[Proposed mechanism of action of metalloendopeptidase-F in the treatment of patients with chronic hepatitis B or C infection].

Chronic hepatitis B and C virus infections have been characterized by the pathophysiological features with a high incidence of progression to cirrhosis and development of hepatocellular carcinoma. The viral persistence produced by escape mutations from virus-specific cytotoxic T lymphocytes (CTL) response may lead to upregulation of delayed-type hypersensitivity immune response, which causes hepatic tissue damage through non specific macrophage activation and CTL response and promotes pathogenesis of hepatic fibrosis. In a preliminary clinical study, a novel metalloendopeptidase-F (MEP-F) has been shown to be effective in the treatment of patients with either chronic hepatitis B or C infection. Oral administration of MEP-F resulted in a significant reduction of the serum levels of HBs antigen and HCV RNA and improvement in the liver function abnormalities. However, the mechanism of action of MEP-F is not yet well understood. There are accumulating evidences showing an important role of alpha 2-macroglobulin-proteinase complexes in regulatory mechanisms of immune response and repairing within impaired and inflammatory tissues. In this article, reviewing the pharmacological and biological properties of alpha 2-macroglobulin-proteinase complexes, the mechanism of anti-viral effect of MEP-F is examined based on the clinical findings. It is indicated that alpha 2-macroglobulin-MEP-F complexes may induce macrophage/Kuppfer cell activation and proliferation through binding their receptors on the cells and activating signaling cascades, which enhance both anti-viral specific and nonspecific immune responses. alpha 2-Macroglobulin-MEP-F complexes may also augment cellular immunity and hepatic regeneration by neutralizing the immunosuppressive and fibrogenic activities of transforming growth factor-beta.

Prefrontal and striatal dopamine metabolism during enhanced rebound hyperphagia induced by space restriction--a rat model of binge eating.

BACKGROUND: Several lines of evidence indicate that abnormalities in brain dopamine and serotonin metabolism may play an important role in bulimia nervosa. However, the regional neurochemical mechanism of the binge eating is poorly understood. Our purpose was to elucidate brain neurochemical mechanisms of binge eating using a rat model. METHODS: The dopamine release and metabolism in the prefrontal cortex (PFC) and in the ventrolateral striatum (VLS) of rats were studied using microdialysis during enhanced rebound hyperphagia induced by space restriction (an animal model of binge eating). RESULTS: The rats showed rebound hyperphagic state when they were released from scheduled feeding (2 hours/day feeding for 7 days). The hyperphagia was further enhanced when they were put in a space-restricted cage where their mobility was restricted. Dopamine release and metabolism were increased both in the PFC and in the VLS during the enhanced rebound hyperphagia. CONCLUSIONS: These results tentatively suggest that increased dopamine release and metabolism in the PFC and in the VLS may be related to space restriction and to activation of motor function involved in feeding behavior, respectively. The enhanced rebound hyperphagia induced by space restriction may be useful as an animal model of binge eating.

Effects of fluvoxamine on food intake during rebound hyperphagia in rats.

We examined the effects of fluvoxamine on food intake during rebound hyperphagia induced by a time-restricted feeding schedule in rats. Rats were allowed access to food for only 2 h daily for 7 days, and then had free access to food for 7 consecutive days. The daily food intake of the rats was dramatically increased, by 42.5% (rebound hyperphagia), for 7 days of the free-feeding period. Intraperitoneal injection of fluvoxamine decreased food intake significantly in a dose-dependent manner for the first 3 h of feeding during 7 days. When rats were allowed access to one of the standard, carbohydrate-, fat-, or protein-rich diets in the free-feeding period following the time-restricted feeding schedule, fluvoxamine significantly decreased food intakes of standard, carbohydrate- and fat-rich diets on all days, and the protein-rich diet after the 2nd day of the free-feeding period. These results indicate that fluvoxamine, irrespective of the diet composition, suppresses rebound hyperphagia induced by a time-restricted feeding schedule, but that its effect is short-lived.

