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Osamu Yokosuka,
Koichi Takaguchi,
Shinichi Fujioka,
Michiko Shindo,
Kazuaki Chayama,
Haruhiko Kobashi,
Norio Hayashi,
Chifumi Sato,
Kendo Kiyosawa, Kyuichi Tanikawa,
Hiroki Ishikawa,
Nobuyuki Masaki,
Taku Seriu,
Masao Omata
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ABSTRACT: To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients.
One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples.
After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset.
Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.
Journal of Hepatology 06/2010; 52(6):791-9. · 9.26 Impact Factor
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Haruhiko Kobashi,
Shin-Ichi Fujioka,
Mitsuhiko Kawaguchi,
Hiromitsu Kumada,
Osamu Yokosuka,
Norio Hayashi,
Kazuyuki Suzuki,
Takeshi Okanoue,
Michio Sata,
Hirohito Tsubouchi, [......],
Hiroki Ishikawa,
Akinobu Takaki,
Yoshiaki Iwasaki,
Toshiya Osawa,
Toshiyuki Takaki,
Kosaku Sakaguchi,
Yasushi Shiratori,
Kazuhide Yamamoto,
Daniel J Tenney,
Masao Omata
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ABSTRACT: Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB).
Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2.
ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after <0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.
Hepatology International 06/2009; 3(2):403-10. · 2.64 Impact Factor
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Masao Omata,
Haruhiko Yoshida,
Joji Toyota,
Eiichi Tomita,
Shuhei Nishiguchi,
Norio Hayashi,
Shiro Iino,
Isao Makino,
Kiwamu Okita,
Gotaro Toda, Kyuichi Tanikawa,
Hiromitsu Kumada
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ABSTRACT: Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH-C) therapy; however, sustained virological response is achieved in only about half of the patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon non-responders.
CH-C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200) or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) were assessed. This study is registered at ClinicalTrial.gov, identifier NCT00200343.
ALT, AST and GGT decreased at week 4 and then remained constant during drug administration. The median changes (150, 600 and 900 mg/day, respectively) were: ALT, -15.3, -29.2 and -36.2%; AST, -13.6, -25.0 and -29.8%; GGT, -22.4, -41.0 and -50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/l. Serum HCV-RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups.
A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH-C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.
Gut 01/2008; 56(12):1747-53. · 10.11 Impact Factor
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ABSTRACT: We have experienced two patients with alcoholic lactic acidosis complicated with liver disease and diabetes mellitus who were successfully treated. They developed hypoglycemia, dehydration, lactic acidosis, and renal failure after drinking a large volume of alcohol without eating for 1 week before onset. Acidosis was thought to be directly related to excessive alcoholic intake, because it was not associated with severe liver failure and rhabdomyolysis. During monitoring of respiratory and circulatory functions, a rapid infusion of fluids adjusting to water and electrolyte imbalance was performed. A mixture of physiological saline and 5% glucose solution was thought to be effective in these cases. Patients recovered from renal failure and lactic acidosis without hemodialysis. Our experience will hopefully provide a key to successful treatment of fatal alcoholic lactic acidosis.
Alcoholism Clinical and Experimental Research 04/2006; 20(s9):387A - 390A. · 3.34 Impact Factor
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ABSTRACT: Oxidative stress has recently been shown to play an important role in various liver diseases. Therefore, further studies on oxidative stress in liver diseases are urgently required. In this review, oxidative stress is discussed from the aspects of molecular morphology, metabolism, and aging.
