薬理と治療

Background　Elderly patients with multiple diseases take numerous medicines. Suspending the administration of unnecessary medicines and potentially inappropriate medications to elderly patients will lead to prescription optimization. A template used at Tokyo University Hospital for evaluating medicines that patients bring to the hospital（the template）is a screening tool for patients who require prescription optimization. Methods　We used the template to screen patients over 65 years of age who were admitted to the general wards of six hospitals in Fukuoka Prefecture. Results　The patients who responded to the screening item took more medicine before hospitalization. In addition, the rate of discontinuance of medication at discharge was higher in the corresponding patient group than in the non-corresponding patient group. In most cases, the condition of the patients improved or remained the same, despite the discontinuance of medicine. Conclusions　The template was a useful screening tool for prescription optimization in general hospitals.

Background　Kuromoji（Lindera umbellata Thunb.）is a deciduous shrub of the Lauraceae with pleasant aroma, and has long been used as a material of stomach medicine. We found that a hot-water extract of branches of Kuromoji（Kuromoji extract）has suppressive effect on plaque formation caused by influenza viral infection. However, the persistence of protective effect of Kuromoji extract against viral infection has not been clarified. Methods　Madin-Darby canine kidney cells were treated with Kuromoji extract simultaneously with or after infection with influenza virus strain（A╱Puerto Rico╱8╱34, H1N1）. The effect on influenza virus infection was evaluated by the observation of cytopathic effect and quantitative analysis of viral protein mRNA expression in cells. Results　Kuromoji extract significantly suppressed the cytopathic effect caused by influenza virus. Expression of viral protein mRNA in cells was also significantly suppressed by the treatment with Kuromoji extract. The suppressive effect on viral mRNA expression was also observed in cells that had finished the treatment with Kuromoji extract 24 hours prior to viral infection. Conclusions　Our study showed that Kuromoji extract has a sustained suppressive effect on the infection of influenza virus. We believe that Kuromoji extract becomes a useful food or medical material with protective effects against influenza infection.

We have investigated the influence of resistant protein on lipid digestion. Resistant protein was prepared from soy protein and kori-tofu protein, respectively by using microorganism enzymes and digestive enzymes, respectively. Regardless of the enzymes, content of the resistant protein of the kori-tofu protein was higher than that of the soy protein. We have developed lipid digestion system based on reported method in vitro, have determined time of reaction and amount of resistant protein to the system. Each resistant protein and cholestyramine have caused lower the rate of lipid digestion. On the other hand, casein and chitosan have had no effect on the rate of lipid digestion. We conclude that the lowering effect on lipid digestion rate by resistant proteins caused by its bile acid binding property.

Background/Objectives　Low-density lipoprotein cholesterol（LDL-C）levels are inconsistently associated with intracerebral hemorrhage（ICH）risk. We assessed the relationship between LDL-C levels and ICH onset using a database of Japanese electronic health records. Methods　This retrospective observational study used data from patients hospitalized between April 1, 2001 and March 31, 2015. Patients with two consecutive LDL-C measurements were classified into four LDL-C level groups: very low, ＜50 mg╱dL; low, ≥50 ＜100 mg╱dL; moderate, ≥100 ＜140 mg╱dL; and high, ≥140 mg╱dL. ICH onset and patient characteristics were compared between groups. Additionally, the association of LDL-C and other risk factors with ICH onset were investigated by adjusting for the effects of covariates. Results　44,029 patients were investigated, 739（1.7％）with very low LDL-C, 32,206（73.1％） with low LDL-C, 9346（21.2％）with moderate LDL-C, and 1738 （3.9％）with high LDL-C. Median follow-up was 3.3 person-years. The very low group included a higher proportion of patients with hypertension, cardiovascular disease, diabetes and aged ≥75 years. Risk factors with the highest hazard ratios （HRs）for ICH onset were age ≥75 years and non-hemorrhagic stroke; HRs（95％ confidence interval）men ≥75 years, 2.145（1.683, 2.735）; women ≥75 years, non-he 2.384（, 1.836, 3.094）［both vs. males aged ＜75 years］;morrhagic stroke, 2.032（1.637, 2.522）. No statistically significant associations were found between ICH onset and LDL-C level. Conclusions　LDL-C levels, including very low levels, were not significantly associated with ICH onset. Males and females aged ≥75 years, and patients with non-hemorrhagic stroke were at the highest risks of developing ICH.

