Takeshi Kurihara

Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid

tive and well tolerated (3). In this study, although the majority of the patients cleared or significantly decreased HBV DNA, only 7.4% cleared HBeAg and 5.6% seroconverted to anti-HBe. Similar to interferona treatment, high baseline ALT values were the only predictive parameter for response. Efficacy and tolerability of treatment beyond 1 yr needs to be investigated and our patients are continuing to take lamivudine. Although we could not examine mutation in the YMDD motif, development of resistance to lamivudine might be a possible explanation in our nonresponder patients. A combination anti-HBV regimen using lamivudine and other agents with different mechanisms of action should be investigated to maximize the elimination of the viral infection while minimizing or preventing damage to the liver cells and tissues and the development of viral resistance (6). In conclusion, although lamivudine alone reduces HBV DNA levels significantly, it is ineffective on HBeAg to anti-HBe seroconversion during 1 yr of treatment.

Investigation into the efficacy of bezafibrate against primary biliary cirrhosis, with histological references from cases receiving long term monotherapy

yps smaller than 2 cm (5). Our case also showed a change in shape from semipedunculated to pedunculated with a long stalk from the first to the second endoscopic examinations and displayed rapid growth to more than 2 cm between the second and the third endoscopic examinations. We used p53, Ki-67, and PCNA as indices of cell proliferation and malignant transformation markers because they are simple and easy to use. Because the major pool of proliferating cells resides in the superficial area of gastric carcinoma (6), the investigation of tumor-proliferating activity from biopsy specimens could be a very useful indicator to diagnose malignancy. Abnormal accumulation of p53 protein occurs only in cancerous lesions, and p53 overexpression is also detected in cases of hyperplastic polyps harboring carcinoma (2, 7). The rate of p53 mutation in gastric carcinoma, however, is about 60% (8). PCNA-positive cells also tend to localize within cancer tissues (9). Our case showed that PCNA-positive cells existed only in dysplastic or cancer cells. In early gastric cancer, the mean Ki-67–labeling index is about 30% (6, 10). The mean Ki-67 index at second endoscopic examination in our case was 36.3%, which indicated the possibility of malignant transformation. Thus, a combination of several proliferative markers may be necessary to detect malignant transformation. The results of these immunohistochemical findings showed malignant transformation at least at the second endoscopic examination, when, in retrospect, malignant transformation could have been recognized from the slight macroscopic change; this consideration may be useful in deciding the course of treatment. To detect malignant transformation of hyperplastic polyps, an immunohistochemical examination could avoid unnecessary follow-up and lead to economical treatment because of early carcinoma diagnosis.

Relationship between endothelin and thromboxane A2 in rat liver microcirculation

In our previous study, we determined changes in hepatic blood flow using a Laser Doppler blood flow meter after i.v. injection of endothelin-1 (ET-1) or endothelin-3 (ET-3) at 2 nmol/kg in rats and found that ET-3 caused greater decreases in blood flow than ET-1. In the present study, we determined how the arachidonic acid cascade, mainly thromboxane A2 (TXA2), is related to ET-1 and ET-3 using indomethacin (INDO), which inhibits the biosynthesis of prostaglandin (PG), and OKY-046, a selective inhibitor of TXA2 synthesis. In the first series of experiments, ET-1 and ET-3 were administered after inhibiting the biosynthesis of PG by s.c. injection of 2 mg/kg of INDO. While INDO failed to inhibit the slight decrease in hepatic blood flow induced by ET-1, it significantly inhibited the marked decrease in hepatic blood flow elicited by ET-3. In the next series of experiments, ET-1 and ET-3 were administered after administration of 20 mg/kg of OKY-046. OKY-046 showed no effects in animals treated with ET-1, as in those pre-treated with INDO, while it significantly inhibited the decreases in hepatic blood flow induced by ET-3. These findings suggest that ET-1 decreases hepatic blood flow due to its direct effects although to a lesser extent than ET-3, while ET-3 does so due not only to its direct effects but also to TXA2-mediated effects. It is therefore likely that in addition to ET family peptides, PG-mediated mechanisms are involved in the regulation of hepatic microcirculation by ETs.

ET-3 sensitive reduction of tissue blood flow in rat liver.

