of auxiliary treatment with Suanzaoren Decoction (SZRD) on patients with chronic severe hepatitis (CSH). METHODS: Sixty patients, with the diagnosis in accordance with the diagnostic criterion of CSH, were assigned to the treated group and the control group, 30 in each group. Patients in the control group were treated with comprehensive therapy including symptomatic supportive treatment, anti-infective therapy and artificial liver plasmapheresis etc., while those in the treated group were orally taken SZRD additionally. Patients' condition of sleeping and changes of total bilirubin (TBIL), prothrombin activity (PTA), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) were observed before and after treatment, and the adverse reactions were observed as well. RESULTS: The sleeping status were significantly improved in the treated group after treatment, and the serum levels of TBIL, TNF-alpha and IL-1 were significantly decreased. The improvement rate was 66.7% (20/30) and significantly higher than that (40.0%, 12/30) in the control group. CONCLUSION: SZRD can significantly improve the sleeping status of CSH patients, alleviate the hepato-cellular injury by inflammatory cytokines and without obvious adverse reaction.

Silymarin treatment of viral hepatitis: a systematic review.

Silymarin from the milk thistle herb (Silybum marianum) is used by many patients with chronic viral hepatitis, but its efficacy remains unknown. We performed a systematic review of silymarin for the treatment of chronic viral hepatitis B and C. An exhaustive search strategy identified 148 papers that studied silymarin compounds in liver disease. Of these, four trials included patients with hepatitis C, one included hepatitis B patients, and two, unspecified chronic viral hepatitis. However, only one trial exclusively studied patients with hepatitis C, and none involved patients with only hepatitis B. Silymarin treatment resulted in a decrease in serum transaminases compared with baseline in four studies, and compared with placebo in only one study. There is no evidence that silymarin affects viral load or improves liver histology in hepatitis B or C. No studies were found that investigated the use of silymarin concomitantly with interferon, nucleoside analogues, or other conventional treatments for hepatitis B or C. In conclusion, silymarin compounds likely decrease serum transaminases in patients with chronic viral hepatitis, but do not appear to affect viral load or liver histology. Nevertheless it may be worthwhile to determine its effects in conjunction with standard antiviral treatment.

Effects of selenium on peripheral blood mononuclear cell membrane fluidity, interleukin-2 production and interleukin-2 receptor expression in patients with chronic hepatitis.

AIM: To study the effect of selenium on peripheral blood mononuclear cell (PBMC) membrane fluidity and immune function in patients with chronic hepatitis. METHODS: PBMCs were pretreated with selenium (1.156x10(-7) mol/L) for 6 h in vitro or extracted directly from patients after administration of selenium-yeast continuously for 8-12 wk (200 microg/d), and then exposed to Con-A for 48 h. The membrane fluidity, interleukin-2 (IL-2) production and interleukin-2 receptor (IL-2R) expression in PBMCs and malondialdehyde (MDA) concentration in medium and lipid peroxide (LPO) in plasma were determined. RESULTS: The PBMC membrane fluidity, IL-2 production and IL-2R expression in patients with chronic hepatitis were significantly lower than those in healthy blood donators (particle adhesive degree R, 0.17+/-0.01 vs 0.14+/-0.01, P<0.01; IL-2, 40.26+/-9.55 vs 72.96+/-11.36, P<0.01; IL-2R, 31.05+/-5.09 vs 60.58+/-10.56, P<0.01), and the MDA concentration in medium in patients with chronic hepatitis was significantly higher than that in healthy blood donators (1.44+/-0.08 vs 0.93+/-0.08, P<0.01). Both in vitro and in vivo administration of selenium could reverse the above parameters. CONCLUSION: Supplement of selenium can suppress lipid peroxidation, and improve PBMC membrane fluidity and immune function in patients with chronic hepatitis.

Effects of homeopathic preparations on the liver in rats with acute and chronic toxic hepatitis.

Ultralow doses of antibodies to phenobarbital and their mixture (1:1) with ultralow doses of antibodies to cholecystokinin reduced the severity of structural and metabolic disturbances in the liver of rats with acute CCl4-induced hepatitis. The mixture of antibodies had no effect on the course of CCl4-induced hepatitis.

[Different therapeutic approaches for chronic diffuse liver lesions using ornicetil, lactulose, etimizol and corinfar]. / Dyferentsiiovani pidkhody do likuvannia khronichnykh dyfuznykh urazhen' pechinky iz zastosuvanniam ornitsetylu, laktulozy, etymizolu ta korynfaru.

Different therapeutic regimens were tried in 67 patients with hepatic cirrhosis and in 54 patients with chronic hepatitis depending on the leading pathological syndrome. Treatment schemes involved the use of the drug ornicetil in patients having acute episodes of portal systemic encephalopacy, lactulose in those presenting with an increased content of ammonia in the blood and symptoms of chronic portal systemic encephalopacy; etimizol was given to those patients with an apperant antioxidant imbalance. Differentiated approaches to the institution of curative measures permitted improving considerably the patients' medical rehabilitation, achieving regression of pathological manifestations. It has been found out that the above drugs exert a positive effect on the cytolytic and mesenchimal-inflammatory syndromes and will, we believe, come to be widely used for treating diffuse lesions of the liver.

Hepatoprotective properties of aqueous extract from Pentaphylloides fruticosa during chronic toxic hepatitis.

Hepatoprotective properties of Pentaphylloides fruticosa L. aqueous extract were studied using rat model of chronic toxic hepatitis. The preparation normalized alanine aminotransferase activity and bilirubin concentration in the plasma. Aqueous extract of Pentaphylloides fruticosa produced a protective effect on microsomal metabolism of xenobiotics and lipid peroxidation activity in the plasma and microsomal liver fraction.