Bioequivalence of orally disintegrating（OD）tolvaptan tablets to conventional ones at 15 and 30 mg was evaluated in an open-label, three-period, three-way crossover trial. Total 84 healthy adult male volunteers were divided into two cohorts and randomized to three groups: conventional tablet（CT）first, OD tablet with water （ODT＋W）first, and OD tablet without water（ODT-W）first. 90％ confidence intervals（CIs）for geometric mean ratios（GMRs）of AUCt and Cmax of tolvaptan for 15 mg of ODT-W to those for 15 mg of CT were log（0.95）―log（1.06）and log（1.07）―log（1.23）, respectively. Those for the GMRs of the AUCt and Cmax of tolvaptan for 15 mg of ODT＋W to those for 15 mg of CT were log（0.94）―log （1.05）and log（0.89）―log（1.02）, respectively. Those for the GMRs of the AUCt and Cmax of tolvaptan for 30 mg of ODT-W to those for 30 mg of CT were log （0.97）―log（1.06）and log（1.04）―log（1.17）, respectively. Those for the GMRs of the AUCt and Cmax of tolvaptan for 30 mg of ODT＋W to those for 30 mg of CT were log（0.95）―log（1.05）and log（0.94）―log（1.06）, respectively. These results were within the range of log（0.80）―log（1.25）specified for bioequivalence, indicating that the two formulations were bioequivalent. All observed adverse events were mild and resolved spontaneously. There were no consistent trends indicating clinical concerns in clinical laboratory tests, vital signs, body weight, or 12-lead electrocardiogram.

Objective　This randomized, double-blind, parallel-group study examined the effects of a reduced form of coenzyme Q10（ubiquinol）on stress and sleep in healthy subjects. Methods　Subjects were randomly allocated to two groups and received test food containing 100 mg ubiquinol or placebo every day for 8 weeks. Primary outcome measures were scores on the Brief Job Stress Questionnaire and the Japanese version of the Epworth Sleepiness Scale. Secondary outcome measures were OSA sleep inventory MA version（OSA-MA）scores; visual analogue scale （VAS）scores for stress, sleep, and fatigue; and autonomic nervous system activity and pulse wave data from a wearable monitoring system. Laboratory tests were performed and adverse events（AEs）analyzed. Results　Safety data were evaluated for 30 subjects from each group（16 males）who completed the study. Data from 24 （ubiquinol group）and 28（placebo group）subjects were evaluated for efficacy after exclusion of subjects who deviated from the study protocol. Ubiquinol produced statistically significant changes from baseline values, but the effects were not significantly greater than the placebo effects. In contrast, stratified analysis of subjects with VAS stress scores≥70 demonstrated that ubiquinol had a significantly greater effect than placebo on VAS stress score; OSA-MA initiation╱maintenance of sleep, frequent dreaming, and refreshing scores, and VAS sleep quality score. Neither clinically relevant AEs nor abnormal laboratory test values were observed. Conclusions　Ubiquinol reduced stress and improved sleep-related problems in subjects with high stress sensitivity. Additional extended studies on ubiquinol are warranted（. UMIN Clinical Trail Registry ID：000032233）

