Repeated administration of recombinant human serum albumin caused no serious allergic reactions in patients with liver cirrhosis: a multicenter clinical study.

BACKGROUND: We carried out a multicenter study to evaluate the safety of recombinant human serum albumin (rHSA), developed using the methylotrophic yeast Pichia pastoris, during and after repeated administration in patients with liver cirrhosis. METHODS: rHSA was administered to 423 cirrhosis patients with ascites or edema. rHSA was administered three times over 3 days, and each 3-day treatment course was repeated at least three times with an interval of at least 2 weeks between courses. Adverse drug reactions (ADRs) were monitored during and after repeated rHSA administration. Specific antibody titers against Pichia yeast components were measured before and after treatment. Efficacy was evaluated on the basis of changes in serum albumin level, colloid osmotic pressure, and body weight. RESULTS: ADRs were observed in 96 of 423 patients (22.7%), with no serious allergy or difference in the incidence of ADRs observed among the first, second, and third administrations. Specific IgE and IgG antibodies were detected before treatment in 19 and 422 patients, respectively. However, allergic ADRs were observed in 14 patients in whom specific IgE antibodies were not detected. No obvious relationship between allergic ADRs and specific IgE or IgG titers was identified. Serum albumin levels and colloid osmotic pressure increased significantly (P < 0.0001), and body weight decreased significantly (P < 0.0001) after rHSA administration. CONCLUSIONS: rHSA caused no serious allergic reactions even when three treatment courses were administered at intervals of at least 2 weeks.

Eicosapentaenoic acid supplementation for chronic hepatitis C patients during combination therapy of pegylated interferon alpha-2b and ribavirin.

Eicosapentaenoic acid (EPA) (1.8 g/day) was administered to 12 chronic hepatitis C patients receiving combination therapy of pegylated interferon (PEG-IFN) alpha-2b and ribavirin for 48 weeks (EPA group). Twelve patients were not administered EPA (control group). All patients also received vitamin E and C (300, 600 mg/day, respectively) during the therapy. Serum alanine aminotransferase improved to a normal level in 8 of 12 patients from the EPA group and 6 of 12 patients from the control group after 12 weeks. Lymphocyte counts decreased significantly after 8 weeks in the control group, but not the EPA group. T-helper (Th) 1 decreased after 4 weeks in the control group, but not in the EPA group (two-way ANOVA; P < 0.05). Th1/Th2 ratios were elevated in 9 of 12 patients in the EPA group, and 3 out of 12 in the control group (P < 0.05) after 8 weeks. After 12 weeks, the arachidonic acid/EPA molar ratio of erythrocyte membrane phospholipid correlated negatively with the leukocyte count (n = 24, r = -0.439, P < 0.05) and the neutrophil count (n = 24, r = -0.671, P < 0.02). The hemoglobin level improved after 48 weeks compared with 24 weeks in only the EPA group. These findings suggest that EPA supplementation may be useful in therapy for chronic hepatitis C.

Zinc supplementation prevents the increase of transaminase in chronic hepatitis C patients during combination therapy with pegylated interferon alpha-2b and ribavirin.

We investigated the effects of zinc supplementation on clinical observations in chronic hepatitis C patients receiving pegylated interferon (PEG-IFN) alpha-2b plus ribavirin combination therapy. Patients were randomly allocated to receive 150 mg polaprezinc (zinc group, n=11) or no supplement (control group, n=12) daily in addition to PEG-IFN alpha-2b plus ribavirin therapy and 300 mg vitamin E and 600 mg vitamin C supplementation daily for 48 wk. Among the patients who continued treatment, the serum alanine aminotransferase (ALT) level at 12 wk in the zinc group was significantly lower than that in the control group. All patients in the zinc group (9/9) and 67% (8/12) of the control patients at 24 wk, and all patients in the zinc group (7/7) and 60% (6/10) of the control patients at 48 wk showed a decrease in serum ALT levels to within the normal range (7-44 U/L). HCV RNA disappeared in all patients (7/7) in the zinc group and in 8 of 10 control patients at 48 wk. Polaprezinc supplementation decreased plasma thiobarbituric acid reactive substances and prevented the decrease of polyunsaturated fatty acids of erythrocyte membrane phospholipids. No significant differences were observed in the dosage of medicines or other clinical data during the treatment. These observations indicate that polaprezinc supplementation may have induced some antioxidative functions in the liver which resulted in reduced hepatocyte injury during PEG-IFN alpha-2b plus ribavirin therapy.

