Initial daily interferon administration can gain more eradication of HCV-RNA in patients with chronic hepatitis C, especially with serum intermediate viral load.

BACKGROUND/AIMS: We studied the effect of initial daily administration of interferon for the treatment of chronic hepatitis C, especially in patients with intermediate viral load. METHODOLOGY: Consecutive patients who met the inclusion criteria were randomly enrolled into two groups in this study. All patients analyzed could be treated with interferon-alpha for 6 months. Patients in group A were administered 6 million units of interferon-alpha subcutaneously daily initially for 2 weeks and then thrice weekly. Patients in group B were treated with the same dose of interferon-alpha thrice weekly from the first administration. We decided the criteria of complete remission as the absence of serum HCV-RNA at both points of the end of interferon treatment and 6 months later. RESULTS: Due to the relationship between the efficacy and serum viral load, we decided the criteria of the intermediate load as the quantitative value of serum HCV-RNA to be not lower than 10(5.0) and not higher than 10(6.5) copies/ml. Seventy-six and 78 patients, whose genotype and quantitative value of serum HCV-RNA could be measured before treatment, were analyzed in group A and B, respectively. The rate of complete remission in group A (40.8%) was higher than that in group B (25.6%), significantly (p = 0.046). In the intermediate viral load group, the rate of complete remission in group A (52.3%) was significantly higher than that in group B (29.3%) (p = 0.045). In the patients with genotype 1 b virus, the rate of complete remission had a tendency to be higher in group A (33.3%) than in group B (17.4%) (not significant). In the patients with genotype 2, the rate of complete remission was higher in group A (77.8%) than in group B (41.2%) (significant, p = 0.041). CONCLUSIONS: These results suggest that the initial daily interferon administration is necessary to gain a higher rate of serum HCV-RNA eradication in patients with intermediate viral load in chronic hepatitis C.

The importance of initial daily administration of interferon alpha for the eradication of hepatitis C virus in patients with chronic hepatitis C: a multicenter randomized trial.

BACKGROUND/AIMS: We studied the effect of initial daily administration of interferon for the treatment of chronic hepatitis C, to clarify a more effective treatment protocol for the eradication of the hepatitis C virus. METHODOLOGY: Consecutive patients who met the inclusion criteria were randomly enrolled in two groups in this study. One hundred and five patients were randomized and assigned to two groups. Patients, who enrolled in group A, were treated with 6 million units of natural interferon-alpha given subcutaneously daily for an initial two weeks and then thrice a week for 22 weeks. Patients, who were enrolled in group B, were treated with the same dose of interferon-alpha given for 26 weeks thrice a week from the first administration. RESULTS: In groups A and B, 58 and 47 patients were analyzed, respectively. At the end of treatment, 37 patients in group A (63.8%) had negative serum HCV-RNA test, compared with 26 in group B (55.3%), but at 6 months after discontinuation of interferon administration, 27 patients in group A (46.6%), compared with 8 in group B (21.3%). The rate of complete remission in group A (46.6%) was higher than that in group B (21.3%) (P<0.01). In patients with genotype 1b virus, the rate of complete remission was higher in group A (31.3%) than in group B (12.5%) (not significantly), and the relapse rate was lower in group A (9.4%) than in group B (37.5%), significantly (p<0.05). CONCLUSIONS: This study suggests that initial daily interferon administration is necessary to gain a higher rate of serum HCV-RNA eradication in patients with chronic hepatitis C.

Serum HDL-cholesterol-increasing and fatty liver-improving actions of Panax ginseng in high cholesterol diet-fed rats with clinical effect on hyperlipidemia in man.

Effects of Panax ginseng on plasma and hepatic lipids were investigated in the high cholesterol diet-fed rats and in patients with hyperlipidemia. Oral administration of red ginseng powder reduced plasma total cholesterol, triglyceride and NEFA, while plasma HDL-cholesterol was elevated. Platelet adhesiveness was also reduced by ginseng administration. The plasma lipid-improving actions were also observed in patients with hyperlipidemia. Hepatic cholesterol and triglyceride contents were decreased and phospholipid increased by ginseng administration in the high cholesterol diet-fed rats, corresponding to improvement of the fatty liver.

Effect of Nocardia rubra cell wall skeleton on T-cell-mediated cytotoxicity in mice bearing syngeneic sarcoma.

