Randomized clinical trial: rikkunshito in the treatment of functional dyspepsia--a multicenter, double-blind, randomized, placebo-controlled study.

BACKGROUND: Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large-scale, randomized, placebo-controlled trials of rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD). METHODS: FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo-controlled, parallel-group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment. KEY RESULTS: Two hundred forty-seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori-infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori-uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori-positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups. CONCLUSIONS & INFERENCES: Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954).

Inhibitory effects of macrocarpals on the biological activity of Porphyromonas gingivalis and other periodontopathic bacteria.

BACKGROUND/AIMS: Macrocarpals, which are phloroglucinol derivatives contained in eucalyptus leaves, exhibit antimicrobial activity against a variety of bacteria including oral bacteria. This study examined effects of macrocarpals A, B, and C on periodontopathic bacteria, especially Porphyromonas gingivalis. METHODS: Macrocarpals A, B, and C were purified from a 60% ethanol-extract of Eucalyptus globules leaves. To investigate antibacterial activity, representative periodontopathic bacteria were cultured in media with or without various amounts of macrocarpals; subsequently, the optical density at 660 nm was measured. Macrocarpal inhibition of P. gingivalis Arg- and Lys-specific proteinases was assessed by spectrofluorophotometric assay and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. The effect of macrocarpals on P. gingivalis binding to saliva-coated hydroxyapatite beads was examined with (3)H-labeled P. gingivalis. RESULTS: Growth of P. gingivalis was inhibited more strongly than growth of Prevotella intermedia or Prevotella nigrescens and Treponema denticola by macrocarpals, however, Actinobacillus actinomycetemcomitans and Fusobacterium nucleatum were much more resistant. Macrocarpals inhibited P. gingivalis Arg- and Lys-specific proteinases in a dose-dependent manner. The enzyme-inhibitory effect of macrocarpals was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis in which hemoglobin degradation by P. gingivalis proteinase was inhibited by macrocarpals. P. gingivalis binding to saliva-coated hydroxyapatite beads was also strongly attenuated by macrocarpals. CONCLUSIONS: Macrocarpals A, B and C demonstrated antibacterial activity against periodontopathic bacteria. Among tested bacteria, P. gingivalis displayed the greatest sensitivity to macrocarpals; additionally, its trypsin-like proteinase activity and binding to saliva-coated hydroxyapatite beads were inhibited by macrocarpals. These results indicate that eucalyptus leaf extracts may be useful as a potent preventative of periodontal disease.

Inhibition of hepatic metastasis in mice treated with cell-binding domain of human fibronectin and angiogenesis inhibitor TNP-470.

BACKGROUND: To prevent tumor metastasis, we administered the cell-binding domain of fibronectin, in combination with the angiogenesis inhibitor TNP-470, to mice with hepatic metastasis. We then assessed the prevention of tumor metastasis resulting from the inhibition of adhesive interactions and the inhibition of angiogenesis. METHODS: A hepatic metastasis model was created by injecting 1 x 10(3) colon 26/TC-1 cells into the anterior mesenteric vein of CDF1 mice. The cell-binding domain obtained from fibronectin included the Arg-Gly-Asp (RGD) sequence. A fibronectin-binding domain (FND)-treated group, an FND plus TNP-470 group, and a control group were established. The animals were killed 4 weeks after the injections of the treatment agents had been completed and the number of metastatic liver nodules was counted. In a simultaneous experiment with the same design, the mice were not killed at 4 weeks, and their survival was observed. RESULTS: The mean number of nodules in the FND plus TNP-470 group was significantly lower than that in the control group (P = 0.019337). The inhibition rate was 51% in the FND group, 60% in the FND 10 micrograms plus TNP-470 10 mg/kg group, and 64% in the FND 10 micrograms plus TNP-470 100 mg/kg group compared with the control group. Mice from the FND group that were not killed died after 6-8 weeks, but mice from the FND plus TNP-470 group died after 8-12 weeks. CONCLUSION: The cell-binding domain of fibronectin may, potentially, be an effective form of antiadhesive therapy that competes with native adhesion molecules and blocks adhesion during the metastatic process. When the cell-binding domain of fibronectin is combined with TNP-470 to inhibit angiogenesis, more effective inhibition of metastatic tumor growth and prolongation of survival can be achieved than after treatment with the cell-binding domain alone.

