薬理と治療

近年，グローバル試験の増加に伴い，治験依頼者（以下，依頼者）から提供される同意説明文書案（以下，依頼者版ICF）は，依頼者ごとに構成が異なり，医学専門用語等，患者がわかりにくい言葉が用いられている。そのため，多くの医療機関では独自の同意説明文書雛形（以下，施設版ICF 雛形）を作成している。結果，同じ試験の同意説明文書（以下，ICF）でありながら，医療機関ごとに内容（目次の並び順や表現方法等）が異なる状況が発生している。そこで本プロジェクトでは，依頼者および医療機関を対象にICF 作成に関する実態調査を行い，同時に依頼者，医療機関のICF 雛形を収集し，ICF 雛形目次順の調査を行った。

Background　MOVICOL® for treatment for chronic constipation, is an osmotic laxative containing polyethylene glycol as its main ingredient and various electrolytes. To collect the detailed safety and efficacy data, we planned the large-scale post-marketing surveillance study of MOVICOL®. Method　From May 2019 to June 2021, we performed the post-marketing surveillance study of MOVICOL® in daily medical practice. We summarized the safety and efficacy data as an interim report. Results　In this study, we registered 887 patients and collected data for 571 patients. We included 544 patients in the safety analysis set of this surveillance protocol; males were 217 （39.9％）and females were 327（60.1％）, and the average age was 42.2±34.1 years. The safety results showed that adverse events were reported in 20（3.7％）of 544 subjects. The efficacy results showed that the defecation frequency increased at 4 weeks after treatment. The results of the Bristol Stool Shape Scale demonstrated the improvement of the stool shape. The satisfaction with defecation also improved.　Conclusion　These results demonstrated that MOVICOL® improved the symptoms of constipation without any safety concerns.

Objective　Juzen-Taiho-To（JTT）is well known to be one of Japanese herbal medicines, and used for the supplemental therapy of cancer patients with remarkable success. Although it is also well known that periostin promotes tumor cell growth and metastasis, the influence of Japanese herbal medicines on the production of periostin. The present study, therefore, was undertaken to examine the influence of Japanese herbal medicines on periostin production in vitro and in vivo through the choice of JTT and B16 melanoma cell（B16 cell）╱experimental mouse system. Methods　JTT was well mixed with tragacanth gum at concentrations of 0.05 mg╱mL to 0.3 mg╱mL, and orally administered for 2 weeks, which was started 1 day before B16 cell injection. Tumor metastasis in lungs was assessed 2 weeks after intravenous injection of 2×105 B16 cells in a volume of 0.1 mL. Aqueous lung extracts were prepared B16-injected and JTT- treated mice, and periostin contents in the extracts were examined by enzyme-linked immunosorbent assay（ELISA）.In the second part of experiments, mouse lung fibroblasts（2×103 cells） were stimulated with 10 ng╱mL of mouse interleukin（IL）-13 in the presence of various concentrations of mouse serum obtained from JTT-treated mice for 48 hours. Periostin levels in the culture supernatants were also examined by ELISA. Results Oral administration of JTT at more than 0.1 mg╱mL significantly inhibited lung metastasis of B16 cells. JTT at more than 0.1 mg also caused significantly decrease in the appearance of periostin in aqueous lung extracts, which was increased by B16 cell injection. Addition of JTT︱treated mouse serum into cell cultures caused the suppression of periostin production from lung fibroblasts after IL-13 stimulation. The minimum concentration of the mouse serum that caused significant suppression of periostin production was 15％. Conclusion　Judging from the present results, there is possibility that Japanese herbal medicines, especially JTT suppress the production of periostin in the lung tissues induced by tumor cell stimulation and results in inhibition of tumor metastasis.