Cell-mediated cytotoxicity against syngeneic MC104 fibrosarcoma cells was detected in C57BL/6N mice 7 days after tumor inoculation in the hind foot. This cytotoxicity was undetectable by Day 14 in the Winn test using spleen and draining popliteal lymph node (DPLN) cells. Similar results were obtained with the 51Cr release assay following in vitro activation of these lymphoid cells with mitomycin C-treated tumor cells. The antitumor cytotoxicity was shown to be mediated by T-cells. Spleen but not DPLN cells from 14-day tumor bearers enhanced tumor growth in the Winn test, suggesting the presence of immunosuppressor cells in the spleen. Two intralesional injections of 50 microgram of cell wall skeleton (CWS) of Nocardia rubra on Days 2 and 7 resulted in apparent tumor growth inhibition and prolongation of the survival period of tumor bearers. DPLN cells from tumor bearers treated with N. rubra CWS exhibited significant recovery in the cytotoxicity tested on Day 14, whereas the recovery in that of spleen cells was not apparent. The cytotoxicity augmented by N. rubra CWS was specific to MC104 tumor cells and was shown to be mediated by T-cells. These cytotoxic T-cells were shown to be able to localize not only in DPLN but also in the spleen and tumor in mice receiving the intralesional immunotherapy with N. rubra CWS. These results suggest that T-cell-mediated cytotoxicity against syngeneic tumor can be augmented by N. rubra CWS and might play an important role in the systemic development of its antitumor effect, although the effector cell increase in the spleen might be suppressed by splenic suppressor cells during tumor growth.

Adjuvant activities of quinonyl-N-acetyl muramyl dipeptides in mice and guinea pigs.

The adjuvant and tumor-suppressive activities of the quinonyl [2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (QS-10)] derivatives of N-acetyl muramyl dipeptides were examined. N-Acetyl muramyl-L-valyl-D-isoglutamine (MurNac-L-Val-D-isoGln), QS-10-MurNAc-L-Val-D-isoGln, and their methyl esters were shown to have potent adjuvant activity on the induction of delayed-type hypersensitivity to monoazobenzenarsonate-N-acetyl-L-tyrosine in guinea pigs and on the primary immune response against sheep erythrocytes in vitro; however, only QS-10-MurNAc-L-Val-D-isoGln methyl ester, i.e., QS-10-MurNAc-L-Val-D-Glu(OCH3)NH2 (quinonyl-MDP-66), was shown to be an active adjuvant for the induction of allogeneic killer T cells in mice and the suppression of tumor growth in syngeneic mice when it was administered as a suspension in phosphate-buffered saline. The effectiveness of the chain length of the quinonyl moiety in quinonyl-MDP-66 and the replacement of the L-valine residue with L-serine or L-threonine were also examined in comparison with the adjuvant and tumor-suppressive activities of quinonyl-MDP-66.

Antitumor activity of cell-wall skeleton of Propionibacterium acnes C7 in mice and guinea pigs.

The antitumor activity of the cell-wall skeleton (CWS) of Propionibacterium acnes C7 was examined by using transplantable tumors in syngeneic mice and in guinea pigs, and autochthonous tumors in mice. P. acnes-CWS was shown to suppress the growth of fibrosarcomas, EL4 leukemia, and MH134 hepatoma in syngeneic mice, and to regress the established tumors of a fibrosarcoma (MC104) in C57BL/6J mice, and a hepatoma (line-10) in strain-2 guinea pigs. The oil-attached P. acnes-CWS mixed with fructose mycolate was effective for suppression of the autograft of fibrosarcoma in mice. The repeated intralesional injections of suspension of P. acnes-CWS in phosphate-buffered saline was effective for prolongation of survival period of mice bearing 3-methylcholanthrene-induced fibrosarcoma. The test results on the cell fractions of P. acnes indicated that the CWS, but not the cytoplasmic or glucan fraction, of P. acnes had anti-tumor activity. The activation of peritoneal macrophages of mice was observed when P. acnes-CWS, but not the cytoplasmic fraction, was injected intraperitoneally 4 days before. The relationship between the cytolytic activity of peritoneal macrophages and antitumor activities of P. acnes-CWS was also discussed.

Adjuvant activity of 6-O-mycoloyl derivatives of N-acetylmuramyl-L-seryl-D-isoglutamine and related compounds in mice and guinea pigs.

