Improvement of QOL and prognosis by treatment of superfine dispersed lentinan in patients with advanced gastric cancer.

BACKGROUND/AIMS: Intravenous lentinan administration has life prolongation effect for gastric cancer patients when combined with chemotherapy. Recently, superfine dispersed lentinan--an oral formulation--has become clinically available. In order to evaluate the efficacy of superfine dispersed lentinan, was conducted multicenter clinical study. METHODOLOGY: Twenty-seven patients with unresectable or recurrent gastric cancer were enrolled and answered the quality of life questionnaire before and 4, 8, and 12 weeks after the initiation of superfine dispersed lentinan administration. Survival times were evaluated according to results of 3-year follow-up survey. RESULTS: There was no adverse event with causal relation to superfine dispersed lentinan. Median survival time was 17.1 months (95% confidence interval: 6.9-25.9 months) in 26 eligible patients. Six (23%) out of 26 patients were alive longer than 3 years. There was a significant correlation between the quality of life scores at 12 weeks of superfine dispersed lentinan treatment and survival times. CONCLUSIONS: Superfine dispersed lentinan is deemed free of anything harmful. Quality of life status at 12 weeks of superfine dispersed lentinan treatment appears to be a promising prognostic predictor.

[Provision for adverse effect of S-1 containing chemotherapy in patients with advanced digestive cancer--combination with superfine dispersed lentinan].

PURPOSE: Recently, in drug therapy for patients with advanced digestive cancer, S-1 (tegafur x gimeracil x oteracil potassium) alone or S-1 combined with other chemotherapeutic agents (S-1+alpha) is prescribed. However, many patients are often forced to give up long-term S-1 treatment owing to high incidence rates of adverse effects. The purpose of this study was to evaluate the efficacy of superfine dispersed lentinan (SDL) for the suppression of adverse effects of S-1 or S-1+alpha. SUBJECTS AND METHOD: The subjects were 72 patients who had unresectable or recurrent advanced digestive cancer. The subject group consisted of 45 men and 27 women, with a median age of 64 (31-85) years; 29 gastric, 25 colorectal, 10 pancreatic and 8 other digestive cancer patients. Thirty -one patients were administered S-1 alone and 41 patients were administered S-1+alpha. SDL (15mg of lentinan/bag/day) was orally administered to all patients for 12 weeks. Adverse events and overall survival time were evaluated according to the CTCAE ver 3.0 and the Kaplan-Meier method, respectively. RESULTS: Seventy-two patients were enrolled in this study. Adverse events which had an undeniable causal relationship to SDL were observed in 2 patients (2.7 %, constipation [Grade 2] and nausea [Grade 1]) out of 72 patients; all of the events were not severe and disappeared when the SDL administration was discontinued. Adverse events associated with S-1 or S-1+ alpha were observed in 9 patients (12.5% ) (11 events) out of 72 patients. Grade 3 adverse events were observed in 3 patients (4.2% ) (leukopenia, 2; thrombocytopenia, 1). Incidence rates of both hematological and nonhematological adverse events were very low. In no gastrointestinal toxicity associated with S-1 or S-1+alpha was observed, which was estimated to be an effect of SDL combination. Mean survival times in gastric cancer and colorectal cancer patients were 9. 5 months (95%confidential interval [CI], 7.0-22.4 months) and 18.4 months (95% CI, 13.2 -28.5 months), respectively. CONCLUSIONS: From the results of the present study, SDL is considered completely free of anything harmful to advanced digestive cancer patients and is effective for the suppression of adverse effects of S-1 or S-1+alpha therapy. It is suggested that SDL can prolong the administration period of S-1 and, as a result, contribute to prolongation of survival in patients with advanced digestive cancer.

Efficacy of orally administered superfine dispersed lentinan (beta-1,3-glucan) for the treatment of advanced colorectal cancer.

