薬理と治療

Objective The present study was designed to examine the influence of hyaluronic acid（HA） on the ability of synoviocytes to produce nitric oxide（NO）, which is the important effector molecule in the development of osteoarthritis, in response to periostin stimulation in vitro. Methods Synoviocytes（5⊠105 cells╱mL）derived from an osteoarthritis patient were stimulated with 100 ng╱mL periostin in the presence of various concentrations of HA for 24 hours. The levels of NO in culture supernatants was examined by NO2╱NO3 assay kits. To examine the influence of HA on transcription factor, NF︱κB, activation and iNOS mRNA expression, synoviocytes（5⊠105 cells╱mL）were also cultured in a similar manner for 4 and 12 hours, respectively. The levels of both mRNA expression and transcription factor activation were measured by ELISA. Results Addition of HA into cell cultures caused the suppression of periostin︱induced NO production from synoviocytes. The minimum concentration that caused significant suppression of NO production was 5.0 mg╱mL. HA at more than 5.0 mg╱mL also inhibited iNOS mRNA expression and NF︱κB activation, which were increased by periostin stimulation in synoviocytes. Conclusion These results strongly suggest that HA favorably modify the clinical condition of osteoarthritis patients through the suppression of NO production from synoviocytes after periostin stimulation.

Background and aim Jumihaidokuto（JHT）is a traditional Japanese medicine used in the early phases of purulent skin disease and acute dermatoses, and is effective for treatment of urticaria, eczema, and the like. JHT was evaluated in two animal models of ear dermatitis showing acute edema against a stimulus. Methods JHT （0.5, 1, and 2 g╱kg, p. o.）was examined in a model of irritant contact dermatitis（ICD）induced by applying phorbol 12-myristate 13-acetate（PMA）, a major constituent of croton oil, to mouse ears. The ear thickness was measured using a dial thickness gauge micrometer 6 h after PMA application. Moreover, in an acute dermatitis model induced by injecting heat-killed Propionibacterium acnes（P. acnes）intradermally into rat ears, the effect of JHT on ear edema was evaluated 2 h after P. acnes injection. Antioxidative activities of JHT, its components and constituents were determined in assays of hydrogen peroxide-dependent oxidation and superoxide generation. Results JHT significantly suppressed cutaneous inflammation induced by PMA or P. acnes, especially showing higher efficacy on dermatitis evoked by P. acnes. JHT showed concentration-dependencies on the two assays of antioxidative action. Of JHTʼs ten components, keigai, bokusoku, and kanzo, exerted antioxidative activity, and six flavonoids contained in the three components exhibited the activity strongly. Conclusions JHT suppressed ICD-like dermatitis and pathogen-induced dermatitis, consistent with the clinical uses of JHT. The flavonoids of keigai, bokusoku, and kanzo exerted antioxidative activities and may contribute to the anti-dermatitis effect of JHT, although it needs further investigation.

Globin digest（GD）, an oligopeptide mixture derived from edible globin proteins, improved hyperlipidemia and hyperglycemia in human and other mammals, and is used as Food for Specified Health Use（FOSHU）in Japan and Health Food in China, but the effect of GD on the blood pressure was unknown. In the present study, the effect of GD on the blood pressure in spontaneously hypertensive rats（SHR╱Izm： SHR）was examined. At first, GD was administered orally once to SHR（15-18 weeks old）. GD（500 mg and 1000 mg╱kg body weight）suppressed the systolic blood pressure in SHR after a single administration. Next, SHR（7weeks old）were fed a diet containing GD（0.5 wt％）, magnesium（Mg）hydroxide（1.95 wt％, as Mg 0.81 wt％）or the combination of Mg hydroxide with GD for 12 weeks. The elevation of the systolic blood pressure in SHR was suppressed by GD or Mg hydroxide and most suppressed by the combination of Mg hydroxide with GD. GD inhibited the activity of angiotensin-converting enzyme in vitro. These findings indicate that GD has the antihypertensive effect and more effective by use with Mg in SHR.

