Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the ß-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-48)) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [(3)H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion-transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (K(m)) = 84.3 µmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC(50) = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine.

Effect of lycopene on cytoplasmic maturation of porcine oocytes in vitro.

The aim of the present study was to improve cytoplasmic maturation of porcine oocytes by the addition of lycopene into in vitro maturation (IVM) media. We designed six experimental groups; IVM medium was supplemented with 10 IU/ml FSH, FSH and 10 IU/ml human chorionic gonadotrophin (hCG), or FSH and 7 µm lycopene in the first half of the IVM culture (0-22 h) followed by further culture (22-44 h) with or without hCG. The addition of lycopene into IVM media delayed the interruption of communication between an oocyte and the cumulus cells. Although meiotic competence was similar among the six groups, the glutathione level of matured oocytes was significantly higher in the lycopene-supplemented group (9.89 pmol per oocyte) than that in other groups (7.25 and 7.81 pmol per oocyte). Fertilization rate was significantly improved in lycopene-supplemented groups (58.3%) more than that in the group supplemented with FSH only (43.1%), whereas there were no differences in developmental competence among the groups (blastocyst rate: 20.1-29.5%). These results indicate that insufficient cytoplasmic maturation during conventional IVM resulted by disconnection of the gap junction between an oocyte and the cumulus cells in the early phase during IVM culture. We concluded that lycopene induced a prolonged sustainment of gap junctional communication between an oocyte and the cumulus cells during porcine IVM culture, which was an effective cytoplasmic maturation of porcine IVM oocytes.

Modulation of gonadotrophin-releasing hormone pulse generator activity by the pheromone in small ruminants.

In small ruminants, such as goats and sheep, a primer pheromone produced by males induces an out-of-seasonal ovulation in anoestrous females, a phenomenon known as the male effect. The male effect is unique in that an external chemical stimulus can immediately modulate the activity of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator. We have established a monitoring method of the GnRH pulse generator activity in Shiba goat. Using this method as a sensitive bioassay to assess the male effect pheromone activity, we have shown that the male effect pheromone is synthesised in an androgen-dependent manner in the sebaceous glands or their vicinity in specific body regions in goats. Although chemical identity of the pheromone is yet to be determined, analyses of male goat hair extracts by gas chromatography fractionation suggest that the male effect pheromone is a volatile substance with relatively small molecular weight. From morphological and molecular biological studies in goats, it is suggested that the pheromone molecule is detected by a member of the V1R family located on both the olfactory neurones and the vomeronasal sensory neurones, and the pheromone signal is conveyed to the medial nucleus of amygdala via the main olfactory and vomeronasal pathways and, subsequently, to the hypothalamic GnRH pulse generator to enhance its activity.

Honeybee royal jelly inhibits autoimmunity in SLE-prone NZB x NZW F1 mice.

Royal jelly (RJ) is a gelatinous secretion from young nurse worker bees (Apis mellifera), which serves as the sole food for the queen bee. Because of its pleiotropic functions for queen bees, RJ has also been used as a dietary supplement with various health benefits for humans. Because RJ is being indicated to have immunomodulatory potential for humans, we undertook the study to determine whether the oral administration of RJ could alter the development of systemic autoimmunity in New Zealand Black (NZB) x New Zealand White (NZW) F1 mice that genetically exhibit many manifestations similar to human systemic lupus erythematosus (SLE). We herein reported that mice administered with RJ showed a significant delay in the onset of the disease, as manifested by decreased proteinuria and a prolongation of lifespan. In addition, RJ administration after the onset of the disease significantly improved the renal symptoms, leading to an extended lifespan. RJ administration to mice caused a significant decrease in the serum level of IL-10, and in the autoantibodies against ssDNA, dsDNA and erythrocytes, as well as a reduction in the number of splenic autoreactive B cells. In conclusion, our data suggest that the use of RJ may be beneficial in the prevention of the early onset of SLE and in the control of the active progression of the manifestations of SLE.

In vivo approach for the evaluation of mechanism-based inhibition of cytochrome P450 3A in rats.