BACKGROUND: Lentinan (LNT) is an immune adjuvant medicine for advanced gastric cancer in Japan. Recently, an oral formulation of superfine dispersed lentinan (SDL) has become clinically available. To investigate the safety and effectiveness of SDL, a multi center clinical study in patients with advanced colorectal cancer was conducted. PATIENTS AND METHODS: Adverse events were assessed and the patients' quality of life (QOL) and the binding ability of peripheral blood monocytes (PBM) to LNT were also evaluated. RESULTS: Four grade 2 adverse events associated with SDL treatment were observed among the 80 patients. Adverse events associated with chemotherapy were observed in 9 out of the 64 chemotherapy-treated patients. Among the 48 patients assessed for QOL, the patients with low QOL scores before SDL treatment (n=23) reported a significant improvement in their QOL scores after 12 weeks of SDL administration. The rates of LNT-binding PBM in the QOL-improved group were significantly higher than those in the QOL-not-improved group (p<0.05). CONCLUSION: SDL was safe and effective for suppressing the adverse effects of chemotherapy as well as improving QOL. The binding ability of PBM to LNT appears to be a promising predictor of QOL improvement after SDL administration.

Clinical efficacy of superfine dispersed lentinan (beta-1,3-glucan) in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Recently, complementary alternative medicine is actively performed for cancer therapy. We investigated the effectiveness of supplementary food containing superfine dispersed lentinan (beta-1,3-glucan) in patients with unresectable or recurrent hepatocellular carcinoma in a multi-center study. METHODOLOGY: Peripheral blood was collected prior to the test food ingestion and was incubated with fluorescein-labeled lentinan. The rates of lentinan-binding CD14+ monocytes were determined by flow cytometry. Patient survival times were followed up for 3 years. RESULTS: Thirty-six patients were eligible among 40 enrolled patients. Median survival time of eligible patients was 13.6 months (95% confidence interval, 8.7-18.9 months). Survival times of patients who ingested test food for a mean period of 47 weeks (range, 26 to 145 weeks) were significantly longer than that of patients who ingested for 7 to 12 weeks (p < 0.05). The rates of lentinan-binding cells in CD14+ monocytes showed individual variations (0.1-19.7%; Median, 1.6%). Survival times (median survival time, 16.3 months) of lentinan-high-binding group were significantly longer than those (median survival time, 12.5 months) of lentinan-low-binding group (p < 0.05). CONCLUSIONS: A superfine dispersed lentinan-containing supplementary food is effective for hepatocellular carcinoma patients' survival. Long-time ingestion is preferable. Assessment of lentinan-binding CD14+ monocytes is a promising prognostic predictor.

Efficacy of oral administered superfine dispersed lentinan for advanced pancreatic cancer.

BACKGROUND/AIMS: Recently, complementary alternative medicine is actively performed for cancer therapy. Superfine dispersed lentinan (beta-1,3-glucan)--an oral effective form--was recently developed and available. We investigated the effectiveness of superfine dispersed lentinan in advanced pancreatic cancer patients in a multi-center study. METHODOLOGY: Twenty-nine patients with unresectable and recurrent pancreatic cancer were enrolled, and adverse events and quality of life scores were assessed. Survival times were evaluated according to results of a 3-year follow-up survey. RESULTS: Although a diarrhea of grade-1 adverse event dependent on the test article (3.4%) was observed, the symptom was remitted without any treatment. This indicates that test article was free of anything harmful. Median survival time was 12.1 months (95% confidence interval: 7.3-25.7 months) in 25 eligible patients. Five (20%) out of 25 patients were alive for 3 years. There was a significant correlation between the quality of life scores after the superfine dispersed lentinan treatment and survival times. CONCLUSIONS: A superfine dispersed lentinan is deemed safe and effective for advanced pancreatic patients' survival and improvement of quality of life. And the assessment of quality of life status after the administration of superfine dispersed lentinan is a promising prognostic predictor.

Effect of oral vitamin E administration on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator.