Medical Molecular Morphology 04/2006; 39(1):22-7. · 1.39 Impact Factor
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Masaru Harada MD,
Shotaro Sakisaka,
Masao Yoshitake,
Masahito Ohishi,
Satoshi Itano,
Satoshi Shakado,
Yoshihiro Mimura,
Kazunori Noguchi,
Michio Sata,
Hiroshi Yoshida, Kyuichi Tanikawa
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ABSTRACT: The process of receptor-mediated endocytosis is common to a variety of species and cell types. One of the best characterized receptor-ligand systems is the hepatocyte receptor for asialoglycoproteins. We investigated the morphological features of the uptake and intracellular transport of gold-conjugated asialofetuin in isolated rat hepatocyte couplets. We assessed the effects of colchicine, lumicolchicine, cytochalasin B, and chloroquine on the uptake and intracellular transport of asialoglycoproteins. Isolated rat hepatocyte couplets were incubated with gold-conjugated asialofetuin, and transmission electron micrographs of these cells were analyzed to determine the density and distribution of gold particles in the peripheral and pericanalicular areas. Results were analyzed morphometrically. Colchicine significantly inhibited the uptake and intracellular transport of asialoglycoproteins, but did not affect membrane fusion of endocytic compartments in the peripheral area. Lumicolchicine and cytochalasin B had minimal effects on these processes. Chloroquine inhibited the uptake of asialoglycoproteins, but did not affect the intracellular transport of asialoglycoproteins. Results suggest that the microtubule is essential for intracellular movement of endocytosed asialoglycoproteins and receptor recycling, and that endocytic structures in the peripheral regions can fuse in the absence of intact microtubules. We also found that uptake and intracellular transport of asialoglycoproteins were independent of the microfilaments, and the pH gradient in endocytic compartments was important in receptor-mediated endocytosis of asialoglycoproteins.
Hepatology 12/2005; 21(5):1413 - 1421. · 11.66 Impact Factor
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ABSTRACT: The concentration of plasma vitronectin was determined and compared with various parameters of liver function including the blood coagulation system in patients with liver diseases. The severity of cirrhosis was graded according to Child's criteria and compared with the plasma vitronectin level. Furthermore, the distribution of vitronectin in the liver of patients with liver diseases was studied by light and electron microscopy using the indirect immunoperoxidase method.The plasma vitronectin level was low in all liver disease groups as compared with the healthy controls. The difference from the controls was significant in patients with hepatocellular carcinoma and decompensated cirrhosis. Moreover, the plasma vitronectin level was positively correlated with the levels of serum cholinesterase, albumin, plasma α2 plasmin inhibitor-plasmin complex and the prothrombin time and results of the hepatoplastin test. Plasma vitronectin decreased with increasing severity of cirrhosis according to Child's criteria. These results suggest that the plasma vitronectin level is a useful parameter of hepatic synthetic function in patients with liver diseases; it may also reflect the severity of cirrhosis.Light microscopy revealed vitronectin in the area of focal necrosis and the portal tracts in the liver of patients with acute viral hepatitis, in the area of piecemeal necrosis in the liver of patients with chronic hepatitis and along the area of fiber deposition in the liver of patients with cirrhosis. Immunoelectron microscopy showed vitronectin in the rough endoplasmic reticulum of hepatocytes. Moreover, vitronectin was seen around inflammatory cells, endothelial cells, Ito cells and hepatocytes in the perisinusoidal area near focal necrosis and piecemeal necrosis and on collagen fibers.These results suggest that vitronectin may be produced by hepatocytes and that they play an important role as an extracellular matrix component in the injured liver. (Hepatology 1992;15:629–636).
Hepatology 12/2005; 15(4):629 - 636. · 11.66 Impact Factor
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ABSTRACT: The contractile response of cultured Ito cells to endothelin-1 and substance P was examined. Ito cells were obtained from rat liver by perfusion with collagenase, followed by separation through centrifugal elutriation, and were cultured for 24 hr. The area of the Ito cells was measured after treatment with endothelin-1 or substance P at various concentrations in the culture medium. The area of the cells decreased dose dependently after treatment with endothelin-1 or substance P. The area of Ito cells before addition of interleukin-1 or substance P was defined as 100%. The area of the cells after treatment with endothelin-1 or substance P medium was expressed as the percentage against the area before treatment with endothelin-1 or substance P. The percentage in area after treatment with 200 nmol/L endothelin-1 was as follows: 81% ± 13% at 30 min, 77% ± 15% at 60 min, 87% ± 15% at 120 min and 99% ± 18% at 180 min. The maximal decrease in area occurred at 60 min after treatment. The percentage values for 200 nmol/L substance P were as follows: 88% ± 15% at 10 min, 95% ± 17% at 30 min and 101% ± 17% at 60 min. The maximal decrease in area was noted at 10 min. Thus Ito cells contracted in response to treatment with endothelin-1 or substance P. The mode of the extent and onset of the contraction was different for the two peptides. These findings suggest that Ito cells are involved in the regulation of the hepatic sinusoidal microcirculation. (HEPATOLOGY 1993;18:978-983).