Objectives　The aim of this study was to investigate the effect of Selaginella tamariscina （P.Beauv.）Spring extracts on cellular oxidative stress, proliferation, and ultraviolet B（UVB）- induced stress in human keratinocytes. Methods　Experimental samples extracted from Selaginella tamariscina（P.Beauv.）Spring using water, 50％ ethanol, and 100％ ethanol were used. Human keratinocyte HaCaT cells were cultured at 37℃ in a 5％ CO2 atmosphere in Dulbeccoʼs modified Eagleʼs medium containing 10％ fetal bovine serum. Antioxidant activity was assessed using a 2,2-diphenyl-1-picrylhydrazyl （DPPH）assay in vitro and cellular reactive oxygen species（ROS）levels were determined using 5-（and-6）-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester（CM- H2DCFDA）. Cell survival, with or without exposure to UVB radiation, was measured using Cell Counting Kit-8. Mitochondrial dehydrogenase activities were measured using 3-（4,5-dimethylthiazol-2-yl）-2,5 diphenyl tetrazolium bromide（MTT）. Results　The water extract of Selaginella tamariscina（P.Beauv.）Spring showed DPPH radical scavenging activity, and it decreased cellular ROS levels and significantly prevented UVB-induced HaCaT cell death. The 50％ ethanol extract significantly inhibited HaCaT cell proliferation. Moreover, the water extract may decrease mitochondrial activity, despite increasing HaCaT cell proliferation. Conclusions　Components derived from Selaginella tamariscina（P.Beauv.）Spring increased HaCaT cell proliferation and protected HaCaT cells from UVB-induced stress. These components are expected to be useful as auxiliary components for maintaining the barrier function of keratinocytes. In addition, the fact that the functionality of the extracts varies depending on the extraction solvent, suggesting that the purposeful extraction is important for utilization in cosmetics.

Background　Reishi（Ganoderma lucidum）is a first-year mushroom belonging to the family of Ganodermataceae. No clinical trial has been conducted to show the effects of Reishi on activation of immune response. Methods　We evaluated the effects of Reishi on NK cell activation for 24 Japanese men and women between the ages of 50 and 70, continuously ingested the Reishi capsule for 12 weeks. It was evaluated by a placebo-controlled, randomized, double-blind, parallel-group comparative study. Results　NK cell activity has tended to increase both in the test food intake group and the placebo food intake group after 12 weeks of ingestion. In subjects with LDL-C levels less than 135 mg╱dL before ingestion, NK activity following 12 weeks of ingestion was higher in the test food ingestion group than in the placebo food ingestion group. In subjects with HbA1c levels less than 5.5％, NK activity following 12 weeks of ingestion was higher in the test food intake group than in the placebo food intake group. The blood glucose level at any time, in the test food intake group, tended to decrease in those who had a high blood glucose level before ingestion（90 mg╱ dL or more）as compared with the placebo food intake group. The HDL-C level was statistically significantly higher in the test food intake group than in the placebo food intake group, following 4 weeks of ingestion. Triglyceride（TG）level tended to be slightly lower in the test food intake group than in the placebo food intake group following 4 weeks of ingestion. The safety study showed no clinical problems, no side effects or medically problematic adverse events. Conclusion　It was suggested that intake of Reishi induced activation of NK cell in the people with low LDL-C and HbA1c levels. In addition, intake of Reishi increased the HDL-C level, which is expected to lead to improvement of the dyslipidemia symptoms. The blood glucose evel at any time, tended to decrease in those who had a high blood glucose level after 12 weeks of Reishi ingestion. （UMIN 000043856）

Objective　This study evaluated the effect of consuming NO-NAI-KAKUSAN, a nucleic acid-containing food, for 12 weeks on cognitive function in Japanese adults with memory decline. Methods　A randomized, placebo-controlled, double-blind, parallel-group comparison study was conducted from November 2020 to May 2021 in healthy Japanese adults aged ≥40 years. First, a computer was used to randomly but equally assign 66 subjects who met the eligibility criteria to the NO-NAI-KAKUSAN or placebo group. Then, eight NO-NAI-KAKUSAN or placebo tablets were administered daily for 12 weeks. The primary outcome was composite memory from the Cognitrax cognitive test, and the secondary outcomes were other cognitive functions and subjective symptoms for memory. We also conducted a safety assessment during the intervention period. Results　Per-protocol data set was used for efficacy analysis. Each group included 30 subjects （the NO-NAI-KAKUSAN group, 54.2±8.0 years, and the placebo group, 54.2±7.5 years）.The standardized score of composite memory and verbal memory after the 12-week intervention was significantly higher in the NO-NAI-KAKUSAN group than in the placebo group（P＝0.045, P＝0.049, respectively）. There were no clinical adverse events due to food intake. Conclusions　The results indicated that consuming NO-NAI-KAKUSAN improved the memory of healthy Japanese adults aged 40 years or older who experienced memory decline. Trial registration　UMIN000042446 Foundation　MAINICHIGENKI. CO., LTD.