Objectives　A randomized, double-blind, placebo-controlled, cross-over study was conducted to confirm the effect of food containing Terminalia bellirica extract on postprandial elevation of blood glucose levels. Methods　Fifty volunteer subjects with either high-normal plasma glucose levels after fasting, or with borderline diabetes were selected. These subjects had fasting blood glucose levels between 100 and 125 mg╱dL, or 2-hour glucose values between 140 and 199 mg╱dL in the 75g oral glucose tolerance test, and causal blood glucose levels under 200 mg╱dL. The subjects were randomly divided into two groups. The experimental group ingested food containing T. bellirica extract（containing 20.8 mg gallic acid）, while the control group ingested unmodified food as a placebo, before both groups ingested the loading diet. Blood glucose levels were measured before ingestion, and 30, 60, 90, and 120 min after ingestion. Results　Consumption of the food with T. bellirica extract significantly suppressed the postprandial elevation blood glucose levels compared to the food consumed by the placebo group. The incremental area under the curve representing change in blood glucose levels from 0 min was smaller in the experimantal group than in the placebo group（P＜0.05）. Also, the changes in blood glucose levels from 0 to 30 min after loading were significantly lower in the experimental group than in the placebo group（P＜0.05）. During this study period, no adverse events were observed that could be attributed to the food containing T. bellirica extract. Conclusions　These results indicate that ingestion of food containing T. bellirica extract can inhibit postprandial elevation of blood glucose levels.（ UMINCTR ID: UMIN000035710）

Objective　In this study, we evaluated the effects of a composite supplement containing curcumin, ferulic acid, and soybean-derived phosphatidylserine on cognitive function in healthy middle-aged and senior adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted for 40 healthy Japanese subjects aged 50 to 69 years with memory complaints, ingested the dietary supplement containing 40 mg of curcumin, 200 mg of ferulic acid, and 25 mg of soybean-derived phosphatidylserine or placebo for 20 weeks. Cognitive function and quality of life were measured at baseline, after 6 weeks, 12 weeks, and 20 weeks of supplementation. Results　Regarding subjective symptoms of cognitive function, significant improvement of memory and attention was found in the active group compared to the placebo group after 20 weeks. In the subgroup analysis with lower cognitive function（≤25 MoCA-J scores）, significant improvement of Verbal Paired Associates-no semantic relation test at 20 weeks, both hands test of Purdue Pegboard at 12 weeks, and step1 and step2 subtests of Stroop Test at 12 weeks was found in the active group compared to the placebo group. No side effects induced the composite supplement were observed during the study. Conclusion　These results suggest that the ingestion of the composite supplement improves cognitive function including memory, attention, and judgment in healthy middle-aged and senior adults.（ UMIN- CTR ID: UMIN000029559）

Objective　The aim of this study was to investigate the effect of oral intake of rice koji amazake on skin on healthy subjects. Methods　A randomized, double-blind, placebo-controlled parallel-group, comparison study was conducted in 46 healthy subjects（39-59 years old）. The subjects were randomized into two groups and given either the test product（125 mL rice koji amazake）per day or the control product（placebo drink）for 8 weeks. Stratum corneum water content, trans-epidermal water loss（TEWL）, viscoelasticity and pore-sagging of the face were evaluated for skin condition. Results　The elasticity and pore-sagging were significantly improved at 8 weeks in the test product group who took rice koji amazake compared to the placebo group. Conclusions　The results suggested that oral intake of rice koji amazake may be effective for elasticity and pore-sagging of the face（. UMIN-CTR000035919）

Objective　Vine tea extract made from the leaves of Ampelopsis grossedentata is known to perform multiple pharmacological rules. The purpose of the present study was to evaluate the safety of an excessive intake of the vine tea extract in healthy adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted on 100 healthy adults aged between 20 and 64 years of age（both female and male）. Subjects consumed either dietary supplement containing 2500 mg of vine tea extract that contained 750 mg of ampelopsin or placebo for four consecutive weeks. Safety of an excessive intake of the vine tea extract was evaluated by the physical measurements, blood tests, urinalysis and adverse events. Results　The results showed several significant differences in physical measures and blood tests between the two groups, but these differences were considered to be unrelated to the intake of the vine tea extract nor placebos. In addition, there was one case of constipation in the vine tea extract group, which may not deny the relation to the intake of the supplement. However, it was judged as a mild adverse event by the investigator, and was considered as a gastrointestinal symptom. Conclusions　No safety problem was observed in an excessive intake of the vine tea extract under the present evaluation condition. （UMIN ID: UMIN000033201）

