Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: A randomized clinical trial (the DREAM study).

BACKGROUND: Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS: FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS: Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P < .001), postprandial fullness/early satiety (r = .226, P = .014), dyspepsia (r = .215, P = .019), and PDS (r = .221, P = .016). CONCLUSION & INFERENCES: Rikkunshito may be beneficial for FD patients to simultaneously treat gastrointestinal and psychological symptoms.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by -0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (-0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Fatigue strength of Ce-TZP/Al2O3 nanocomposite with different surfaces.

Ce-TZP/Al(2)O(3) nanocomposite (NANOZR) has not only higher strength, but also higher fracture toughness than conventional Y-TZP, indicating its potential for use in dental implants. Surface treatment to obtain osseointegration, however, may alter its surface topography, thus affecting the cyclic fatigue strength that plays such an important role in the durability of this material. The aim of this study was to evaluate the influence of surface treatment on cyclic fatigue strength in NANOZR as compared with grit-blasted and acid-etched Y-TZP (125BE Y-TZP). Bi-axial flexure strength was measured in both static and cyclic fatigue tests, as recommended by ISO 6872. The cyclic fatigue test was performed by the staircase method in distilled water at 37°C, with a load of 10(6) cycles and 10 Hz. Bi-axial flexure strength of NANOZR was 1111-1237 MPa and 667-881 MPa in the static and cyclic fatigue tests, respectively. The bi-axial flexure strength of NANOZR under all conditions was greater than that of 125BE Y-TZP in the static and cyclic fatigue tests. The cyclic fatigue strength of NANOZR was more than twice that of Y-TZP as specified in ISO 13356 for surgical implants (320 MPa), indicating the promise of this material for use in dental implants.

A trial of oolong tea in the management of recalcitrant atopic dermatitis.

BACKGROUND: Mild cases of atopic dermatitis (AD) generally improve with standard treatment. However, standard treatment fails many patients with recalcitrant AD skin lesions. Study results in animal models have demonstrated that the administration of tea (ie, green, black, or oolong) has suppressed type I and type IV allergic reactions. OBJECTIVE: To test the effectiveness of oolong tea in the treatment of recalcitrant AD. PATIENTS: Although 121 patients with recalcitrant AD were enrolled in the study, 118 patients completed the open study. METHODS: Patients were asked to maintain their dermatological treatment. However, they were also instructed to drink oolong tea made from a 10-g teabag placed in 1000 mL of boiling water and steeped for 5 minutes. This amount was then divided into 3 equal servings and 1 serving was drunk daily after 3 regular meals. Photographs of 2 or 3 representative lesion sites were taken at baseline and at 1 and 6 months and the severity of pruritus was assessed on a 6-point Lickert-like scale ranging from markedly improved (>50% improvement) to worsened. RESULTS: After 1 month of treatment 74 (63%) of the 118 patients showed marked to moderate improvement of their condition. The beneficial effect was first noticed after 1 or 2 weeks of treatment. A good response to treatment was still observed in 64 patients (54%) at 6 months. CONCLUSION: The therapeutic efficacy of oolong tea in recalcitrant AD may well be the result of the antiallergic properties of tea polyphenols.

Differential alteration of cardiotonic effects of EMD 57033 and beta-adrenoceptor agonists in volume-overload rabbit ventricular myocytes.