Antioxidative action of flavonoids, quercetin and catechin, mediated by the activation of glutathione peroxidase.

Antioxidative action of flavonoids have been attracted attention of many investigators and a good deal of studies on it were reported. While their interests were mostly centered to the direct scavenging action of flavonoids against free radicals and active oxygen species, we expected that the interaction of flavonoids and intracellularly occurring antioxidative agents such as glutathione peroxidase (GSH-PO) could synergistically enhance their antioxidative activities. For this purpose, cultured rat hepatocytes (BL-9), which are highly expressing GSH-PO, were employed. One group of the cells were cultured with Se deficient media (Se(-) cells) to diminish the activity and the expression of GSH-PO protein and mRNA, and the other group was cultured with Se supplemented media (Se(+) cells). The oxidative cell damage was induced by the addition of H2O2 and two representative antioxidative flavonoids, quercetin and catechin, were added to the media to test their cytoprotective action. In Se(+) cells, the remarkable cytoprotective activity of those flavonoids were confirmed, whereas none of such activity was evidenced in Se(-) cells. It was proved that the intracellular antioxidative function of flavonoids requires the interaction with GSH-PO, at least in the cells expressing the enzyme. Interestingly, the flavonoid activated GSH-PO clearly, and its mechanism is discussed.

Synthesis and antitumor activity of 20(S)-camptothecin derivatives. A-ring-substituted 7-ethylcamptothecins and their E-ring-modified water-soluble derivatives.

Twenty-six novel A-ring-modified 7-ethylcamptothecins (6) were synthesized by Friedländer's condensation of the chiral tricyclic ketone (5) with aminopropiophenones (4). The compounds substituted with fluorine at the 11 position showed strong cytotoxicity to KB and L1210 cells. The 11-fluoro derivatives also exhibited strong inhibitory activity on DNA topoisomerase I. Nine compounds 6 with four to ten times stronger cytotoxicity than that of camptothecin were selected and converted into water-soluble 17-O-acyl amide derivatives (8). Compounds 8e (10-Me, O-COCH2CH2SCH3) and 8f (11-F, O-COC2H5) showed activity towards Meth A in mice that was comparable to that of CPT-11, at lower doses than CPT-11.

Effect of KCA-098, a new benzofuroquinoline derivative, on bone mineral metabolism.

The effect of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoli ne-6-one designated as KCA-098) on the bone mineral metabolism of chick embryonic bone was examined. KCA-098 dose-dependently inhibited bone resorption of cultured chick embryonic femora and calvariae. It increased the length, dry weight, and calcium and phosphorus contents of 9-d-old chick embryonic femurs cultivated for 6 d, indicating that it stimulated bone formation. These results show that KCA-098 has the unique effects of inhibiting bone resorption and stimulating bone formation of chick embryo. In addition, in an in vivo experiment, oral administration of KCA-098 (3.0 mg/kg/d) for 16 weeks led to an increase in calcium and phosphorus content as well as an increase in the amount of force required to break the femur from ovariectomized rats, suggesting that it may be useful for the treatment of bone diseases.

In vitro effect of KCA-098, a derivative of coumestrol, on bone resorption of fetal rat femurs.

The effects of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoli ne-6-one (KCA-098), a derivative of coumestrol, on bone resorption was studied in organ cultures of 20-day fetal rat femora. KCA-098 increased the length, dry weight, and calcium and phosphorus contents of parathyroid hormone (PTH)-treated fetal rat femur. As PTH significantly reduced the calcium and phosphorus contents of the femora, probably by stimulating bone resorption, KCA-098 seems to inhibit bone resorption. In fact, KCA-098 inhibited the PTH-induced release of 45Ca from pre-labeled fetal rat femora into the medium in organ culture. Coumestrol also inhibited the release of 45Ca from bone into the medium. However, KCA-098 did not increase the uterine weight of ovariectomized rats, whereas coumestrol did so. Thus KCA-098 is a unique, new inhibitor of bone resorption that has no estrogenic activity.

[Relationship between volume and concentrations of various components of breast milk in early and 2-6 months lactation].