The effect of oral vitamin E administration on acute gastric mucosal lesion progression was examined in rats treated once with compound 48/80 (C48/80) (0.75 mg/kg, i.p.) in comparison with that of subcutaneously administered superoxide dismutase (SOD) plus catalase (CAT). Vitamin E (50, 100 or 250 mg/kg) administered at 0.5 h after C48/80 treatment reduced progressive gastric mucosal lesions at 3 h after the treatment dose-dependently, like SOD plus CAT administered at the same time point. The gastric mucosa of C48/80-treated rats had decreased Se-glutathione peroxidase activity and vitamin E, ascorbic acid, and hexosamine contents and increased myeloperoxidase and xanthine oxidase activities and thiobarbituric acid reactive substances content at 3 h after the treatment. Administered vitamin E attenuated all these changes found at 3 h after C48/80 treatment dose-dependently, like administered SOD plus CAT. C48/80-treated rats administered with vitamin E (100 or 250 mg/kg) had higher gastric mucosal vitamin E content than C48/80-untreated rats. Neither administered vitamin E nor SOD plus CAT had any effect on the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow found at 3 h after C48/80 treatment. In the gastric mucosa of C48/80-untreated rats administered with vitamin E, thiobarbituric acid reactive substances content decreased with an increase in vitamin E content. These results indicate that orally administered vitamin E prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing oxidative stress, neutrophil infiltration, and mucus depletion in the gastric mucosa like administered SOD plus CAT.

Preventive effect of Shigyaku-san on progression of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats.

The study examined whether Shigyaku-san (Si-Ni-San) extract (TJ-35), a traditional Kampo medicine, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80). Rats treated with C48/80 (0.75 mg/kg body weight, i.p.) received TJ-35 (0.15, 0.35 or 0.75 g/kg body weight, p.o.) 0.5 h after the treatment at which time gastric mucosal lesions appeared. At 0.5 h after C48/80 treatment, the gastric mucosa of the treated rats had increased myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. At 3 h after C48/80 treatment, the gastric mucosa of the treated rats showed progressive lesions and further increases in myeloperoxidase and xanthine oxidase activities and thiobarbituric acid reactive substances content and decreases in vitamin E, ascorbic acid and adherent mucus contents and Se-glutathione peroxidase activity. Post-administered TJ-35 attenuated all these changes found at 3 h after C48/80 treatment dose-dependently. These results indicate that TJ-35 prevents the progression of C48/80-induced acute gastric mucosal lesions in rats possibly by attenuating enhanced neutrophil infiltration, enhanced lipid peroxidation associated with decreased vitamin E and ascorbic acid contents and Se-glutathione peroxidase activity, and destruction of the defensive barrier in the gastric mucosa.

Effect of gefarnate on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator, in comparison with that of teprenone.

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.

Efficacy of a Low-Dose Omeprazole-Based Triple-Therapy Regimen for Helicobacter pylori Eradication Independent of Cytochrome P450 Genotype : The Japanese MACH Study.

OBJECTIVES: To investigate the efficacies of two different triple-therapy regimens (standard versus low doses), and the influence of cytochrome P450 enzyme (CYP) genetic polymorphism on these efficacies, in Japanese patients undergoing Helicobacter pylori eradication treatment. METHODS: All patients received 1 week of triple therapy. Patients in group A (low-dose regimen) received omeprazole 40 mg/day + amoxicillin 1500 mg/day + clarithromycin 800 mg/day; patients in group B (standard-dose regimen) received omeprazole 40 mg/day + amoxicillin 2000 mg/day + clarithromycin 1000 mg/day. RESULTS: A total of 225 patients (113 in group A and 112 in group B) were randomised to one of the two triple-therapy regimens. The eradication rates were 78.8% (89/113 patients; 95% CI 70.1, 85.9) in group A and 83.0% (93/112 patients; 95% CI 74.8, 89.5) in group B. Genetic polymorphism of CYP2C19, a major metabolic enzyme of omeprazole, did not affect eradication rates, while susceptibility to clarithromycin greatly affected the success of eradication. The cumulative ulcer relapse rate at 24 weeks after endoscopically documented ulcer healing (30 weeks after completion of the drug regimen) was 8.3% for group A and 12.5% for group B (log rank test: p = 0.6248). However, comparison of the cumulative relapse rate of 6.7% in patients after successful H. pylori eradication with the relapse rate of 27.3% in those who failed H. pylori eradication revealed a significant difference in the remission-time curve (log rank test: p = 0.0047). This finding suggested the existence of a relationship between H. pylori eradication failure and ulcer relapse. Both drug regimens were well tolerated. Endoscopically proven reflux esophagitis developed in about 10% of patients after eradication, but was not clinically significant. CONCLUSIONS: One week of triple therapy with a low-dose regimen provides adequate H. pylori eradication in Japanese patients. CYP genetic polymorphism is of minimal clinical significance with both triple-therapy regimens.