BACKGROUND: We investigated the effects of EMD 57033, a prototype Ca2+ sensitizer, and beta-adrenoceptor agonists in ventricular myocytes isolated from the volume-overload (V-O) heart failure model of the rabbit. METHODS AND RESULTS: V-O cardiac hypertrophy was induced in rabbits by the formation of an arterio-venous shunt between the carotid artery and jugular vein 12 to 15 weeks after the operation. Ventricular myocytes were enzymically isolated from normal and V-O rabbit hearts. The myocyte was loaded with a fluorescence Ca2+ dye, indo-1, and Ca2+ transients, and cell lengths were measured simultaneously. V-O myocytes were significantly larger than control myocytes. Duration of Ca2+ transients and cell shortening was significantly longer in the V-O myocytes than in control myocytes. Effects of cardiotonic interventions, including EMD 57033, isoproterenol, and dobutamine, on Ca2+ transients and cell shortening in V-O myocytes were compared with those in control rabbit myocytes. Isoproterenol and dobutamine increased the systolic cell shortening and peak Ca2+ transients and abbreviated the duration of cell shortening and Ca2+ transients. These responses were markedly attenuated in V-O myocytes. By contrast, the response of cell shortening to EMD 57033 was unaltered, and the Ca2+ sensitizing effect of EMD 57033 was rather enhanced in V-O myocytes. CONCLUSION: Our results indicate that the effectiveness of Ca2+ sensitizers is maintained in the V-O rabbit hypertrophy and heart failure model in contrast to the blunted response to beta-adrenoceptor agonists, which provides an insight on therapeutic strategy with Ca2+ sensitizers for the treatment of contractile dysfunction in congestive heart failure.

[Importance of drug selection and the use of sensitivity tests for the eradication therapy for Helicobacter pylori].

Drug selection for eradication therapy of H. pylori, considering their drug resistance was evaluated. The measurement of resistant colonies was performed in blood agar plates using the MIC method and the criteria for resistance was as follows: MIC > 1 mg/l with AMPC, MIC > 2 mg/l with CAM and MIC > 8 mg/l with MNZ. Primary resistant colonies were found in 0% with AMPC, 8.9% with CAM and 5.9% with MNZ. Secondary resistant colonies were found in 0% with AMPC, 50.0% with CAM and 54.5% with MNZ. CAM and MNZ showed high resistance rate and among them, colonies resistant to CAM were also highly resistant to MNZ. But colonies resistant to MNZ (acquired after CAM) were all sensitive to AMPC. Considering this issue and the absence of resistance to AMPC, we considered the triple therapy with AMPC, MNZ and a PPI as the best option for the eradication of H. pylori.

Anti-inflammatory activity of superoxide dismutase conjugated with sodium hyaluronate.

Superoxide dismutase (SOD) from bovine erythrocytes was conjugated with sodium hyaluronate (HA) with a mean molecular weight of 10(6) to have greater anti-inflammatory activity in vivo. Amino groups of SOD were coupled with carboxyl groups in the hyaluronate molecule using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The HA-SOD conjugate was composed of 1.5 mol of SOD molecule per 1 mol of hyaluronate on the average, and retained 70% of the activity of unmodified SOD. The conjugate was essentially non-immunogenic in mice, and exhibited much higher anti-inflammatory activities than HA or SOD in models of inflammatory diseases such as ischemic oedema of the foot-pad in mice, carrageenin-induced pleurisy and adjuvant arthritis in rats.

Effects of thermochemotherapy [1-hexylcarbamoyl-5-fluorouracil (HCFU) combined with hyperthermia]: a basic study on the most effective timing and sequence in vivo.

1-Hexylcarbamoyl-5-fluorouracil (HCFU) is known to be hydrolyzed to 5-fluorouracil (5-FU) by heating. We have previously reported the enhancement of the antitumor effects of HCFU when combined with hyperthermia (1). This study aimed at determining the most effective timing schedule for HCFU combined with hyperthermia for clinical application. On the third, 6th, 9th, 12th and 15th day after transplantation, HCFU (80 mg/kg) was administered and hyperthermia induced. The antitumor effect was evaluated by the measurement of tumor volume. 5-FU concentration in the tumor tissue was analyzed on the 12th day after transplantation after administering 150 mg/kg HCFU, with or without hyperthermia (43.5 degrees C, 45 min). 5-FU concentration in serum and other tissues (kidney, liver and submandibular gland) were also analyzed. The concentration was measured by a high performance liquid chromatograph (HPLC) following Mori et al 's method (2). An enhanced antitumor effect and a significant increase in 5-FU concentration in tumor tissue were observed in post-heated groups of mice as compared with pre-heated groups and groups given HCFU alone. The results showed that HCFU given 1 to 2 hours prior to hyperthermia was the most effective treatment.