Objective　This study aimed to examine the effect of food containing matured red ginseng extract（MRGE）on fatigue and stress in healthy Japanese adults who complain of tiredness in daily life. Methods　Twenty-eight participants were randomly divided into two groups using a computer. One group consumed two tablets of the test food（MRGE-containing food）and the other consumed placebo with water at any time for 12 weeks. The evaluation items included fatigue assessment using the visual analogue scale, mood symptom assessment using the Profile of Mood States（second edition）, autonomic nerve function test, oxidative stress-related biomarkers, and subjective symptom assessment using the Likert scale. Furthermore, the Uchida-Kleppelin test was performed as a workload, and each evaluation（except for some items）was performed before and after the workload. Results　The efficacy analysis data set was per protocol set, including 28 subjects from the MRGE and 26 from the placebo groups. The primary outcome of subjective fatigue assessment before and after workload significantly improved, and the sympathetic and parasympathetic nerves were activated in the MRGE group compared with the placebo group. Additionally, the overall autonomic function of the MRGE group improved extensively, approaching that of actual age. Among the subgroups, those with women only and those with subjects aged ≥43 years, respectively showed an improvement in oxidative stress indicators. No adverse events or side effects induced by the test foods were observed. Conclusions　The 12-week intake of MRGE-containing food reduced temporary subjective fatigue and alleviated mental stress through adjustment of autonomic nerve function in healthy Japanese adults who feel tired in daily life. Trial registration　UMIN000042442 Foundation　KIMʼs Korean Ginseng Co., Ltd.

Objective　This study aimed to examine the effects of consumption of a test food containing elastin peptides derived from the equine nuchal ligament（EPE）on skin condition and body shape in healthy Japanese adult women with facial skin elasticity problems. Methods　Subjects were allocated into either EPE or placebo group（n＝16 each）using a random number generator. They consumed two tablets╱day during lunch to bedtime of either the food containing EPE or placebo for eight weeks. The assessments included viscoelasticity testing, body measurements, three-dimensional imaging, dermis measurements, and subjective skin symptom. Results　As an efficacy analysis, the number of subjects analyzed was 15 in the EPE group and 16 in the placebo group. After eight weeks, no significant changes in facial skin viscoelasticity were noted in the EPE group, although significant changes were noted in other outcomes. These included a significant height increase in the measurement from the ground to the top of the bust, and a significant decrease in the number and total surface area of hyperpigmentation on facial skin. Additionally, a significant decrease in the total area of wrinkles at the corners of the eyes was observed in women aged ＜40 years. Furthermore, the subjective symptom related to facial skin pores was significantly reduced to the point of no longer being a complaint for some trial participants. There were no adverse effects associated with the test food. Conclusions　The study found that the food containing EPE improved the firmness of the bust and decreased facial skin pigmentation in healthy Japanese adult women with facial skin elasticity problems. In women aged ＜40 years, the EPE decreased the wrinkles observed at the corners of the eyes. Furthermore, EPE was found to improve subjective symptoms related to facial skin pores. Trial registration　UMIN000036807 Foundation　BIOCON（JAPAN）LTD.

