Madoka Ito

Propagermanium: a nonspecific immune modulator for chronic hepatitis B

Although antiviral agents have been adopted for the management of chronic hepatitis B, they have only limited efficacy because of the underlying impaired immune status. Propagermanium, a hydrophilic polymer of 3-oxygermyl propionate, has been reported to have potent immune modulatory activity associated with antiinflammatory and antineoplastic properties. For example, propagermanium augments lymphocyte functions in CD4 and CD8 cells, and in natural killer (NK) cells, and induces the production of several cytokines. A controlled pilot study of 16-week treatment with propagermanium for chronic hepatitis B (of moderate and mild grades on hepatic histology) revealed a sustained clearance of hepatitis B e (HBe) antigen and a favorable biochemical response at week 16 of treatment and at week 48 post-treatment. An open study also supported the clearance of hepatitis B virus from the blood and the possible improvement of histologic grading in the liver. There were few adverse events. A postmarketing survey, however, revealed the occurrence of moderate to severe liver damage after the treatment in about 4% of patients. Despite the exact nature of the liver damage being unclear, a putative cause is the swift removal of virus-infected hepatocytes by an immune reaction through the treatment. A subtle balance between host and viral conditions is the factor which most determines hepatitis B virus persistence. The rationale for a nonspecific immune modulator for the treatment of chronic hepatitis B will be the restoration of cellular immune responsiveness to viral infection. Although the cellular immunity for hepatitis B virus prior to the treatment should be studied, adequate observation of hepatic functions and viral markers in the recipients is clinically useful to predict liver failure during the treatment. In summary, the propagermanium regimen offers a potent and safe approach that is cost-effective for appropriate chronic hepatitis B patients with reserve hepatic capacity, and will provide new perspectives for immune therapy in chronic hepatitis B.

Conversion of γ-glutamylcysteinylethyl ester to glutathione in rat hepatocytes

Abstract The conversion of γ-glutamylcysteinylethyl ester (γ-GCE) to glutathione in a reduced form (GSH) was examined using isolated rat hepatocytes pretreated with diethylmaleate, a GSH-depletor. Incubation of hepatocytes with 0.1 and 5.0 mM γ-GCE (γ-GCE-hepatocytes) over a 30-min period resulted in time-dependent increases in intracellular GSH and nonprotein-SH (NP-SH) concentrations. Hepatocytes incubated with 5.0 mM but not 0.1 mM GSH over a period of 30 min showed a time-dependent increase in intracellular GSH concentration. In the γ-GCE-hepatocytes pretreated with bis-(p-nitrophenyl)phosphate (BNPP), a non-specific esterase inhibitor, an enhancement of intracellular GSH concentration was markedly reduced. γ-GCE concentration in the γ-GCE-hepatocytes with BNPP pretreatment was significantly higher than that in the cells without BNPP pretreatment, although there was no difference in the total amount of intracellular NP-SH, i.e., γ-GCE, GSH, γ-glutamylcysteine, cysteine ethyl ester, and cysteine between both γ-GCE-hepato-cytes. The present results indicate that γ-GCE is transported into liver cells more easily than GSH itself, resulting in its conversion to GSH via esterase and glutathione synthetase within the cells.

Effects of the 5-HT2A Receptor Antagonist Sarpogrelate in Diabetic Patients with Complications

AbstractObjective: To investigate whether the newly developed selective serotonin (5-hydroxytryptamine2A; 5-HT2A) receptor antagonist sarpogrelate is effective in patients with diabetes mellitus in whom lower limb circulatory disorders were suspected. Design and Setting: Open-label prospective study conducted in 23 hospitals in the central area of Honshu, Japan. Patients: One hundred and nine patients with diabetes mellitus in whom lower limb circulatory disorders were suspected. Interventions: Sarpogrelate, a selective 5-HT2A receptor antagonist, was administered at a dosage of 100mg three times daily for 3 months. Main Outcome Measures: Ankle pressure index (API), vibratory sensation threshold determined using a C64 quantitative tuning fork, motor nerve conduction velocity, subjective symptoms (coldness, numbness, spontaneous pain, etc.), and blood serotonin levels. Results: Ninety-nine patients were available for efficacy evaluations. The vibratory sensation threshold showed a positive correlation with API (r =0.358, p = 0.0015) and motor nerve conduction velocity (r = 0.507, p = 0.0002) in patients with suspected blood flow deficiency and API ≤ 0.9, indicating that it is useful as a clinical marker. The test drug significantly increased API (p ≤ 0.05) and improved coldness, numbness and spontaneous pain. The vibratory sensation threshold, a marker for neurological disorders, increased significantly (p = 0.004). Lower limb peroneal motor nerve conduction velocity increased significantly in patients in whom it was ≤40 m/sec before treatment (p < 0.05). Blood serotonin levels increased significantly after treatment (p < 0.01), suggesting that the test drug inhibits the release of serotonin from platelets. Adverse events (allergic symptoms, anaemia, headache, anorexia and nausea) occurred in eight of 109 patients (7.3%). All adverse events disappeared during treatment or after its discontinuation, and none was serious. Conclusions: Sarpogrelate is well tolerated and the present results suggest that it is useful for both lower limb circulatory disorders and neuropathy associated with diabetes mellitus.