[A case of gastric arteriovenous malformation forming faded depression].

A 48-year-old man was referred to our hospital because of anemia. Upper gastrointestinal endoscopy showed discolored depressive lesion like gastric cancer, 30mm in diameter, in the greater curvature of the upper gastric body. During the endoscopic examination, pulsative bleeding from the lesion was occurred and we performed clipping hemostasis. We diagnosed a gastric arteriovenous malformation by endoscopic ultrasonograph and angiography. A pylorus preserving-gastrectomy was performed and Pathohistological examination revealed arterio-venous connection in the submucosal layer of the gastric wall.

Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C.

In contrast to the United States, Japanese patients with chronic hepatitis C currently treated with interferon are generally 10 to 15 years older. Older patients, however, tend to experience more frequent adverse events. This study was conducted to clarify the effect of patient age on the efficacy and safety of combination therapy. We consecutively enrolled 208 patients with naïve chronic hepatitis C. Patients were classified into three groups according to age: younger than 50 years of age (n = 52); 50 to 59 years old (n = 83); and 60 years of age or older (n = 73). Interferon alpha-2b therapy was administered daily for 2 weeks, followed by 3 times per week for 22 weeks, while ribavirin was administered daily. Of the 208 study patients, discontinuation of therapy or dose reduction was required in 116 (56%) and was more frequent in older patient groups: 38%, 48%, and 77% for the < 50, 50-59, and > or = 60-year-old patient groups, respectively (P < .001). Multivariate analysis showed patient age to be independently associated with adherence to therapy. A sustained virological response was achieved in 77 (37%) patients, with genotype, viral load, and adherence to therapy associated with this achievement. A tendency toward a lower sustained virological response rate was seen in the older patients. In conclusion, patient age is an important factor contributing to the safety of combination therapy. Thus, treatment schedule should be modified, or other therapeutic modalities should be considered for older patients with chronic hepatitis C.

New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure.

BACKGROUND: Many patients with fulminant hepatic failure die before receiving liver transplantation because of the difficulty of pinpointing the suitable timing for liver transplantation. The revised King's College criteria are useful for patients with acetaminophen-related fulminant hepatic failure; however, in those with non-acetaminophen-related fulminant hepatic failure, a new prognostic system that can accurately identify the suitable timing for liver transplantation is required. METHODS: Using the first sample consisted of eighty patients with fulminant hepatic failure, we examined 2-week poor prognostic parameters at the time of diagnosis of fulminant hepatic failure (day 1) and on days 4, 8, and 15, respectively, and a 2-week prognostic scoring model was constructed. To confirm the accuracy of this model, validation was performed in the second sample consisting of 26 patients. RESULTS: Cause of fulminant hepatic failure (hepatitis B virus or indeterminate), hepatic coma grade (III or IV), systemic inflammatory response syndrome (yes) and ratio of total to direct bilirubin (> 2.0) were associated with 2-week outcomes during days 1-15. Each of these four parameters was valued at +1. The 2-week survival rate in patients scoring <3 was > or = 80% in contrast to less than 30% in patients scoring > or = 3. When this scoring model was applied to the second sample, the sensitivity, specificity, and positive and negative predictive values were 87.5%, 90.0%, 93.3%, and 81.8%, respectively. CONCLUSIONS: This scoring model may be useful for predicting 2-week outcomes and determining the suitable timing for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure.

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-alpha.

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-alpha (PEG-IFN-alpha). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-alpha was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-alpha and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-alpha with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.

Effects of eicosapentaenoic acid supplementation in the treatment of chronic hepatitis C patients.

Eicosapentaenoic acid (EPA) has been shown to exert anti-inflammatory actions. To evaluate the effects of EPA on chronic hepatitis C, we administered EPA ethyl ester capsules to patients receiving the combination therapy of interferon alpha-2b and ribavirin. EPA (1,800 mg/d) was supplemented in combination with vitamin E (300 mg/d) and C (600 mg/d) to 5 chronic hepatitis C patients (EPA group). Five patients were administered vitamin E and C but not EPA (control group). Blood samples were obtained before and after 4, 8, 12 and 24 wk of therapy and analyzed for fatty acid compositions of erythrocyte and plasma and serum 8-hydroxy-2'-deoxyguanosine. EPA in erythrocyte membrane rose to 3 fold the basal level in the EPA group, while it decreased significantly in the control group after 24 wk of therapy. Lymphocyte counts in the EPA group increased to 120.8 +/- 25.4% after 4 wk of therapy and maintained the basal level throughout therapy, whereas the counts decreased significantly in controls. The serum alanine aminotransferase level was improved significantly in the EPA group. Changes in lymphocyte counts following 24 wk of therapy correlated with the EPA level in erythrocyte. The serum 8-hydroxy-2'-deoxyguanosine level at 24 wk in the EPA group was significantly lower than that in controls. These observations may suggest the beneficial effect of EPA supplementation in the treatment of chronic hepatitis C patients.

Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferon therapy.

BACKGROUND: Although a variety of papers demonstrated inhibited hepatocarcinogenesis with interferon (IFN) therapy for chronic hepatitis C, a small number of hepatocellular carcinomas (HCCs) were still observed even in sustained virologic responders. AIMS: To clarify factors affecting the development of HCC, we analyzed the frequency of HCC in sustained virologic responders over a long-term observation period. METHODS: Seven hundred and ninety-two out of the 2623 IFN-treated hepatitis C patients who had undergone liver biopsy showed sustained virologic response. Screening for development of HCC was performed periodically during an average follow-up of 5.1 years. Fibrosis of the pretreatment liver biopsy sample was graded. Risk factors for HCC were analyzed by using Cox proportional hazards regression. RESULTS: Of 792 patients, 23 developed HCC. Univariate analysis showed that stage of hepatic fibrosis, age, and alcohol consumption were significantly associated with a risk of HCC (P<0.001). There was a significant difference in the cumulative incidence between patients stratified according to these variables (P<0.001). CONCLUSIONS: Pretreatment hepatic fibrosis score, age, and alcohol consumption may affect development of HCC even in sustained virologic responders. Thus, patients with these factors should be carefully followed even after eradication of the virus.

[Effect of antiulcer agents on the urea breath test--Comparison between rebamipide and ecabet sodium].

In this study, we assessed whether standard doses of antiulcer drugs rebamipide, and ecabet sodium influence the accuracy of the urea breath test (UBT). Without medication, values of UBT estimated with nondispersive isotope-selective infrared spectrometry did not significantly change during follow-up (average 4.4 months). Then, we randomized 21 H. pylori-positive patients without serious disease to receive either rebamipide or ecabet sodium for 28 days. UBT was performed at baseline, on day 14, on day 28, and 2 weeks after cessation of drugs. On day 14, the median value of UBT declined significantly (p = 0.0113) compared to baseline with ecabet sodium but not with rebamipide. This caused a false-negative result of UBT in one of 11 patients who received ecabet sodium. The decline of UBT resolved 2 weeks after drug cessation. In addition, we performed a crossover study in 11 H. pylori-positive volunteers with these drugs, and ecabet sodium but not rebamipide significantly reduced UBT values (p = 0.0058). These findings indicate that ecabet sodium adversely influences the accuracy of UBT and that the withdrawal of this drug before testing appears to be necessary to avoid false-negative results.

Detection of hepatitis B virus DNA in the liver and serum of patients with hepatitis B surface antigen and hepatitis C virus antibody negative chronic liver disease.

To elucidate the positive frequency of hepatitis B virus (HBV) DNA in patients with hepatitis B surface antigen (HBsAg) and antibody to hepatitis C virus (HCVAb) negative (NBNC) chronic liver disease, we detected serum HBV-DNA using the real-time detection polymerase chain reaction method (RTD-PCR) in comparison with HBsAg and HCVAb negative individuals with normal alanine aminotransferase (ALT). We also revealed the nucleotide sequence of the X-pre-C gene-coding region of intrahepatic HBV-DNA. Serum HBV-DNA was detected in 12 of 36 NBNC patients (five of 22 chronic hepatitis, three of eight liver cirrhosis and four of six hepatocellular carcinoma), whereas none of 31 control individuals were positive for serum HBV-DNA (P<0.01). Serum antibody to hepatitis B core antigen (HBcAb) was positive in nine of 36 in patients with NBNC patients and was positive in nine of 31 in control individuals (n.s). Five of six NBNC patients with serum HBV-DNA positive by RTD-PCR were also positive for intrahepatic HBV-DNA. Analysis of the nucleotide sequence of the X-pre-C coding region of HBV-DNA in the liver showed similar mutation sites of 1677, 1679, 1709, 1753, 1762, 1764. These findings suggested that serum HBV-DNA was more frequently detected in NBNC patients than normal individuals and the presence of low levels of serum HBV-DNA was correlated to the 1677--1764 X-pre-C mutations.