Hepatology 12/2005; 18(4):978 - 983. · 11.66 Impact Factor
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ABSTRACT: Biliary copper excretion was examined in rats with acute, continuous and chronic copper loads. Copper was excreted into bile, and the concentration peaked 40 min after a venous injection of copper sulfate (127 ng/gm body weight). The excretion was significantly inhibited by colchicine. Therefore some copper may be transported in hepatocytes by a vesicular pathway and excreted into bile. Biliary copper output increased over time and reached a plateau 180 min after a continuous venous infusion of copper sulfate (318 ng/gm body weight/hr) had started, when the concentration of copper in bile was much higher than that in plasma; the bile/plasma ratio of copper concentrations was 4.32 ± 0.46. These data support the idea that copper transport involves a specific uptake and transport system. In chronically copper-loaded rats, hepatic copper content was significantly increased compared with controls, and reaction products for copper were observed in hepatocyte granules by light microscopic examination with p-dimethylaminobenzylidene rhodanine stain. The number of lysosomes in hepatocytes increased and the shape changed. In chronically copper-loaded rats the number of tubular lysosomes was very high. However, other organelles appeared to be normal. In these rats biliary excretion of not only copper but also acid phosphatase, a Iysosomal enzyme, was significantly greater than the control. Therefore hepatocyte lysosomes may play an important role in biliary copper excretion. Furthermore, when biliary Iysosomal excretion increases, the tubular lysosomes actively participate in this excretion. (HEPATOLOGY 1993;17:111–117.)
Hepatology 12/2005; 17(1):111 - 117. · 11.66 Impact Factor
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ABSTRACT: The aim of this study was to determine whether MAGE-4 protein is detectable in sera of patients with hepatocellular carcinoma and other liver diseases. An enzyme-linked immunosorbent assay was employed for detection of MAGE-4 protein in sera of liver disease patients, healthy men and women (control I) and those undergoing prostatic cancer screening (control II). MAGE-4 protein levels in sera of patients with hepatitis C virus-associated HCC (HCC-C) (n=45, mean=2.160 ng/ml) and HCV-associated cirrhosis (LC-C) (n= 55, 1.072 ng/ml) were significantly higher (P< 0.0001) than those of control I (0.327 ng/ml) or control II (0.394 ng/ml). MAGE-4 protein was positive in 21/45 (46.7%) HCC-C patients and 18/55 (32.7%) LC-C patients (cut-off, mean plus 2 SD in healthy controls) but in 0/12 (0%) hepatitis B virus-associated HCC (HCC-B) patients, 3/49 (6.1%) hepatitis B virus-associated LC (LC-B) patients, 4/47 (8.5%) alcoholic liver disease patients, and 1/49 (2.0%) controls. Serum MAGE-4 protein level may be useful as a marker for identification of LC-C patients suffering from HCC that is undetectable by presently available methods.
Cancer Science 08/2005; 88(9):915 - 918. · 3.33 Impact Factor
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Akihiro Matsumoto,
Eiji Tanaka,
Akinori Rokuhara,
Kendo Kiyosawa,
Hiromitsu Kumada,
Masao Omata,
Kiwamu Okita,
Norio Hayashi,
Takeshi Okanoue,
Shiro Iino, Kyuichi Tanikawa
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ABSTRACT: A retrospective survey of Japanese patients histologically diagnosed with chronic hepatitis B was conducted to determine the effectiveness of lamivudine in preventing hepatocellular carcinoma (HCC). Of the 2795 patients who satisfied criteria for analysis after treatment from any of 30 medical institutions, 657 had received lamivudine and the remaining 2138 had not. A Cox regression model with liver biopsy as the starting point revealed seven factors related to HCC: lamivudine therapy, gender, family clustering of hepatitis B, age at liver biopsy, hepatic fibrosis stage, serum albumin level, and platelet count. In a matched case-controlled study, 377 patients in a lamivudine-treated group and 377 matched patients in a non-treated group were selected based on their propensity scores. The mean follow-up period was 2.7 years in the lamivudine group and 5.3 years in the control group. In the lamivudine group, HCC occurred in four patients (1.1%) with an annual incidence rate of 0.4%/(patient/year), whereas in the control group HCC occurred in 50 patients (13.3%) for a rate of 2.5%/(patient/year). A comparison of the cumulative HCC incidence between the two groups by the Kaplan-Meier method showed a significantly lower incidence of HCC in the lamivudine group (p<0.001). These findings suggest that lamivudine effectively reduces the incidence of HCC in patients with chronic hepatitis B.
