薬理と治療

Background　As COVID-19 has emerged, most government recommended home quarantine. Recent studies reported home quarantine may cause patients to refrain from visiting a clinic for healthcare. The aim of this study is to evaluate the visiting frequency of Japanese patients with gastrointestinal diseases. Methods　We used the Medilead Healthcare Panel, one of the largest Japanese survey database, and identified 5260 patients with gastrointestinal diseases age of over 20 and having in-outpatient visit within a year before the survey conducted on October 2019. We conducted a web survey of them on September 2020. Of 5260, 3475 answered the survey and 650 of them expressed consent on web form and were enrolled the study. The survey includes sociodemographic variables, frequency of visits, prescribed medications, change of lifestyles, usage of telemedicine, scores of quality of life, health literacy and medical adherence. Logistic regression was used to investigate factors affecting reduction of visits. Results　About 20％ of eligible patients reduced their visit and 70％ of them had not restored the frequency of visits. Their symptoms changed more widely than those who not. We identified longer duration of disease and higher medical adherence score as the factors not reducing visits. Few patients used telemedicine. A quarter of patients were recording their symptoms and they had higher medical adherence score. Conclusions　Some patients with gastrointestinal disease are suspected to get worse because of reduction of their visits to clinics caused by COVID-19. To prevent the reduction, telemedicine and improving medical adherence are possible solutions.

The aim of this study was to evaluate the toxicity of sprayed hypochlorous acid water. The stability of hypochlorous acid in plasma was evaluated by in vitro contact stability test with rat plasma. The toxicity of hypochlorous acid water was evaluated by 28-day repeated inhalation study in rats when exposed through the inhalation route（nose-only）for 6 hours/day on 5 day/week for 4 weeks at dose levels of 0.5 mg/L, 1 mg/L and 5 mg/L. Local toxicities of hypochlorous acid water in eyes, skin and airway were tested by MTT tissue viability assay in three-dimensional human corneal epithelial model, epidermis model and airway epitherial model, respectively. Hypochlorous acid water was decomposed more than 99％ within 3 seconds in contact with rat plasma. The exposure of hypochlorous acid water did not have any relevant effects on body weight, food consumption, clinical observation and ophthalmological evaluation. Some isolated statistically significant differences in haematology, blood biochemistry, BALF examination and organ weight were found at the end of the exposure period for both genders, although these changes were considered devoid of toxicological significance or not related to the treatment. No microscopic alteration related with inhalation of hypochlorous acid water was observed in the pathological evaluation. The no observed adverse effect level （NOAEL）of inhaled hypochlorous acid water was 5.12 mg/L. 1000 ppm of hypochlorous acid water did not affect the cell viability rate in human corneal epithelial model and epidermis model, but reduced the cell viability rate in airway epitherial model to 57％. These results suggest that spraying hypochlorous acid water with a concentration of 100 ppm or less has no adverse event on the human health.

Objective　The pharmacological contribution of multiple bioactive ingredients contained in food in vivo is defined by the amount of each ingredient in the food, its bioavailability（BA）, and its in vitro biological effect. We have precisely determined these values to calculate the pharmacological contribution of 15 kinds of anthocyanins（ACNs）to antioxidant effect in vivo. Methods　We constructed a simultaneous quantitative analysis method by liquid chromatography/mass spectrometry（LC-MS/MS）of 15 kinds of ACNs. Moreover, we analyzed the membrane permeation rate of individual ACNs using Caco-2 cells and compared them with the reported BA of ACNs. Furthermore, petunidin-galactoside（Pt-Gal）was orally administered to rats, and the possibility that Pt-Gal was converted to malvidin-galactoside（Mv-Gal）was investigated. Finally, the contribution rate of 15 kinds of ACNs to the biological activity in vivo was considered based on the content, BA and antioxidant effect of the product. Results　Using the LC-MS/MS method, 15 kinds of ACNs could be analyzed simultaneously. We could quantify ACNs in foods using this method. The permeability ratio of each ACN in Caco-2 cells showed a good correlation with the reported BA. In addition, Mv-Gal was detected in the blood of rats orally administered with Pt-Gal, suggesting that ACN was metabolized by catechol-O-methyltransferase（COMT）as a glycoside. Conclusions　When the contribution rate of each ACN in food was calculated from its content, BA and antioxidant activity, the contribution rate of delphinidin and cyanidin were found to be high for the aglycone part, and that of glucoside was high for the sugar part.