1. There have been no reports showing that the area under the concentration-time curve (AUC) of a probe drug is elevated due to mechanism-based inhibition (MBI) of drug-metabolizing enzymes in animals. This study ascertained that mechanism-based inhibitors reported to induce drug-drug interactions (DDIs) in humans also caused MBI in rats. 2. Midazolam (MDZ), mainly metabolized by cytochrome P450 3A in rats, and mibefradil, which showed the most intense time-dependent inhibition among the inhibitors tested, were selected as the probe and the inhibitor, respectively. Following pretreatment of mibefradil at 24 h before MDZ administration in rats, the C(max) and AUC values of MDZ were significantly elevated in comparison with the control. The free plasma concentration of mibefradil was substantially lower than the IC(50) value observed in the in vitro inhibition study, suggesting that the DDI was due to MBI. 3. It is concluded that the evaluation of MBI in rats in vivo in combination with in vitro data using human enzymes could be useful to evaluate risk in clinical studies.

Hop bract polyphenols reduced three-day dental plaque regrowth.

Previous research has shown the inhibitory effects of hop bract polyphenols (HBP) on cariogenic streptococci in vitro, but their effects in humans have not been investigated. This double-blind, crossover clinical study tested the hypothesis that HBP delivered in a mouthrinse suppresses plaque regrowth in humans. Twenty-nine healthy male volunteers had all plaque removed, and refrained from all oral hygiene for 3 days, except for rinsing with a mouthrinse containing 0.1% HBP or a placebo. The results showed that the mean amount of plaque assessed by the Patient Hygiene Performance score after the volunteers used the HBP mouthrinse was significantly less than that after they used the placebo (p < 0.001). The number of mutans streptococci in the plaque samples after volunteers used the HBP mouthrinse was significantly lower than that after they used the placebo (p < 0.05). These findings suggested that HBP, delivered in a mouthrinse, successfully reduced dental plaque regrowth in humans.

Outbreak of Legionnaires' disease on a cruise ship linked to spa-bath filter stones contaminated with Legionella pneumophila serogroup 5.

In January 2003, two cases of Legionnaires' disease associated with a ship's cruise were registered in the database of National Epidemiological Surveillance of Infectious Diseases. A 70-year-old male heavy smoker with mild emphysema contracted the disease during a cruise. Legionella pneumophila serogroup (sg) 5 was isolated from the patient's sputum and the ship's indoor spa. The isolate from the spa matched the patient's isolate by genotyping performed by pulsed-field gel electrophoresis (PFGE). The second case was in a 73-year-old female. During epidemiological investigation, a third case of Legionnaire's disease in a 71-year-old male was subsequently diagnosed among passengers on the same ship on the following cruise. Environmental investigation revealed that porous natural stones (Maifanshi) in the filters of the spas had harboured L. pneumophila, a phenomenon which has not been reported except in Japan. This is the first documented evidence of L. pneumophila sg 5 infection on a ship and of porous stones as a source of Legionella infection.

Blue light inhibits melanin synthesis in B16 melanoma 4A5 cells and skin pigmentation induced by ultraviolet B in guinea-pigs.

BACKGROUND: Little has been known about the effects of visible light in mammalian cells. We recently found that blue light not only suppressed the growth of B16 melanoma cells in a time-dependent manner but also inhibited metastasis of the B16 melanoma cells to the lung. These findings suggest that exposure to blue light modifies the functions of B16 melanoma cells. The present study investigated the effects of blue light on B16 melanoma 4A5 cells and Weiser-Maple guinea-pigs to confirm the biological effect of blue light on melanin formation. METHODS: The effect of red, green, and blue light on melanin synthesis in B16 melanoma 4A5 cells was measured. The back skin of brown Weiser-Maple guinea-pigs was exposed to ultraviolet B (UVB; 588 mJ/cm(2) (0.7 mW/cm(2)x 14 min) three times a week for 2 weeks to induce melanin deposition. Thirty minutes after each UVB exposure, blue light was applied for 30 min. Pigmentation of the exposed areas of skin was checked once a week, and photographs of the skin were taken by digital camera. Observation was continued for 18 days after the final UVB exposure. RESULTS: Melanin synthesis in B16 melanoma 4A5 cells was selectively suppressed by blue light, but blue light did not induce decolorization of previously produced melanin. In the back skin of brown guinea-pigs, the brightness of the sites exposed to UVB began to decrease on the fifth day of the experiment, decreasing further from the 12th day to the 18th day after UVB exposure. The brightness of the sites exposed to UVB and blue light decreased in a manner similar during the UVB exposure, but remained relatively unchanged from the 12th day to the 30th day. CONCLUSIONS: These results suggest that blue light suppresses melanin formation following repeated UVB exposure. Further investigation with various light such as blue light may lead to a new approach to the care of ultraviolet-affected skin such as hyperpigmentation.

Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action.

BACKGROUND: H1-receptor antagonists are often effective in the treatment of allergic disorders such as atopic dermatitis. Cetirizine, a putative H1-receptor antagonist, has recently been shown to have anti-inflammatory properties through the inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes. OBJECTIVE: To further elucidate the anti-inflammatory properties of cetirizine, we first examined its effects on antigen-induced eosinophilia and neutrophila in vivo. We then examined the anti-inflammatory effects of cetirizine on a human keratinocyte A431cell line. METHODS: Mice were sensitized subcutaneously with ragweed pollen and were challenged intraperitoneally with the allergen. Cetirizine diluted in sterile water (0-20 mg/kg) or only sterile water was administered orally. Peritoneal cells were obtained at 8 and 24 h after challenge. The eosinophilia and neutrophilia induced by ragweed pollen extract were quantitated. Macrophage migration inhibitory factor (MIF), macrophage inflammatory protein 2 (MIP-2) and eotaxin contents of peritoneal fluid were also measured by mouse ELISA. The effects of cetirizine on MIF-induced IL-8 production in A431 cells were examined by ELISA. The effects of cetirizine on MIF expression and production in A431 cells were examined by human MIF ELISA and Northern blot analysis. RESULTS: Eosinophilia and neutrophilia induced by ragweed pollen extract were found to be significantly reduced in cetirizine-treated mice (20 mg/kg). MIF, a pleuripotent cytokine, was significantly decreased at 8 and 24 h in the peritoneal fluid by cetirizine treatment. MIP-2 and eotaxin were also decreased 8 and 24 h, respectively, after challenge in the peritoneal fluid with cetirizine treatment. MIF stimulates IL-8 production in A431 cells. We found that MIF production in A431 cells was inhibited by 10 microm cetirizine. Consistent with this, cetirizine significantly inhibited MIF-induced IL-8 production. CONCLUSION: These results suggest that cetirizine exerts its anti-inflammatory effects by inhibiting MIF as well as IL-8 production, such as those involved in inflammatory allergic skin disease, suggesting a broad spectrum of action beyond its mere H1-receptor-antagonistic function.

Effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus in elderly patients in a hospital ward.

We investigated the effects of inhalation of tea catechin on MRSA in the 24 elderly in patients, who were known to carry MRSA in sputum. The patients in the catechin group (N=12) were administered an inhalation of tea catechin extracts (in saline/bromhexine) (3.7 g/L catechins, 43% of them are composed of epigallocatechin gallate), three times daily with hand nebulizer for four weeks. The clinical effects were compared with the control group (N=12) who were given an inhalation of saline/bromhexine alone. After a week of the course, the numbers of the patients with decreased or disappearance of MRSA in their sputum was significantly higher in the catechin group, compared with that in the control group (seven vs. no patients; P<0.05). The number of patients discharged during the study was significantly increased, and the days of hospital stay were significantly decreased in the catechin group compared with those in the control group (six vs. one patient; P<0.05, 51+/-22 vs. 85+/-50 days, mean+/-S.D.;P <0.05, respectively). No adverse effects were observed in any patients during the study. Catechin inhalation seemed to be safe, and at least temporarily effective in the reduction of MRSA and shortening of hospitalization.

Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407).