Immunoblastic lymphadenopathy-like T-cell lymphoma displaying rearrangement of both IgH and TCR beta genes after 4-year follow-up of idiopathic eosinophilia.

Immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma (IBL-T) occurred in a 60-year-old female after a 4-year follow-up of idiopathic eosinophilia and upper pharyngeal inflammatory tumor with infiltration of mature eosinophils. Gene analysis of tumor cells revealed rearrangement of both IgH and TCR beta genes. The patient died of lymphoma seven months after the onset of the illness, in spite of chemotherapy against lymphoma. The relationship between eosinophilia and the pathogenesis of IBL-T, as well as the significance of the rearrangement of both IgH and TCR beta genes are discussed.

[NEO-MACOP-B chemotherapy for the treatment of advanced-stage aggressive non-Hodgkin's lymphoma].

We conducted a new chemotherapy, NEO-MAC OP-B (addition of etoposide and mitoxantrone to MACOP-B with half dose of methotrexate and half administration of doxorubicin), to reduce severe mucositis, which is a major toxic effect of MACOP-B, and to increase its effect with etoposide and mitoxantrone as new non-cross resistant drugs. Between Jan. 1989 and Mar. 1993, 12 patients with previously untreated advanced aggressive non-Hodgkin's lymphoma (NHL), 2 patients with adult T cell lymphoma, and 3 patients with relapsed NHL, were treated with NEO-MACOP-B. After termination of NEO-MACOP-B therapy, 83.3% of 12 patients with previously untreated NHL were in complete remission (CR). After median follow-up of 22 months, Kaplan-Meier estimates showed that overall survival of 12 previously untreated patients was 71.4%, and relapse-free survival of complete responder was 83.3%. Toxic effects on all 17 patients were moderate with a lower incidence of severe mucositis (only one patient with relatively severe stomatitis, WHO Grade 3). No treatment related deaths were observed. Thus, NEO-MACOP-B is an effective and safe treatment for advanced stage aggressive NHL.

[Successful treatment of prolonged anemia after major ABO incompatible bone marrow transplantation for a case of myelodysplastic syndrome with recombinant erythropoietin].

A delay in red cell recovery after ABO-incompatible bone marrow transplantation (BMT) is often observed. The authors experienced a case of prolonged anemia after a major ABO incompatible BMT for myelodysplastic syndrome which was successfully treated with recombinant human erythropoietin (Epo). Effects of Epo were confirmed by the recurrence of anemia after withdrawal of Epo as well as the rapid reincrease in reticulocytes on readministration. The patient received a dose of Epo which was similar to the amount used for renal anemia, however serum concentration of Epo after administration exceeded endogenous Epo levels. Epo may have a beneficial role in the treatment of prolonged anemia after BMT.

The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis.

Acute myelofibrosis is often associated with acute megakaryoblastic leukemia (AMKBL). Although the exact mechanism for the progression of myelofibrosis in AMKBL is unclear, certain humoral factors from megakaryoblastic cells, the precursors of platelets, may be involved in the enhancement of collagen synthesis by bone marrow fibroblasts. The present study, therefore, is an investigation of the possible pathogenic role of transforming growth factor-beta (TGF-beta), known to be a very potent collagen-stimulating factor found in platelets in the myelofibrosis of AMKBL. The results obtained were as follows: (1) Conditioned media from peripheral megakaryoblasts taken from an AMKBL patient and from established megakaryoblast cell lines (MEG-01) had much greater stimulatory effects on collagen synthesis in bone marrow fibroblasts than conditioned media from other leukemic cell types. (2) Based on an assessment of soft agar colony formation, there was greater TGF-beta activity in media that had been conditioned from megakaryoblasts than in media from other leukemic cell types. (3) When compared with other leukemic-cell types, megakaryoblasts showed substantially greater expression of TGF-beta mRNA that was hybridized at 2.5 kb with a TGF-beta cDNA probe, and TGF-beta polypeptides were detected at 13 Kd with anti-TGF-beta antibodies. (4) The addition of the anti-TGF-beta antibody inhibited the stimulatory effects of the megakaryoblast conditioned medium on collagen synthesis in bone marrow fibroblasts. These results clearly suggest that megakaryoblasts produce and secrete an active form of TGF-beta and stimulate collagen synthesis in bone marrow fibroblasts in a paracrine manner.