Adjuvant and antitumor activities of synthetic-6-O-mycoloyl-N-acetylmuramyl-L-seryl-D-isoglutamine and 6-O-mycoloyl-N-acetylmuramyl-glycyl-D-isoglutamine were examined in comparison with those of 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine. Synthetic 6-O-mycoloyl-N-acetylmuramyl-L-seryl-D-isoglutamine was active as an adjuvant for the induction of delayed-type hypersensitivity to m-[4-(4'-arsono-phenylazo)-phenyl]-N-acetyl-L-tyrosine in guinea pigs and for cell-mediated cytotoxicity in allogeneic mice. 6-O-mycoloyl-N-acetylmuramyl-glycyl-D-isoglutamine was inactive as an adjuvant for the induction of delayed-type hypersensitivity in guinea pigs; however, it was active for cell-mediated cytotoxicity in allogeneic mice. 6-O-mycoloyl-N-acetylmuramyl-L-seryl-D-isoglutamine and 6-O-mycoloyl-N-acetylmuramyl-glycyl-D-isoglutamine were not pyrogenic in rabbits. The antitumor activity of these 6-O-mycoloyl-N-acetylmuramyldipeptides was examined preliminarily by using transplantable syngeneic mouse tumors.

Adjuvant activity of synthetic 6-O-"mycoloyl"-N-acetylmuramyl-L-alanyl-D-isoglutamine and related compounds.

Adjuvant and antitumor activities of synthetic 6-O-"mycoloyl"-N-acetylmuramyl-L-alanyl-D-isoglutamine were examined. All the synthetic 6-O-corynomycoloyl-, 6-O-mocardomycoloyl-, and 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine were active as adjuvants for cell-mediated immune responses. However, 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine was less active as an adjuvant on circulating antibody formation. It was shown that pyrogenic activity of N-acetylmuramyldipeptide was reduced by 6-O-acylation with mycolic acid, but not with nocardomycolic or corynomycolic acid. Tumor-suppression activity was observed by the synthetic 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine by using transplantable tumor in syngenic mice.

Macrophage dependency of T-lymphocyte mitogenesis by Nocardia rubra cell-wall skeleton.

The mitogenic activity of the cell-wall skeleton (CWS) of Nocardia rubra on purified splenic T-cells (thymus-derived lymphocytes) was investigated. N. rubra CWS showed remarkable mitogenic activity on normal spleen cells of C57BL/6J mice at concentrations ranging from 10 to 100 microgram per milliliter of culture medium, while, on purified splenic T-cells, N. rubra CWS did not act as an mitogen at any concentration. However, mitogenic activity of N. rubra CWS on T-cells was restored if purified splenic T-cells was reconstituted with X-irradiated peritoneal exudate cells (macrophages). The above results suggest the necessity of macrophages for T-lymphocyte activation by N. rubra CWS as well as PHA-P or Con A.

Adjuvant activity of 6-O-mycoloyl-N-acetylmuramuyl-L-alanyl-D-isoglutamine.

Immunological properties of synthetic 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine (6-O-mycoloyl-N-acetylmuramyldipeptide) and 6-O-mycoloyl-N-acetylmuramic acid were examined in guinea pigs and mice in comparison with those of BCG cell-wall skeleton, N-acetylmuramyl-L-alanyl-D-isoglutamine, and 6-O-stearoyl-N-acetylmuramyl-L-alanyl-D-isoglutamine. 6-O-Mycoloyl-N-acetylmuramyldipeptide showed a potent adjuvant activity for the induction of delayed type hypersensitivy to N-acetyl-L-tyrosine-3-azobenzene-4'-arsonic acid (ABA-N-acetyltyrosine). It was also found that 6-O-mycoloyl-N-acetylmuramyldipeptide treated with oil droplets or suspended in phosphate-buffered saline was as effective as oil-attached BCG cell-wall skeleton for the generation of cell-mediated cytotoxic effector cells to mastocytoma P815-X2 cells in the spleen of C57BL/6J mice in vivo. However, 6-O-mycoloyl-N-acetyl-muramyldipeptide was less active as adjuvant than BCG cell-wall skeleton and N-acetylmuramyldipeptide in enhancing the circulating antibody formation to T-independent antigen, 2,4-dinitrophenyl-lysyl (DNP-Lys)-Ficoll in vivo, and on the generation of helper function of carrier-primed T-cells, and was inactive as a mitogen on normal mouse spleen cells. On the other hand, although 6-O-mycoloyl-N-acetylmuramic acid was shown to be inactive as adjuvant on immune systems described above, it was active as a mitogen on normal mouse spleen cells.