Hepatology Research 07/2005; 32(3):173-84. · 2.20 Impact Factor
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Shiro Iino,
Eiichi Tomita,
Hiromitsu Kumada,
Hiroshi Suzuki,
Johji Toyota,
Kendo Kiyosawa, Kyuichi Tanikawa,
Michio Sata,
Norio Hayashi,
Shinichi Kakumu,
Takashi Matsushima,
Masashi Mizokami
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ABSTRACT: The possibility of delaying progression to hepatocellular carcinoma in chronic hepatitis C patients with genotype 1 and high viral titers with baseline ALT levels of >/=50IU/L was examined by administration of IFN plus ribavirin combination therapy using ALT normalization as index and IFN monotherapy as control. The rate of sustained ALT normalization (ALT normal at 24 weeks after the end of treatment) was 28.1% with combination therapy and 10.5% with IFN monotherapy (P=0.001). Furthermore, the number of patients with sustained viral response (SVR) and with sustained ALT normalization in non-SVR patients was also significantly higher in the combination therapy versus monotherapy group. Mean ALT values during treatment and for 6 months after the end of treatment were significantly lower with combination therapy versus monotherapy even in virological nonresponders, as well as significantly lower during the post-treatment observation period in patients who relapsed after the end of treatment. Since increase in the rate of sustained ALT normalization and SVR were successfully achieved, inhibition of progression to hepatocellular carcinoma should be studied with long-term IFN and ribavirin combination therapy.
Hepatology Research 02/2005; 31(2):88-94. · 2.20 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 12/2004; 62 Suppl 11:314-6.
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Kyuichi Tanikawa
Nippon rinsho. Japanese journal of clinical medicine 09/2004; 62 Suppl 8:453-7.
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Takumi Kawaguchi,
Masaru Harada,
Hidetoshi Arimatsu,
Shuichiro Nagata,
Yuriko Koga,
Reiichiro Kuwahara,
Akiko Hisamochi,
Teruko Hino,
Eitaro Taniguchi,
Hiroto Kumemura,
Shinichiro Hanada,
Michiko Maeyama,
Hironori Koga,
Nobuo Tomiyasu,
Hiroyuki Toyomasu,
Motonari Kawaguchi,
Masayoshi Kage,
Ryukichi Kumashiro, Kyuichi Tanikawa,
Michio Sata
Journal of Gastroenterology and Hepatology 04/2004; 19(3):349-50. · 2.87 Impact Factor
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Kyuichi Tanikawa
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ABSTRACT: Few comprehensive reviews on the pathogenesis of hepatitis C virus (HCV)-related liver diseases have been presented to the present. This article was to review the pathogenesis and treatment of HCV-related liver diseases.
Data presented here are mostly taken from Japanese studies.
HCV infection is characterized by persistent inflammation of the liver and frequent development of hepatocellular carcinoma (HCC) in most cases. These characteristic evidences could be explained by immunological alterations and oxidative stress in the hepatocyte caused by HCV infection. Interferon (IFN) treatment is carried out, at present, not only for the elimination of infected HCV for the treatment of chronic liver diseases, but also for both the prevention of HCC and the treatment of advanced HCC with chemotherapy. The treatment for oxidative stress is also important for non-responders to IFN.