The concentrations of total protein, fat, lactose, calcium and s-IgA in human colostrum and matured milk and 24-hour milk production for the same day were measured on 99 and 47 lactating women at 5 days and 2-6 months post-partum, respectively. Relationships between measured concentrations, calculated energy content, and milk volumes were investigated. 1. In colostrum, the concentrations of protein and s-IgA showed significant negative correlations with milk volumes, while those of fat and lactose, and energy content showed significant positive correlations with milk volumes. 2. In matured milk, the concentrations of protein and s-IgA showed significant negative correlations with milk volumes. However, the negative correlation between protein concentration and milk volumes was not statistically significant when subjects were limited to mothers breast-feeding only. In matured milk fat, lactose and calcium concentrations, and energy content were not significantly correlated with milk volume.

[Efficacy of the treatment of gastric cancer as neo-adjuvant chemotherapy of 48 hour continuous intravenous infusion of 5-fluorouracil (5-FU) with leucovorin (LV)].

A 51-year-old female with inoperable gastric cancer and with infiltration of pancreatic tail diagnosed by abdominal CT was treated with leucovorin (LV) and 5-fluorouracil (5-FU). The regimen was: LV 30 mg/body/24 hr prior to 5-FU 1,000 mg/m2/day for 48 hrs. This treatment was repeated 6 times. After treatment, the size of tumor decreased so that the patient was able to be operated (Total gastrectomy with partial distal pancreatico-splenectomy). During the treatment, patient showed no side effect except for slight nausea. This neo-adjuvant chemotherapy might be a recommendable treatment of advanced gastric cancer.

Increased lymphocyte transport by lipid absorption in rat mesenteric lymphatics.

The effect of olive oil administration on lymphocyte transport through mesenteric lymphatics was examined to see the possible involvement of nutritional absorption in lymphocyte traffic from the intestinal mucosa. After the olive oil administration to rats, remarkable increase in lymphocyte flux was observed within 2 h in lymph samples collected from rats with lymphatic fistula. The use of a high-speed microscopic video system made it possible to analyze accurately the lymphocyte transport in rapid movement that could not be detected by any of the ordinary video systems. The direct observation of mesenteric collecting lymphatics by this system showed an increment of lymphocyte transport from the intestinal mucosa by lipid absorption in 2 h. The contraction frequency of intestinal collecting lymphatics was also enhanced by olive oil administration. The densitometric analysis on video image was applied to estimate the extent of lipid absorption. The combination of a high-speed video system and the densitometric analysis revealed that the increase in lymphocyte flux occurred before lipid absorption reached its maximum and also demonstrated that the lymphocyte transport returned to control levels under the maximal absorptive condition. The results suggest that the fat absorption could be an important factor influencing the lymphocyte transport in the lymphatic system of intestine.

Heavy metal concentrations in blood cells in patients with amyotrophic lateral sclerosis.

Manganese (Mn) and selenium (Se) concentrations in blood cells were measured by neutron activation analysis. Blood was obtained from patients with amyotrophic lateral sclerosis (ALS), patients with other neurological diseases and control subjects. Dried blood cells were activated by neutron irradiation. Mn was determined after chemical separation and Se was determined nondestructively. Mn concentrations in blood cells from ALS patients were significantly lower (P less than 0.01) than those from the other groups. The Mn concentrations were also significantly lower (P less than 0.01) in late than in earlier stages of ALS. Se concentrations in blood cells from ALS patients were significantly higher (P less than 0.01) than those from the other two groups. A generalized abnormal distribution of these metals may play a role in the pathogenesis of this disorder. Bromine, zinc, rubidium, and iron concentrations of erythrocytes were the same in all groups.

Pathologic laughing and crying treated with levodopa.

Levodopa or amantadine hydrochloride was administered to 25 patients with pathologic laughing and/or crying. This symptom was markedly improved in ten cases, most of which were devoid of a cortical atrophy or a periventricular lucency in computed tomographic scan and also devoid of a severe dementia or a disturbance in activity of daily living. The concentration of homovanillic acid in the CSF of the patients was significantly decreased, whereas the concentration of 5-hydroxyindoleacetic acid remained within the normal limit. Because part of pathologic laughing and crying seems to be caused by the decreased function of the dopaminergic neuron, levodopa or amantadine is worth trying.