Objectives　The purpose of this study was to evaluate the safety of simultaneous excessive intake of standardized bilberry extract and lutein in healthy adult humans. Methods　We conducted an open-label trial with eighteen healthy adult Japanese subjects （43.1±8.4 years old）. The participants took 1440 mg of standardized bilberry extract and 120 mg of lutein for 4 weeks. Safety was evaluated using hematologic test, blood biochemical test, urine analysis, physical examination and medical interviews. Results　Statistically significant differences observed in some test parameters were considered clinically insignificant. There were no adverse events associated with simultaneous excessive intake of standardized bilberry extract and lutein. Conclusions　Our results suggest that simultaneous excessive intake of bilberry extract and lutein was safe under the test conditions carried out. （ UMIN-CTR ID：UMIN000025414）

Objective　We aimed to investigate the improvement of the oral environment in healthy Japanese adults following ingestion of HGH crystal MD®. Methods　Two open︱label comparative studies were conducted in November 2018（preliminary trial）and March 2019（main trial）in healthy Japanese adults who were not aware of dental caries（n＝11, n＝27, respectively）. HGH crystal MD was taken orally 3 times daily； the intervention period was 1 week（preliminary trial）and 4 weeks（main trial）. Assessments of periodontal disease︱related bacteria, evaluation of subjective symptoms, peripheral hematology tests, and oral examinations were performed before and 1 week（preliminary trial）or 4 weeks（main trial）after the ingestion of HGH crystal MD®. Safety was monitored throughout. Results　Eleven participants for the preliminary trial and 25 participants for the main trial were included in the analysis. In both trials, Tannerella forsythensis, a periodontopathy-related red-complex bacterium, was significantly decreased after ingestion compared with before ingestion（P＜0.05）. Subjective symptom evaluation showed significant improvements in oral odor, gum swelling, tooth roughness, mouth discomfort, mouth dryness, and stickiness in both trials（P＜0.05）. No subjects experienced any change in caries progression during the study, and no ingestionassociated adverse events were observed. Conclusions　HGH crystal MD® significantly decreased T. forsythensis, improved subjective oral cavity symptoms, and was found to be safe for the treatment of periodontal disease in this group of patients. Trial registration　UMIN-CTR: UMIN000034948（preliminary trial）, UMIN000035393（main trial） Foundation　Autobahn Co. Ltd.

Objective　We discuss the efficacy of nattokinase in subjects who have hypertension; the high normal blood pressure in this paper. The data reported here are based on a re-analysis of a previously published study on this trial,26） where we have excluded people with Stage 2 hypertension from our analysis. Our goal was to document that the overall effects of Nattokinase consumption reported by Jensen, et al was also statistically significant in the subgroup with high-normal blood pressure. Methods　This paper presents a sub-group analysis of a previously published study, specifically to document the significant reduction in blood pressure, excluding people from the original study who had Stage 2 hypertension. The study adopted in to assess the efficacy of nattokinae（NSK-SD）is a randomized, double-blind, placebo-controlled, parallel-group clinical study. 79 subjects joined screening for high blood pressure（high-normal blood pressure or high-gradeⅠ hypertension）referring to the study done in Asia. They took placebo or 110 mg nattokinase per day for the 8week study duration. Result　67 subjects were chosen out of 79 subjects in result of screening. Diastolic blood pressure at 8th week in nattokinase group was significantly lower than placebo group（P＜0.05）. The degree of reduction of diastolic blood pressure in male was significantly different compared with placebo group（P＜0.05）. No significant difference was found in diastolic blood pressure in women. In Stratified analyses, we found no significant difference in systolic blood pressure in hypertension subject. However, compared with placebo group, significant differences in diastolic blood pressure were found（P＜0.05）. Conclusion　In hypertension subject, nattokinse leads to beneficial changes in blood pressure.