Changes in gastric mucosal and hepatic tissue blood flow were simultaneously determined using a laser-Doppler blood flow meter in rats given i.v. injection of endothelin-1 (ET-1) and endothelin-3 (ET-3), both at 2 nmol/kg. Gastric mucosal blood flow decreased significantly after administration of ET-1 compared to after administration of ET-3. Decreases in blood flow due to ET-1 were reversed by pre-treatment with 10 mg/kg of BQ-123 (sodium salt), an ETA receptor antagonist, to levels comparable to those induced by ET-3, but BQ-123 had no effects on decreases in blood flow due to ET-3. On the other hand, decreases in hepatic tissue blood flow by ET-3 were significant compared to those by ET-1. Decreases in hepatic tissue blood flow due to ET-1 were slightly inhibited by pre-treatment with 10 mg/kg of BQ-123, but it had no effect at all on decreases due to ET-3. These findings indicate that decreases in gastric mucosal blood flow are mainly caused by ET-1 via ETA receptors inhibited by BQ-123, while decreases in hepatic tissue blood flow are caused mainly by ET-3 via non-ETA receptors not inhibited by BQ-123. The fact that ET-3 decreases blood flow more significantly than ET-1 suggests the involvement of ET-3 selective receptors (ETc). The findings obtained in the present study indicate that complex mechanisms are involved in the regulation of tissue blood flow by ET, with different receptor subtypes and ET family peptides being involved according to the type of tissue.

Study of effectiveness of bezafibrate in the treatment of chronic hepatitis C

1. Wong VS, Hughes V, Trull A, et al. Serum hyaluronic is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepat 1998;5:187–92. 2. Murawaki Y, Ikuta Y, Koda M, et al. Comparison of serum 7S fragment of type IV collagen and serum central triple-helix of type IV collagen for assessment of liver fibrosis in patients with chronic viral liver disease. J Hepatol 1996;24:148–54. 3. Poynard T, Bedossa P, METAVIR and CLINIVIR Cooperative Study Groups. Age and platelet count: A simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. J Viral Hepat 1997;4:199–208. 4. The METAVIR Cooperative Group. Interand intra-observer variation in the assessment of liver biopsy of chronic hepatitis C. Hepatology 1994;20:15–20. 5. Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology 1999;29: 1311–6. 6. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology 1997;112:463– 72. 7. Roudot-Thoraval F, Bastie A, Pawlotsky JM, et al. Epidemiological factors affecting the severity of hepatitis C virus-related liver disease: A french survey of 6,664 patients. Hepatology 1997;26:485–90. 8. Gordon SC, Bayati N, Silverman AL. Clinical outcome of hepatitis C as a function of mode of transmission. Hepatology 1998;28:562–7.

Increase in hepatic tissue blood flow by teprenone

Abstract  The major objective of the present study was to evaluate mechanisms by which teprenone, a gastric mucosal protecting agent, increases hepatic mucosal blood flow using male Sprague‐Dawley rats. Hepatic and gastric blood flow was measured using a laser blood flow meter after administration of teprenone, dissolved in Tween 80, into the inferior vena cava. Teprenone itself increased hepatic and gastric blood flow. It also increased hepatic and gastric blood flow in rats with acute hepatic disorders due to carbon tetrachloride (CCL4) and improved histological changes, such as inflammatory cell infiltration and fatty changes in the liver. The fact that blood endothelin (ET) concentrations increased after administration of teprenone suggest that teprenone has great affinity for ETB receptors and shows ETB ‐receptor antagonist‐like effects. Hepatic blood flow decreased after administration of N‐nitro‐L‐arginine methyl ester, a nitric oxide (NO) synthetase inhibitor, suggesting that teprenone increases NO activity. Teprenone was thought to increase hepatic and gastric blood flow by different mechanisms, because it increased gastric mucosal prostaglandin E2 concentrations.