Preventive effect of teprenone on acute gastric mucosal lesion progression in compound 48/80-treated rats.

The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17-nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion progression was examined in rats with a single intraperitoneal (i.p.) injection of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was orally administered 0.5 h after compound 48/80 treatment at which time gastric mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80-treated rats showed increases in myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreases in Se-glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h after the treatment. Post-administered teprenone attenuated all these changes dose-dependently. These results indicate that teprenone prevents acute gastric mucosal lesion progression in compound 48/80-treated rats possibly by suppressing gastric mucus depletion, neutrophil infiltration and oxidative stress in the gastric mucosal tissue.

Protective effect of teprenone against acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats.

The protective effect of teprenone, an anti-ulcer drug, against acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Teprenone (50, 100, or 200 mg/kg) was orally administered 0.5 h before compound 48/80 treatment. Administered teprenone prevented gastric mucosal lesion development found at 3 h after compound 48/80 treatment dose-dependently, although no dose of teprenone affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. Increases in the activities of myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase and the content of thiobarbituric acid reactive substances (an index of lipid peroxidation) and decreases in the contents of hexosamine (a marker of gastric mucus) and adherent mucus occurred in gastric mucosal tissues at 3 h after compound 48/80 treatment. Administered teprenone dose-dependently attenuated all these changes found at 3 h after compound 48/80 treatment. These results indicate that orally administered teprenone protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its stimulatory action on gastric mucus synthesis and secretion and its inhibitory action on neutrophil infiltration and enhanced lipid peroxidation in the gastric mucosal tissue.

Protective effect of ebselen, a seleno-organic compound, against the progression of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats.

The protective effect of ebselen, which possesses glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, against the progression of acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Ebselen (50, 100 or 200 mg/kg) was orally administered 0.5 h after compound 48/80 treatment, at which time gastric mucosal lesions appeared. Post-administered ebselen suppressed gastric mucosal lesion progression at 3 h after compound 48/80 treatment dose-dependently, although no dose of ebselen affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. A decrease in Se-glutathione peroxidase activity and increases in myeloperoxidase and xanthine oxidase activities and the concentration of thiobarbituric acid reactive substances were found in gastric mucosal tissues at 0.5 h after compound 48/80 treatment, and these changes were further enhanced at 3 h. Post-administered ebselen attenuated all these changes found at 3 h after compound 48/80 treatment dose-dependently. The present results indicate that ebselen exerts a protective effect against the progression of compound 48/80-induced acute gastric mucosal lesions in rats, and they suggest that this protective effect of ebselen could be due to its glutathione peroxidase-like activity and its antioxidative and anti-inflammatory properties.

Protective effect of omeprazole against acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats.

Omeprazole, a proton pump inhibitor is known to function not only as a proton pump inhibitor but also as an anti-inflammatory agent, an antioxidant or a stimulator of gastric mucus secretion. We have shown that the pathogenesis of acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats involves neutrophil infiltration, lipid peroxidation, and mucin depletion, but not acid secretion, in the gastric mucosal tissue. Therefore, we examined whether omeprazole protects against acute gastric mucosal lesions induced by compound 48/80 in rats. Rats were injected with omeprazole (10 or 50 mgkg(-1), i.p.) at 0.5h before injection of compound 48/80 (0.75 mgkg(-1), i.p.). Omeprazole prevented gastric mucosal lesion development at 0.5 and 3h after compound 48/80 injection. Omeprazole attenuated decreased nonprotein sulfhydryl content and increased myeloperoxidase and xanthine oxidase (XO) activities and lipid peroxide (LPO) content in the gastric mucosa at 0.5h after compound 48/80 injection and increased myeloperoxidase and XO activities and LPO content, but not decreased hexosamine and adherent mucus contents, in the gastric mucosa at 3h. These results indicate that omeprazole protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its anti-inflammatory and antioxidant actions.