Fluorescence studies on the complex formation between poly(rA) containing 1,N6-ethenoadenosine and poly(rU).

The interaction of the 1,N6-etheno derivatives of poly(rA) (poly(epsilon rA] with poly(rU) has been studied by absorption and fluorescence spectroscopy. The stoichiometry of the interaction is found to be 1 epsilon A:1 rU and 1 epsilon A:2 rU as well as in the case of poly(rA)-poly(rU) interaction. The fluorescence properties, including the intensity and polarization of fluorescence, respond to the conformational transition of poly(epsilon rA)-poly(rU) complexes. The introduction of epsilon A groups into poly(rA) results in a marked decrease in the melting temperature, suggesting that epsilon A may destabilize the helical structure. The three-exponential decay law obtained with poly(epsilon rA)-poly(rU) complexes indicates the existence of at least three different stacked conformational states.

Fluorescence decay studies of modified dinucleoside monophosphates containing 1-N6-ethenoadenosine.

Five dinucleoside monophosphates containing 1-N6-ethenoadenosine (epsilon A) have been studied using fluorescence measurements. The fluorescence spectra of these dinucleoside monophosphates are almost the same as the fluorescence spectrum of epsilon AMP. Fluorescence quantum yields of these dimers are greatly reduced compared to that of epsilon AMP. Intramolecular base-base interactions may be responsible for fluorescence quenching. It is found that the fluorescence decay kinetics does not obey a simple decay law but that the decay data can be well described as a sum of three exponentials. This implies that these dimers cannot be characterized as a two-state system, but can be described as systems consisting of three or more conformational states. Sequence effects upon the fluorescence behavior are observed. The fluorescence quenching and decay parameters of Gp epsilon A and Up epsilon A indicate a higher degree of base-base interaction than in their epsilon ApG and epsilon ApU counterparts.

Fluorescence studies of polyriboadenylic acid and dinucleoside monophosphates containing 1,N6-ethenoadenosine.

The fluorescence properties of the 1,N6-etheno derivatives of ApA (epsilon Ap epsilon A) and polyriboadenylic acid (poly epsilon rA) have been examined. The fluorescence quantum yield of poly epsilon rA decreases with an increase in the degree of epsilon-substitution and is much smaller than that for epsilon-AMP even for low degrees of epsilon-substitution. The nearest neighbor interactions such as adenine-epsilon-adenine and epsilon-adenine-epsilon-adenine may be responsible for this behavior. It is found that the fluorescence decay kinetics obeys a three-exponential decay law for poly epsilon rA and epsilon Ap epsilon A, suggesting that there exist at least three different stacked conformational states.

Use of an AR-1 resin column to reduce bilirubin-level in modified ascitic fluid.

Intractable ascites has been accompanied by significant jaundice in some patients. In such cases, a newly developed synthetic resin, AR-1, has been successfully employed to reduce excess bilirubin from the ascitic fluid. This resin has proved to be excellent compared with XAD-2, XAD-7 and activated charcoal, for removal of bilirubin from the plasma and ascitic fluid in our experiments. A column containing 100 ml of AR-1 is inserted in the drip infusion line between the modified ascitic fluid reservoir in the Autoascit device and the patient. This method has been used in 7 cases of intractable ascites associated with advanced gastric, pancreatic, hepatic, rectal and ovarian cancers. The column has sufficient capacity to adsorb excess bilirubin from the modified ascitic fluid. Other biochemical parameters were eseentially unchanged from pre-column values.