Enhancement of antitumor effects of new analogue of platinum, cis-diammine (glycolato) platinum (254-S) combined with hyperthermia in vivo.

Cis-diammine (glycolato) platinum (254-S) is a second generation platinum complex with reduced nephrotoxicity. In this study the antitumor effect of 254-S combined with hyperthermia in vivo in mice was studied. On the 6th day after inoculation of the Ehrlich ascites tumour cells, 254-S (15mg/kg) was administered intraperitoneally (i.p.) and hyperthermia was induced by using a circulating water bath at 42.5 degrees C for 45 min. The antitumour effect was evaluated by relative tumour volume. Furthermore, platinum concentration in tumour tissue was determined by using atomic absorption spectrophotometry. The most effective condition was found to be the combination of 254-S with hyperthermia. A significantly higher concentration of platinum in the tumour tissue was observed when treatment with 254-S was combined with hyperthermia, than with treatment using 254-S alone. Our study suggested that the accumulation of 254-S in the tumour tissue, and its retention at a high concentration within the tumour tissue long term was one of the reasons for the enhancement of antitumour effect of 254-S treatment when combined with hyperthermia.

Antitumor effect of carboplatin combined with hyperthermia on Ehrlich-ascites tumor in vivo.

We examined the optimal timing for the enhancement of antitumor effects of CDDP analogues, cis- diammine-1,1- cyclobutane dicarboxylate platinum (II); CBDCA combined with hyperthermia against the CD-1 mice bearing Ehrlich ascites tumor (EAT) cells in vivo. The prolonged tumor doubling time was observed when two modalities were combined. The longest tumor doubling time was obtained by simultaneous administration of CBDCA combined with hyperthermia. The findings indicated that the most effective condition was the simultaneous combination of CBDCA with hyperthermia. An increase in intratumoral platinum concentration was observed by the treatment of CBDCA simultaneous combined with hyperthermia.

Protection by baicalein against ascorbic acid-induced lipid peroxidation of rat liver microsomes.

The effect of baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid isolated from Scutellaria baicalensis Georgi, on lipid peroxidation in rat liver microsomes was studied. Ascorbic acid-induced lipid peroxidation in microsomes obtained from baicalein-treated rats was inhibited by treatment on different days and at different doses. Iron release induced by ascorbic acid from microsomes of baicalein-treated rats was markedly lower than from microsomes of control rats. However, no statistical differences in total, nonheme and nonprotein-bound (free iron) iron contents could be detected in the two microsomes. The degradation of calf thymus DNA, an indicator of free iron existence, was observed in the reactions of microsomes obtained from control and baicalein-treated rats with ascorbic acid in the presence of bleomycin. These results suggest that baicalein can inhibit lipid peroxidation in microsomes induced by ascorbic acid by forming an inert complex of iron.

Manganese deposition in the brain during long-term total parenteral nutrition.

BACKGROUND: Manganese deposition was suspected in a pediatric patient who received long-term total parenteral nutrition. T1-weighted magnetic resonance images revealed high intensity areas in the globus pallidus. This study was designed to clarify if these abnormal findings were related to manganese deposition and clinical neurological manifestations. METHODS: Whole-blood manganese concentrations were measured during manganese supplementation to total parenteral nutrition and after 5 months without manganese. Magnetic resonance images were also examined on each occasion and compared with the blood level of manganese. RESULTS: The whole-blood manganese level during supplementation was 135 micrograms/L (normal range 14.6 +/- 4.7 micrograms/L), whereas the level was 20 micrograms/L after a manganese-free period of 5 months. Accompanied with normalization of manganese level, abnormal high intensity lesions in the globus pallidus on T1-weighted images also disappeared. No neurological manifestation related to the high manganese level was recognized. CONCLUSIONS: It is probable that the high manganese level was elicited by manganese supplementation to total parenteral nutrition. This high manganese condition was confirmed by the measurement of whole-blood manganese level, which was associated with the abnormal high intensity lesions on T1-weighted magnetic resonance images.