Efficacy of bezafibrate in a patient with primary sclerosing cholangitis

on these observations, we diagnosed typical localized PSC of the intrahepatic bile ducts. We additionally diagnosed idiopathic hypereosinophilic syndrome, based on the increased eosinophilic leukocyte count (2035/mm3). A daily dose of 30mg prednisolone was administered to treat this condition, and the eosinophilic leukocyte count normalized within approximately 2 weeks. The dose was subsequently decreased to 10mg/day as maintenance therapy. An initial dose of 900mg/day of UDCA was used to treat the PSC; however, unsatisfactory results necessitated an increase to 1200mg/day from May 2000. Further elevations in biliary enzyme levels were recorded in the months following January 2001, as well as an elevated total bilirubin level of 2.8mg/dl. The patient was hospitalized in June 2001 for further investigation, and liver transplantation was considered. At this time, the level of ALT was 165IU/l, and levels of biliary enzymes were particularly high, with ALP at 1711IU/l, LAP at 865U/ml, and γ-GTP at 466IU/l (Fig. 1). ERCP revealed further evident stricturing and obstruction of the intrahepatic bile ducts. Liver biopsy revealed an “onion-skin” appearance, formed by concentric circles surrounding the intrahepatic bile ducts in the region of the portal vein. Based on the deterioration in the disease state over 6 years, we began administration of bezafibrate, at 40 mg/ day. After 2 months of treatment, ALT, ALP, LAP, and γ-GTP levels had decreased to 73IU/l, 407 IU/l, 441U/ml, and 199 IU/l, respectively. The level of total bilirubin had normalized at 1.2mg/dl, and reached a plateau. After 10 months of treatment, levels of hepatobiliary enzymes had stabilized at slightly or moderately elevated levels, with ALT, ALP, LAP, and γ-GTP at 79 IU/l, 412 IU/l, 429U/ml, and 192 IU/l, respectively. The peroxisome proliferator-activated receptor (PPAR) is deeply involved in the inflammatory response, in addition to being involved in lipid metaPrimary sclerosing cholangitis (PSC) is a progressive chronic inflammatory disease. An autoimmune disorder is thought to play a role in the mechanism of its development; however, no satisfactory drug therapy has been established for patients with PSC. Many cases are resistant to the ursodeoxycholic acid (UDCA) therapy currently used, and there are no reports demonstrating improvement of the longterm prognosis. We recently reported the efficacy of bezafibrate in improving both the biochemical and the histological status of patients with primary biliary cirrhosis (PBC).1–3 In common with PSC, PBC is a chronic liver disease, causing marked impairment of the biliary system, and an autoimmune disorder plays a role in its development. Here we describe marked improvement in the biochemical status of a patient with PSC on the administration of bezafibrate. To our knowledge, this is the first demonstration of the efficacy of bezafibrate against PSC, and indicates its potential as a new therapeutic drug for this disease. The patient (male, now aged 21 years) was first hospitalized in 1995 (aged 15 years) to investigate the cause of elevated hepatobiliary enzyme levels and eosinophilic leukocyte count. Biochemical test results showed a moderately elevated serum level of alanine aminotransferase (ALT), at 120IU/l (normal range, 5–45IU/l), and marked elevations in serum levels of biliary enzymes, with alkaline phosphatase (ALP) at 1445IU/l (normal range, 100–325 IU/l), leucine aminopeptidase (LAP) at 664U/ml (normal range, 100–200U/ml), and gamma-glutamyl transpeptidase (γ-GTP) at 258IU/l (normal range, 80IU/l). Endoscopic retrograde cholangiopancreatography (ERCP) revealed multifocal stricturing and a beaded, “prunedtree” appearance of the intrahepatic bile ducts. Based

Effects of a gastric mucosal protecting agent in rats with liver cirrhosis

Male Sprague–Dawley rats were fed a 0.1% ethionine‐added choline‐deficient diet for 8 weeks to induce liver cirrhosis. At the same time 100 mg/kg/day teprenone was administered orally in order to evaluate its effects on the liver and gastric mucosal blood flow. Blood flow increased not only in gastric mucosa but also in liver tissues in the teprenone group. Serum transaminase levels and histopathologic findings of the liver also improved. These findings suggest that teprenone alleviates hepatocellular injuries. This effect may be partly attributable to cytoprotective effects of the catenoid isoprenoid moiety of teprenone on liver cells.

Effects of eicosapentaenoic acid on blood rheology in rats with fatty liver

Abstract A blood rheology study was conducted using Kikuchis microchannel method in male Sprague Dawley rats with fatty liver induced by choline deficiency. Effects of eicosapentaenoic acid (EPA) on blood rheology were also evaluated. Male Sprague Dawley rats given normal feed served as the control. One group was given choline-deficient feed for 4 weeks (EPA (−) group), while another was given EPA (1000 mg/kg) once daily for 4 weeks together with choline-deficient feed (EPA (+) group). The microchannel passage time was determined using 100 mL of whole blood during observation under a microscope with a video camera. The passage time increased significantly in the EPA (−) group compared with the control group, while it was significantly shorter in the EPA (+) group compared with the EPA (−) group. Changes in platelet aggregation and leukocyte adhesion were less in the EPA (+) group than in the EPA (−) or the control groups. EPA supplementation appeared to correct blood flow changes induced by choline deficiency in rats.