Magnesium is a food with nutrient function claims（FNFC）in Japan, but the effect of magnesium（Mg）hydroxide containing Mg of the amount of the FNFC limit on the blood pressure was unknown. In the present study, the effect of the combination of magnesium（Mg）hydroxide with globin digest（GD）, an oligopeptide mixture derived from edible globin proteins, on the blood pressure and life span in stroke-prone spontaneously hypertensive rats（SHRSP╱Izm： SHRSP）was examined. Male SHRSP at 6 weeks of age were fed a diet containing the combination of Mg hydroxide（1.22 wt％, as Mg 0.51 wt％）with GD（1.67 wt％）for 27 weeks. The elevation of the systolic blood pressure in SHRSP was suppressed after ingestion of the combination of Mg hydroxide with GD compared with the control group. The combination of Mg hydroxide with GD extended the life span in SHRSP compared with the control group. These findings indicate that the combination of Mg hydroxide with GD has the antihypertensive effect and protective effect against stroke in SHRSP.

Objectives We evaluate efficacy of a dietary supplement containing bovine alpha S1-casein tryptic hydrolysate, Hemerocallis flower extract, Arginin, and Ornithine on sleep disorders among Japanese adults. Methods Ten subjects with sleep disorders were provided dietary supplement for two weeks. Each subject ingested every night during the treatment period. We evaluated sleep quality by using PSQI（Pittsburgh sleep quality index）, OSA-MA（OSA sleep inventory MA version）, and portable physiological signal recorder. Subjects completed the PSQI and OSA-MA before treatment, after two weeks, and after the cooling-up one week. Results The result of this study provided evidence that improvement due to this supplement was observed for the sleep quality score. After two weeks treatment, sleep quality, daytime dysfunction, sleep disturbance, initiation and maintenance of sleep, sleepiness on rising, sleep length, and refreshing were improved. And these improvements did not remain after following one week. Conclusions Bovine alpha S1-casein tryptic hydrolysate and Hemerocallis flower extract were effective for sleep disorders. Arginin and Ornithine have the helpful effect for improvement of sleep quality.

Objective The study aimed to verify that ingestion of a multiple dietary supplement containing gymnemic acid, mulberry leaf extract, green tea extract, chitosan, and kidney bean extract would reduce the postprandial blood glucose level of subjects. Methods A randomized, double︱blind, cross︱over study was conducted for 20 participants aged 30 to 59 years whose postprandial blood glucose levels increased more than 130 mg╱dL, ingested the multiple dietary supplement containing 9.4 mg of gymnemic acid, 200 mg of mulberry leaf extract, 200 mg of green tea extract, 100 mg of chitosan, and 4.8 mg of kidney bean extract or placebo with rice as a test meal. The blood glucose and insulin levels were measured before and 30, 60, 90, and 120 minutes after the intake of a test meal, and compared with the changes between placebo and the multiple dietary supplement. Results Intake of the multiple dietary supplement was significantly suppressed the delta AUC （area under the curve）values of postprandial blood glucose and insulin levels after ingestion of a test mea（l P＜0.05）. We also observed significant suppression of the elevation of postprandial blood glucose and insulin levels at 30 min after ingestion of a test meal by intake of the multiple dietary supplement（P＜0.05）Conclusions These results suggest the multiple dietary supplement containing 9.4 mg of gymnemic acid, 200 mg of mulberry leaf extract, 200 mg of green tea extract, 100 mg of chitosan, and 4.8 mg of kidney been extract suppresses the elevation of postprandial glucose level.

Objectives Krill oil is extracted from Euphausia superba. Krill oil that contains n-3 fatty acids such as eicosapentaenoic acid（EPA）and docosahexaenoic acid（DHA）is expected as ingredients to improve serum lipids. The purpose of this study was to verify ingestion of krill oil containing supplement makes serum lipids decrease in Japanese subjects. Methods This test was carried out as a double-blind placebo-controlled randomized controlled trial. Japanese men and women whose ages were between 30 and 59 consumed soft capsules containing krill oil or placebo for 12 weeks, examine by variation of serum lipids in krill oil normal quantity group, krill oil 3︱fold quantity group and placebo group. Blood was collected and tested prior to ingestion, after 4 weeks, 8 weeks, 12 weeks and 16 weeks（after 4 weeks to stop ingestion）. Results In the group who took krill oil supplement, triglyceride（TG）was significantly decreased after ingestion for 8 weeks. Also, HDL-cholesterol was significantly increased through administration period. Free fatty acids significantly decreased after 12-week ingestion. Conclusion It is suggested that krill oil supplement is a useful food maintaining the TG to the proper value for Japanese adults.