It is important to understand the pathogenesis of HCV-related liver diseases for a successful treatment.
Hepatobiliary & pancreatic diseases international: HBPD INT 03/2004; 3(1):17-20. · 1.08 Impact Factor
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Shiro Iino,
Eiichi Tomita,
Hiromitsu Kumada,
Hiroshi Suzuki,
Joji Toyota,
Kendo Kiyosawa, Kyuichi Tanikawa,
Michio Sata,
Norio Hayashi,
Shinichi Kakumu,
Takashi Matsushima,
Tomoyoshi Ohno
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ABSTRACT: Data on 334 patients with HCV genotype 1b and high viral levels were extracted from two multicenter double-blind studies conducted in Japan comparing IFN alpha-2b plus ribavirin (n = 209) with IFN alpha-2b alone (n = 125) for 24 weeks. HCV RNA assay was conducted before and 4, 12, and 24 weeks after the start and 4, 12, and 24 weeks after the end of treatment. Both sustained viral response (SVR) rate and relapse rate after the end of treatment were analyzed in relation to baseline viral levels and the time of first disappearance of virus. In the combination treatment group, the percentage of patients who were HCV RNA-negative within 4 weeks decreased with increase in baseline viral levels (i.e. 42%, 15%, and 11% were HCV RNA-negative in the groups exhibiting <500, 500 to <850, and >/=850kcopies/mL, respectively). In the IFN monotherapy group, the response rates were lower at 13%, 15%, and 1%, respectively. Disappearance of virus within 12 weeks after the start of combination treatment was indicative of higher probability of SVR. The risk of relapse was more highly correlated with the timing of initial viral disappearance than with baseline HCV levels; it was 4.8 and 10.3 times higher in patients who became HCV-negative at 4-12 and 13-24 weeks compared with in those who were HCV-negative within 4 weeks.
Hepatology Research 02/2004; 30(2):63-70. · 2.20 Impact Factor
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Ryukichi Kumashiro,
Takahiro Kubota,
Yuriko Koga,
Masatoshi Tanaka,
Chizuko Inada,
Nobuhide Kusaba,
Hiroshi Yoshida,
Akiko Hisamochi,
Tatsuya Ide,
Yuko Tomita,
Naoko Masumoto, Kyuichi Tanikawa,
Tatsuji Iga,
Michio Sata
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ABSTRACT: An anti-diabetic agent, troglitazone, was withdrawn from the market because of its association with liver injury. However, the mechanism of the injury has not been elucidated. We examined, retrospectively, the frequency of the polymorphisms of the cytochrome P450 (CYP) 2C19 and 2D6 genes in eight patients with type 2 diabetes who had troglitazone-induced liver injury and 31 subjects who tolerated troglitazone well. Polymorphisms of CYP 2C19 and 2D6 genes were analyzed by polymerase chain reaction using peripheral white blood cells. The incidence of mutations was compared with known population data for the Japanese. Homozygous or compound heterozygous mutations in CYP 2C19 alleles were found in four of the eight (50.0%) patients with troglitazone-induced liver injury. This rate was significantly higher than that in patients without liver injury (four of 31, 12.9%). The frequency of P450 2D6 mutations was the same in both groups. In conclusion, troglitazone-induced liver injury occurred more frequently in subjects with the CYP 2C19 mutations in Japanese patients.
Hepatology Research 09/2003; 26(4):337-342. · 2.20 Impact Factor
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ABSTRACT: We treated a patient simultaneously infected with hepatitis E virus and Leptospira interrogans, both acquired in China. Severe hyperbilirubinemia required nearly 200 days to resolve, transminase elevation showed a fluctuating course, and liver biopsy specimens showed fibrosis unusual for hepatitis E. Leptospirosis appeared to have altered the course of hepatitis E virus infection in this patient, even though infection with Leptospira was cleared with antibiotics by 50 days after the onset of the hepatitis symptoms.
The Kurume Medical Journal 02/2003; 50(3-4):155-9.
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Kyuichi Tanikawa
Gan to kagaku ryoho. Cancer & chemotherapy 03/2002; 29 Suppl 1:106-9.