Objective　We developed a new fermented tea by mixing thinned fruit of satsuma mandarin and third crop green tea leaves at the level of 1：3. We investigated the effects of feeding fermented tea beverages for 8 weeks on the flexibility of arterial blood vessel in healthy volunteers. Methods　We conducted a randomized, double-blind, placebo-controlled, parallel-group comparative study. Subjects were divided into the two groups, and were either given fermented tea beverages containing 53.8 mg hesperidin or placebo beverages not containing hesperidin. The arterial velocity pulse indexes（AVIs）which indicate the stiffness of central arterial blood vessel were measured. Results　The AVIs in subjects fed fermented tea beverages containing hesperidin were significantly lower than those in subjects fed beverages not containing hesperidin after 8 weeks. Conclusions　These results suggested that the fermented tea made from thinned fruits of satsuma mandarin and green tea leaves containing 53.8 mg hesperidin is effective for making arterial blood vessel flexible.（UMIN-CTR：UMIN000023967）

Objective　Valine-proline-proline（VPP）and isoleucine-proline-proline（IPP）, isolated from fermented milk, are called“lactotripeptides”（LTP）and reported to effect anti-hypertension and improve vascular functions. The aim of the present study was to evaluate the effects of continuous ingestion of LTP on peripheral blood flow. Method　We conducted a randomized, placebo-controlled, double-blind trial in healthy Japanese men and women ranging in age from 30 to 64. Sixty subjects were randomly divided into two groups Subjects ingested three tablets containing casein-hydrolysate powder （total amount; 1.4 mg of VPP and 2.0 mg of IPP）each day. Placebo tablets were replaced casein hydrolysate powder by sodium caseinate. Peripheral blood flow, hand temperature and plasma NOx concentration were measured. We also assessed physical condition by using a questionnaire. Result Blood flow in the LTP-ingestion group after cold water immersion was significantly improved compared with the placebo-ingestion group. Plasma NOx concentrations tended to increase in the LTP group compared with the placebo group. In addition, assessment of the physical condition using a questionnaire showed that the feeling of cold sensitivity in the waist was significantly improved the LTP group compared with the placebo group. Conclusion　These results suggested that continuous ingestion of LTP could improve blood flow and the symptoms caused by impaired blood flow.（UMIN000037706）

Background　Face changes with age, and the wrinkles around eyes are common age-related symptoms. In this study, we examined the effect of a face lotion containing tranexamic acid, which has anti-inflammatory and whitening effects, on these facial wrinkles. Methods　The study was carried out with 13 healthy female subjects with age ranging between 30 and 59 years. They used Sparkle Whitening Mist Lotion, containing tranexamic acid（provided by Mʼz Science Corporation, Fukuoka, Japan）, only to one side of their faces twice a day for 4 weeks. Both sides of their faces were taken by the photo, and the wrinkles were evaluated by a single blind method, judged by the special inspectors according to the wrinkle grade established by Japanese Cosmetic Science Society. Skin condition of both side of their faces was also examined by the questionnaire. Results　The wrinkles only on the side of the faces using the face lotion containing tranexamic acid were significantly improved from the judgement by the special inspectors, while no significant changes were recognized on the other side of the faces. Statistical comparison of the changes in the wrinkle grade between the two sides of the faces also supports the improvement of the wrinkles around eyes by using the face wash. Moreover, result of the questionnaire indicated that almost all the subjects of this experiment realized the improvement effects in the skin condition, such as clarity, moisture, softness, and gloss. Conclusions　Significant effects of a face lotion containing tranexamic acid on the facial wrinkles around eyes and the improvement in the skin condition were statistically confirmed from the study.