BACKGROUND: Surgery for advanced esophageal carcinoma has its limits as regards aggressiveness and therapeutic effect, therefore effective multimodality treatment is required to obtain better survival. The objective of this study was to evaluate whether daily continuous infusion of CDDP could achieve a higher clinical response rate with less toxicity than its drip infusion in the previous phase II study that we had conducted. METHODS: Patients with primary extensive or relapsed esophageal carcinoma after esophagectomy, which had distant organ metastasis and histologically proven SCC, were eligible for this study. A dose of 20 mg/m(2) of cisplatin and 800 mg/m(2) of 5-fluorouracil was given by continuous infusion for 24 h on days 1-5. This treatment was repeated every 4 weeks for up to four cycles. A total of 36 men and six women with a median age of 64 (range 39-75) years were registered and 36 patients were eligible. RESULTS: The overall response rate of the registered patients was 33.3% (12/36) and the median response duration was 175 days. Median survival time was 201.5 days and the 1-year survival rate was 27.8%. Change from bolus to continuous infusion of cisplatin affected neither the type nor the degree of toxicity. CONCLUSION: Daily continuous infusion of cisplatin was not associated with higher response or lower toxicity than those seen with the high-dose bolus or multibolus treatment regimens. We conclude that this regimen in this setting is not worthy of further phase III trials. JEOG is now evaluating other drug combination regimens.

Insulin inhibits coronary endothelial cell calcium entry and coronary artery relaxation.

Hyperinsulinemia is closely related to coronary artery disease. Endothelial cells are important for the control of vascular tone, and dysfunction of endothelial cells has been implicated in coronary artery disease. The direct effects of insulin on coronary endothelial cells are nonetheless unknown. In this study, the acute effects of high-dose insulin were investigated on agonist-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) in porcine coronary endothelial cells and coronary relaxation. Bradykinin (10 n M ) and cyclopiazonic acid (100 microM), an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, provoked large increases in [Ca(2+)](i) in coronary endothelial cells. This increase was dose-dependently inhibited by a 10-min preincubation with high doses of insulin (10, 30, 100 mU/ml). Under Ca(2+)-free conditions, bradykinin and cyclopiazonic acid provoked transient, small increases in [Ca(2+)](i). These increases were not affected by pretreatment with insulin (100 mU/ml). Bradykinin (1, 10, 100, 1,000 n M ) and cyclopiazonic acid (10 microM) significantly relaxed porcine coronary artery rings precontracted with histamine (1 microM). The vasodilator effects of bradykinin and cyclopiazonic acid were dose-dependently inhibited by insulin. These acute effects were not observed at physiologic concentrations. Our data indicate that high-dose insulin inhibits agonist-induced Ca(2+) response in coronary endothelial cells and attenuates agonist-induced coronary vasodilatation. The study suggests that hyperinsulinemia might be associated with coronary artery disease via derangement of endothelial Ca(2+)-dependent functions.

Inappropriate discharges by fourth generation implantable cardioverter defibrillators in patients with ventricular arrhythmias.

The study prospectively investigated the incidence, cause and efficient management of inappropriate discharge by the fourth generation implantable cardioverter-defibrillator (ICD) system in 45 patients (mean age, 57+/-16 years). During the follow-up period of 27+/-17 months, 18 patients (40%) experienced one or more inappropriate therapies: sinus and supraventricular tachycardia (15 patients) and T wave oversensing (3 patients). In the 15 patients, re-programming of the tachycardia detection interval and/or additional treatment with beta-blocking agents were effective. In the 3 patients with T wave oversensing, the arrythmia was associated with an increase in T wave amplitude, change in T wave morphology and decreased R wave amplitude, and re-programming of the sensitivity of the local electrogram or changing the number of intervals to detect ventricular tachycardia decreased the number of inappropriate discharges in all 3 patients. In conclusion, inappropriate therapies are common problems in patients treated with the fourth generation ICD system, but most of them can be resolved using the dual-chamber ICD system. However, in patients with T-wave oversensing, it is difficult to avoid inappropriate discharge completely, even if the dual-chamber ICD system is implanted.

Prevention of the development of preneoplastic lesions, aberrant crypt foci, by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male F344 rats.