Enzymatic assays of l-ornithine and l-Δ1-pyrroline-5-carboxylate in tissues, and ornithine-load test in human subjects

Abstract A specific enzymatic method was developed for the determinations of l -ornithine and l -Δ 1 -pyrroline-5-carboxylate using two coupling enzymes, ornithine aminotransferase and Δ 1 -pyrroline-5-carboxylate reductase. Using this method, ornithine in rat tissues and human serum could be determined at the nanomole level. The fluorometric modification of this method was used for the assay of ornithine in blood. In the ornithine-load test in human subjects, diabetic patients showed an abnormally low peak and liver cirrhotic ones gave a delayed peak in their blood ornithine response curve.

A case of small bowel carcinoma in Crohn’s disease

SummaryA 46-year-old man had symptoms of ileus four years and five months after being diagnosed as Crohn’s disease. Upon small bowel radiography, a short, spindle shaped stenosis on the distal site of the ileum was found. In the resected specimen, there was a constricted area with wall hypertrophy, and the mucosal surface of this region was rough and granular. At the site of this region, well differentiated adenocarcinoma was noted, which infiltrated the serosa in the form of mucous adenocarcinoma. Transmural dispropotinal inflammation and non-caseating granuloma were also around there. The X-ray findings in this case are considered to be useful for diagnosis of carcinoma during the long term observation period for Crohn’s disease.

Cholesterol uptake of isolated rat hepatocytes is accelerated by several kinds of phosphatidylcholine

Cholesterol uptake (Isolated rat hepatocyte) Phosphatidylcholine Unsaturated fatty acid Dioleoylphosphatidylcholine Dipalmitoylphosphatidylcholine

Low-dose oral interferon-α in the treatment of chronic viral hepatitis type B: A double-blind, randomized, placebo-controlled, clinical trial

Abstract Objective To assess the efficacy of low-dose oral human interferon-α (LDO-IFN) (MR-22A) in the treatment of chronic viral hepatitis type B. Methods One of 4 doses (single tablet: 50 IU, 150 IU, 450 IU, 900 IU) of MR-22A or a single tablet of placebo was administered through the oral mucosa once daily for 24 weeks. Results At the end of the administration period, the proportion of patients who had become hepatitis B virus (HBV)-DNA negative was 6 (20.0%) of 30 in the placebo group, 4 (12.9%) of 31 in the 50-IU group, 6 (18.8%) of 32 in the 150-IU group, 2 (6.9%) of 29 in the 450-IU group, and 4 (16.0%) of 25 in the 900-IU group. The proportion of patients who had become hepatitis B e antigen (HBeAg) negative was 5 (17.9%) of 28, 4 (14.8%) of 27, 5 (16.7%) of 30, 4 (14.8%) of 27, and 1 (5.3%) of 19, respectively. None of the differences were statistically significant between the treatment and placebo groups in the proportion of patients who became HBV-DNA negative or HBeAg negative. No statistically significant differences were observed in patients given LDO-IFN or placebo in improvement of liver function. Adverse drug reactions were observed in 4(12.5%) of 32 patients in the placebo group, 8 (24.2%) of 33 in the 50-IU group, 10 (30.3%) of 33 in the 150-IU group, 10 (29.4%) of 34 in the 450-IU group, and 7 (21.9%) of 32 in the 900-IU group. One patient in the 50-IU group experienced moderate urticaria; all other adverse events were mild. Conclusion LDO-IFN was not shown to be clinically effective in the treatment of chronic viral hepatitis type B with the route of administration, dosing levels, and methods of assessment used in this study.

Mechanism of immunological cell injury in isolated rat hepatocytes with anti-rat liver plasma membrane antiserum treatment

Abstract We examined the changes of phospholipase A 2 (PLA 2 ) activity and of reduced glutathione (GSH), Ca 2+ , and lipid peroxide (LPO) contents in isolated rat hepatocytes treated with anti-liver cell plasma membrane antiserum (ALPMA) following the development of immunological cell injury. Increases in PLA 2 activity and Ca 2+ content and a decrease in GSH content in the ALMA-treated hepatocytes occurred with an increase in release of alanine and asparatate transaminases from the cells. After these changes occurred, LPO level increased in the ALPMA-treated hepatocytes. These results suggest that in ALPMA-treated rat hepatocytes, depletion of intracellular GSH, which has a function of cell membrane stabilization, followed by increases in Ca 2+ level and PLA 2 activity primarily contributes to immunological cell injury and that stimulation of intracellular LPO production consequent of increased PLA 2 activity is secondarily contributory to the cell injury.