Objectives To evaluate the safety of an oyster extract︱based, tablet︱form dietary supplement “Watanabe Active Oyster Tablet”（WAOT）. Methods With the use of a commercial product of WAOT containing 250 mg of oyster extract per tablet as the study diet, two clinical studies were performed in a total of 47 healthy male and female adults. In the first study designed as an excessive dosing study（StudyⅠ）, 12 subjects each received a regular dose（6 tablets）, 3-fold increased dose（18 tablets）, and 5-fold increased dose（30 tablets）daily for 4 weeks with a 2-week follow-up period. In the second study designed as a long-term dosing study （StudyⅡ）, 11 subjects received 12 tablets of the study diet for 12 weeks. Medical inspection and laboratory tests were conducted at week 4 of the intervention period and at week 2 of the follow-up period in the StudyⅠ and at weeks 4, 8and 12 of the intervention period in the StudyⅡ. Results Throughout these two studies, there was no subject who had any intervention-related laboratory abnormalities. In the StudyⅠ, while most of self-reported adverse events were unrelated to intervention, a possible relationship of a total of 11 mild and transient diarrhea events experienced by 3, 2, and 3 subjects in the regular dose, 3-fold increased dose and 5-fold increased dose groups, respectively, were unable to be ruled out. Different from this none of subjects reported diarrhea event in the StudyⅡ. The results of study group-based analyses showed that there were no clinically significant changes from baseline of any demographic, physical or laboratory test parameters in the two studies. Conclusion Intakes of WAOT in daily doses up to 30 tablets（7500 mg as oyster extract）for 4 weeks and those in a daily dose of 12 tablets（3000 mg as oyster extract）for up to 12 weeks were considered to be well tolerable and safe in healthy adults.

Background In recent years, the number of patients with erectile dysfunction（ED）is increasing and becoming a serious problem every year. Korean mountain ginseng（Panax ginseng CA Meyer）are traditional herbal plants to improve sexual functions. In the present study, we investigated the effect of consuming tissue-cultured mountain ginseng（TCMG）for 12 weeks in improving male sexual function, as well as its safety. Methods In a double-blind, placebo-controlled trial, 45 healthy men with partial impotence （range: 35-70 years old）were randomized to oral TCMG（200 or 600 mg╱day）or-placebo administration for 12 weeks. The primary outcomes were International Index of Erectile Function（IIEF）and Aging Male Symptoms（AMS）scores. Results Forty-four subjects completed the study. TCMG compared to placebo could not be significantly effective against male sexual function, but the IIEF score after 12 weeks administration were significantly higher than before administration in the group treated with either 200 mg or 600 mg TCMG（P＜0.05）. Conclusion The present results suggest daily intake of TCMG between 200-600 mg might be beneficial for male sexual function.

Objective Among males with declined sexual function, a different treatment than that against erectile dysfunction may be needed. Korean mountain ginseng（Panax ginseng CA Meyer）are traditional herbal plants to improve sexual functions. In the present study, we investigated the effect of short-term tissue-cultured mountain ginseng（TCMG）intake in improving male sexual function. Methods In a double-blind, placebo-controlled, crossover trial, 26 healthy men（range: 20-49 years old）were randomized to oral TCMG or placebo administration for 7 days. The primary outcomes were International Index of Erectile Function（IIEF）and Aging Male Symptoms （AMS）scores. Results All subjects completed the study. Total score and scores for four out of the five domains of the IIEF after administration were significantly higher than placebo group in the group treated with TCMG（P＜0.05）. Scores at one week post administration period remained significantly higher for the TCMG group（P＜0.05）. Conclusion TCMG administration for 7 days is beneficial in improving sexual function. It was confirmed that its effect also continues 1 week later of administration.