Objective　The aim of the present study was to evaluate the effects of supplementation with a proteoglycan-containing complex diet（PC diet）to improve low back malaise. Methods　The study was a 12-week randomized, double-blind, placebo-controlled parallel-group trial on male and female adults with a feeling of low back malaise. Fifty-four participants were randomly assigned to receive either placebo or PC diet in a tablet form constituting 10 mg of salmon nasal cartilage-derived proteoglycan, 2.25 mg of imidazole dipeptide and 100 mg of type 2 collagen in a daily dose for 12 weeks. Japan Low Back Pain Evaluation Questionnaire（JLEQ）was used as the primary endpoint, and a supplementary QOL questionnaire（SQ）, lumbar mobile ranges（LMRs）and trunk muscles strengths（TMSs）were used as the secondary endpoint. Subjective symptoms were assessed before starting the intervention（baseline）and 6 and 12 weeks after the start of interventions（weeks 6 and 12, respectively）. Results　In analysis of all of the primary and secondary endpoints, the scores of“For the last several days, to what extent has it been difficult due to lower back pain to get up from a chair or Western style toilet?”in JLEQ and“My back hurts when Ⅰ pick up something that has fallen on the floor.”in SQ significantly improved in the PC diet group compared to the placebo group at week 6 and/or week 12. Moreover, measured values of LMRs and TMSs for PC diet group were greater in extent compared with placebo group. In the ad hoc subgroup analysis performed on those participants whose anteflexed TMS was relatively low, more marked improving effects on JLEQ, together with significant improvement of anteflexed TMS were observed. PC diet supplementation was well-tolerated without any problematic side effects nor laboratory abnormalities. Conclusion　These results suggest that PC diet may have some beneficial effects on some aspects of a feeling of low back malaise. This study is registered with UMIN Clinical Trials Registry（ID: UMIN000037671）

Objective　To evaluate the effect of an oral supplementation of a rice bran-containing diet （RB diet）on two skin dryness-related parameters, stratum corneum hydration（SCH）and transepidermal water loss（TEWL）, in adult women. Methods The study was 8-week randomized, double-blind placebo-controlled trial on women aged 30-49 years complaining of skin dryness. Fifty participants were randomly assigned to receive either RB-free placebo or RB diet（14.25 mg/day as of γ-oryzanol）daily for 8 weeks. The SCH and TEWL on the cheek and the volar forearm were measured using a Corneometer® and a Tewameter®, respectively. Results　In analyses of the total evaluable population, significant increase （improvement）in SCH levels on the cheek at weeks 4 and 8 and also significant decrease（improvement）in TEWL levels on the cheek and forearm at week 8 were observed for RB diet group when compared to baseline data, although there was no significant difference from placebo group in the magnitude of changes from baseline. Ad hoc subgroup analyses performed on those participants, whose body weight changes during the 8-week treatment period were less than±5％ and who had SCH levels below the normal range, revealed that intergroup differences in the magnitude of changes in both SCH and TEWL on the cheek and/or forearm at week 4 or 8 reached significant or near-significant levels in favor of RB diet group. RB diet was well-tolerated without any reported untoward side effects nor laboratory abnormalities during the treatment. Conclusion　Although our results are not final, they suggest that the RB diet can improve both stratum corneum hydration and epidermal barrier function in adult women, particularly those with relatively severe skin dryness. This study is registered with UMIN Clinical Trials Registry（ID: UMIN000039183）.

Objectives　The aim of this study was to evaluate the effect of intake of Lactobacillus brevis （L. brevis）NTT001 and galactooligosaccharides on the intestine. Methods　Twenty two healthy volunteers with a tendency for constipation were enrolled in a randomized double-blind placebo-controlled crossover trial. In test, the volunteers were given 16 g of test chocolate containing live L. brevis NTT001（5.0×108 cfu/16 g）and galactooligosaccharides（1.5 g/16 g）or placebo chocolate daily for two weeks, each separated by a 2-week washout period. After intake, the number of fecal Lactobacillus, Bifidobacterium, and L. brevis, the amounts of fecal organic acid, the amount of metabolic products such as indole and ammonia, and questionnaire（defecation frequency, fecal shape, and others）were measured. Results　The number of fecal Lactobacillus was significantly increased after ingestion of test chocolate compared with placebo, but the amounts of fecal organic acid including acetate and decay product such as indole or ammonia were not change during experiment. Compared to placebo, defecation frequency and defecation day tended to be increased after ingestion of test chocolate. Subgroup analysis demonstrated a significant increase in defecation frequency in volunteers with a tendency for constipation, compared with placebo group. Conclusions　In conclusion, intake of L. brevis NTT001（5.0×108 cfu/day）and galactooligosaccharides（1.5 g/day）increase number of fecal Lactobacillus and promote defecation frequency in healthy volunteers with a tendency for constipation. （UMIN000037928）