The modifying effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (MAK) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for three weeks to induce ACF and fed on diets containing 0, 1.25, 2.5 and 5.0% MAK for five weeks, starting one week before the first dose of carcinogen. MAK significantly and dose-dependently prevented the development of ACF, decreasing the total number of AC and inhibiting cyst formation. MAK (2.5 and 5.0%) also significantly reduced the longitudinal-cross section areas of colon epithelium. MAK in all doses significantly reduced the PCNA positive index, area of the germinal region and number of cells per half crypt. In an additional in vitro experiment, MAK inhibited anchorage-independent growth of several colon carcinoma cell lines. The present results thus indicate that dietary MAK could act as a preventive agent for colon carcinogenesis.

Vitamin B-6-supplemented diets compared with a low vitamin B-6 diet suppress azoxymethane-induced colon tumorigenesis in mice by reducing cell proliferation.

Male ICR mice were examined for the effect of vitamin B-6 [pyridoxine (PN) HCl] on azoxymethane-induced colon tumorigenesis. Mice were fed the diets containing 1, 7, 14 or 35 mg PN HCl/kg for 22 wk, and given a weekly injection of azoxymethane (5 mg/kg body) for the initial 10 wk. Compared with the 1 mg PN HCl/kg diet, 7, 14 and 35 mg PN HCl/kg diets significantly suppressed the incidence and number of colon tumors, colon cell proliferation and expressions of c-myc and c-fos proteins. For some variables, 14 and 35 mg PN HCl/kg diets were more effective than the 7 mg/kg diet. Supplemental vitamin B-6 had no influence on the number of colon apoptotic cells. The results suggest that elevating dietary vitamin B-6 suppresses colon tumorigenesis by reducing cell proliferation.

Utility of Etest in choosing appropriate agents to treat fungal keratitis.

PURPOSE: To evaluate the utility of Etest in choosing the appropriate treatment of fungal keratitis. METHODS: Etest was used to determine the drug sensitivities of isolates from the eyes of three patients with fungal keratitis, and the clinical outcomes of treatment with selected drugs were evaluated. RESULTS: In all cases, drug sensitivity demonstrated by Etest accorded with clinical efficacy of the drugs. CONCLUSION: The results in these cases suggest that evaluating drug sensitivities with Etest is an efficient means of selecting optimal pharmacotherapy for fungal keratitis.

Directional distribution of radiation around an accident at a uranium fuel factory in Tokai-mura, 1999.

A beta-ray survey was carried out on concrete walls of the boundary and buildings after a criticality accident at a factory of JCO Co. Ltd. at Tokai-mura. A remarkable distribution of beta counts was observed on the walls depending on the complex internal and external structures of buildings surrounding a precipitation vessel containing uranium 23 days after the accident. The directional distribution function, based on the beta counts on the walls, was consistent with data concerning the neutron dose rate measured in several directions during the accident, suggesting an anisotropic neutron distribution to the residential area.

Combined effect of dietary calcium and iron on colonic aberrant crypt foci, cell proliferation and apoptosis, and fecal bile acids in 1,2-dimethylhydrazine-treated rats.

To investigate the combined effect of Ca and Fe on colon carcinogenesis, cell proliferation, apoptosis and fecal bile acids, male Wistar rats were fed the diet containing 5 g Ca/kg (normal Ca) or 15 g Ca/kg (excessive Ca) with 45 mg Fe/kg (normal Fe) or 500 mg Fe/kg (excessive Fe) for 32 days, and given an injection of 1,2-dimethylhydrazine on day 4. Supplemental Ca reduced colonic aberrant crypt foci (ACF), especially in excess Fe group. Excessive Fe elevated the ACF, especially in the normal Ca diet. When the Ca intake was high, excessive Fe caused no influence on the ACF. Alteration of colonic ACF was associated with those of liver and serum Fe concentration. Also, colonic cell proliferation and concentration of deoxycholic acid (DCA) in fecal water-soluble fraction were reduced by supplementation of dietary Ca, but unaffected by that of dietary Fe. Supplementation of Ca and/or Fe elevated colonic cell apoptosis. The results suggest that dietary Ca markedly suppresses colon ACF in the Fe-overloaded rats through altering Fe status, and that supplemental Ca lowers colonic cell proliferation and fecal DCA in the water-soluble fraction and elevates colonic cell apoptosis irrespective of Fe status.