Novel antitumor sesquiterpenoids in Achillea millefolium.

Three new antitumor sesquiterpenoids, achimillic acids A, B and C, were isolated as methyl esters from Achillea millefolium and their structures were determined spectroscopically. The compounds were found to be active against mouse P-388 leukemia cells in vivo.

Effects of intralesional injection of cisplatin dissolved in urografin and lipiodol on Ehrlich ascites tumor and normal tissues of CD-1 mice.

The response of Ehrlich ascites tumor and the effect on normal tissues (kidney and small intestine) of CD-1 mice were evaluated after intralesional (i.l.) injection of cisplatin dissolved in urografin and lipiodol, which is henceforth termed CUL suspension. The results obtained were compared with the effects of i.p. and i.l. injections of cisplatin dissolved in sterile distilled water. Each of these treatment modalities involves the injection of 10 mg/kg cisplatin. The tumor response was evaluated by tumor growth-delay studies as well as by determining the percentage of cells in the S phase. Toxicity studies were accomplished by evaluation of the change in the body weight of mice and also by S-phase studies. S-phase fraction analyses were done with the use of the Cell Proliferation Kit. This commercial kit was used to measure bromodeoxyuridine (BrdU), a thymidine analogue that is incorporated into cells synthesizing DNA. Tumor, kidney, and small-intestine platinum concentrations were determined by measurement with a flameless atomic absorption spectrophotometer. The results of the tumor growth-delay studies showed that i.p. injection, with water being the drug carrier, produced the weakest antitumor effect, whereas i.l. injection of cisplatin, with lipiodol being the drug carrier, evoked the most enhanced effect. This finding was substantiated by BrdU-uptake analysis of tumor cells, wherein i.p. injections yielded the highest S-phase fraction and CUL treatment gave the lowest. Toxicity studies showed that a very significant decrease in body weight occurred in mice receiving i.p. treatment. No significant decrease in body weight was noted after i.l. treatment. BrdU analysis revealed that DNA synthesis in kidney cells and crypt cells of the small intestine was depressed after i.p. treatment. On the other hand, no significant effect was observed in the kidney or small intestine of CUL-treated mice. A correlation between the effects of the various treatment modalities (on tumors, kidney, and small intestine) and the retention of cisplatin was found.

[Elimination of Japanese cedar (Cryptomeria japonica) aeropollen by rainfall].

The concentration of aeropollens of Japanese cedar decreases on rainy days, due to the rainfall removing pollens from the atmosphere. An analysis was performed of the concentration of pollen grains in rain water samples from Yokohama during the period February 10 to April 30, 1991. Sampling of rain water was performed using an automatic rain water collector, and an analysis performed on each mm of rainfall, from 1 mm to 5 mm. In this collector, 1 mm of rainfall corresponds to 100 ml of accumulated rain water. The pollens in rain water were concentrated by centrifugation to 1/200 volume, and pollen grain count was performed on a Fuchs. Rosenthal hemocytometer. Pollens of Japanese cedar were detected in the rain water during the period, 22 February to 19 April, and peaked on 22 March. The number of pollens at peak was 264,000 grains per 100 ml. The pollen count contained in the 2nd to 5th mm of rainfall compared to that in the first mm of rainwater was 19.4% in the 2nd mm of rainfall, 6.7% in the 3rd, 4.4% in the 4th and 2.3% in the 5th. From a log-log graph plot of this data, a regression line was obtained for a regression equation, y = 100.x-2.29. These data indicate that rainfall quickly clears pollens of Japanese cedar from the atmosphere. Examination of pollen obtained from the rain water, showed a few % of the pollen grains had ruptured, and on the surface of the cytoplasmic membrane of the ruptured pollen were attached suspended particulate matters from atmosphere.