Objective　To verify the effects of 12 weeks of ingestion of fresh royal jelly on fatigue in Japanese women who felt tired and had difficulty in relieving fatigue. Methods　An open-label, before-after trial was carried out from June to October 2019, and subjects of 49 healthy Japanese women aged 40 to 69 years were enrolled. Each capsule of fresh royal jelly contains 4.325 mg of 10-hydroxydecenoic acid. The subjects took four capsules once a day for 12 weeks. The primary outcome was subjective fatigue（visual analog scale）, and the other outcomes were urinary 8-OHdG, simplified menopausal index, OSA sleep inventory MA version, subjective symptoms such as concentration, stiffness in the shoulder and dryness of the skin（Likert scale method）, blood estradiol and free testosterone, and the lymphocyte /neutrophil ratio were assessed. Results　The analysis set was an intention to treat, and 49 subjects（51.1±6.3 years old）were included in the analysis. The results of comparison before and after the taking of fresh royal jelly were as follows. The subjective fatigue as the primary outcome was significantly reduced. All secondary outcome measures except estradiol and lymphocyte/neutrophil ratio were significantly improved. Conclusions　In healthy Japanese women aged 40 to 69 years old, intake of fresh royal jelly capsules for 12 weeks improved subjective symptoms related to fatigue, menopausal symptoms, and sleep. Trial registration　UMIN000036665 Foundation　MediProduce, Inc.

Objective　Lower urinary tract symptoms are caused by aging and decrease quality of life （QOL）even in healthy men and women. The objective of this pilot study was to investigate the effects of a supplement containing pomegranate extract（PE）on QOL compromised by problems in urination（frequent feelings of urinary urgency, etc.）among women who experience frequent daytime voiding. Methods　A randomized, single-blind, placebo-controlled, parallel-group, three-arm study was conducted on 34 women between 20 and 69 years old, receiving 250 mg（Group H）or 125 mg（Group L）of PE or placebo（Group P）daily for 8 weeks. Efficacy on urinary stress was evaluated based on the OverActive Bladder questionnaire（OAB-q）and Kingʼs Health Questionnaire（KHQ）. To assess voiding function and frequent feelings of urinary urgency, a urination diary was also used as an efficacy measure. Results　H and L groups showed significant improvement in“Role limitations”in week 4 and “Incontinence impact”in week 8 in the KHQ. Group H also showed significant improvement in “frequent feelings of urinary urgency”in weeks 4 and 6. No serious adverse events associated with PE were seen in H or L groups. Conclusion　The results of the pilot study showed that pomegranate intake may be effective in significantly improving the QOL associated with reductions in voiding frequency and feelings of urinary urgency. （UMIN-CTR：UMIN000033475）

Objective　Our preceding pilot study showed that the pomegranate fruit extract achieved improvements in quality of life（QOL）deterioration caused by a desire to void and urination problems in women with high daytime urinary frequency. To clarify these issues, the present randomized, double-blind, placebo-controlled, parallel-group study was conducted to investigate the effects of a supplement containing pomegranate fruit-derived punicalagin（PP）on QOL among healthy women who reported mental stress such asʻfeeling botheredʼorʻtoilet anxietyʼ caused by desire to void in daily life. Methods　Forty-two eligible subjects were randomized to receive 69 mg PP or placebo daily for 8 weeks. Efficacy on urinary stress was evaluated based on the Short Form-8（SF-8）comprehensive health-related QOL questionnaire, Overactive Bladder questionnaire（OAB-q）and a visual analogue scale（VAS）. To assess urination function and frequent feelings of urinary urgency, a urination diary was also kept. Results　Analysis of the fully evaluable population revealed that two items of the SF-8（social functioning［SF］; and mental component summary［MCS］）showed significantly improved percentage change at Week 8 in the Group PP compared to the placebo group（Group P）. Furthermore, stratified analysis showed a significant improvement in percentage change for three items of the SF-8（SF; role emotional ［RE］; and MCS）and frequency of desire to void at Week 8 in the Group PP compared to the Group P. During treatment, no PP-induced adverse effects were observed. Conclusion　The results showed that PP intake is effective in significantly alleviating the stress caused by toilet anxiety（fear of a sudden desire to void）, and appears free from safety concerns. （UMIN-CTR: UMIN000039084）

Objectives　The aim of this study was to evaluate the effect and value of energy expenditure by gum chewing. Methods　Fifteen male and five female subjects aged 24-51 participated in a randomized, open, crossover trial. The expired air was collected for 10 minutes using a gas analyzer while the subjects were asked to chew gum, ingest tablets, perform standing or perform walking. The increase in energy expenditure from seated positions in each trial was calculated and between-trial or within-trial differences were compared. Results　The increased energy expenditure of the gum trial was significantly higher than that of the tablet and standing trials. The increased energy expenditure of gum chewing did not extend to walking. Conclusions　In conclusion, energy expenditure by gum chewing was significantly greater than tablet ingestion and standing. （UMIN000041499）