This study was designed to verify the skin-lifting effects of a test food containing salmon nasal cartilage（SNC）-derived proteoglycans（PGs）in healthy Japanese adult women. In this study, 56 subjects were enrolled and randomly divided into the SNC-PGs or placebo group（n＝28 each）using a computerized random number generator. The subjects consumed one tablet of either SNC-PGs or placebo food once a day for 12 weeks. Compared with the placebo group, the SNC-PGs group showed significant facial skin lifting and inhibition of the decrease in skin viscoelasticity（P＜0.05）. Additionally, facial redness in the SNC︱PGs group was significantly decreased compared with that in the placebo group（P＜0.05）. In conclusion, the test food containing SNC-PGs showed skin-lifting effects and inhibition of the decrease in skin viscoelasticity in healthy Japanese adult women. （UMIN000035147）

Objectives　In this study, we investigated the effects of Lacticaseibacillus paracasei K71（formerly designated as Lactobacillus paracasei: L. paracasei K71）intake on maintenance of physical condition and immune parameters in healthy subjects. Methods　In this randomized, double-blind, placebo-controlled, parallel-group trial, 30 subjects were randomly allocated to an L. paracasei K71 group and 29 to a placebo group, and ingested a test food containing 100 mg of L. paracasei K71 or a placebo food once daily for 8 weeks. The subjects answered a questionnaire about their subjective symptoms related to physical condition every day during the intake period. Immune parameters were also evaluated, before the intake and at the 4th and 8th week of intake. Results　The cumulative number of days with all subjective symptoms was significantly lower in the L. paracasei K71 group than in the placebo group, but there was no significant difference in immune parameters between the groups. Subgroup analysis revealed that IL-12 and NK activity were significantly higher in the L. paracasei K71 group in the subgroup with low NK activity, and NK activity was significantly higher in the L. paracasei K71 group in the subgroup over 30 years old at week 8 of intake. No adverse events due to the test food were observed during the test period. Conclusions　The results suggested that the continuous intake of L. paracasei K71 suppressed the cumulative number of days with subjective symptoms related to physical condition caused by viral infections, etc., by maintaining appropriate immune function. UMIN-CTR ID: UMIN000042485

Objectives　Dementia is one of the leading conditions that require long-term care in Japan. The study was aimed to investigate the correlation between the intake frequency of home delivered daily products containing functional ingredients and the risk of dementia in the elderly. Methods　Our cross-sectional survey included 3,298 subjects aged 65 and over（age: 73.5± 5.8, women: 52.0％）who were not certified long-term care and needed support. For the dependent variable, we used the dementia risk assessment scale. The independent variable was the intake frequency of regular dairy products and whether to use home delivery for dairy products, which contain additional functional ingredients. In addition, a stratified analysis of the early- stage and late-stage elderly was conducted. Results　No significant association was found between dairy products use and the dementia risk score in the stratified analysis of all subjects and 65-74 year old subjects. In contrast, the risk of dementia was significantly lower in the group that took two or more home delivered dairy products per day than in those who consumed less than one regular dairy products per day, in the subjects in 75 years old and ove（r［B］＝－0.35［, 95％CI］: －0.65, －0.06）. Furthermore, the risk of dementia was low in people who consumed home delivered dairy products containing functional ingredients six or seven times╱week in the late-stage elderly（［B］＝ －0.26［, 95％CI］: －0.51, 0.00）as compared to those who consumed the same less than six times╱week. Conclusion　High-frequency users of home delivered dairy products with functional ingredients have a lower risk of dementia in the late-stage elderly.

Background　Chrysanthemum flowers contain luteolin as the principal flavonoid and are traditionally used for eye care in Taiwan. We previously demonstrated that luteolin-enriched chrysanthemum flower extract（CFE）reduced serum uric acid levels in humans. Luteolin has also been reported to exert diverse biological effects, particularly anti-allergic activity. Objective　We herein conducted a clinical trial on the effects of CFE on allergic symptoms in the eyes and nose in Japanese healthy subjects. Methods　This was a randomized, double-blind, placebo-controlled trial and CFE（100 mg） containing 10 mg of luteolin was used as the active sample in a capsule. We enrolled 44 healthy Japanese individuals with mild allergic symptoms in the nose and eyes. All subjects were randomly allocated to an active group（n＝22）or placebo group（n＝22）using a computerized random number generator. One active or placebo capsule was taken twice a day for 8 weeks between February and April 2021. Japanese rhino-conjunctivitis quality of life questionnaire （JRQLQ）scores and each questionnaire item were assessed after 4 and 8 weeks as the primary outcomes. Blood, urine, and body parameters were also examined to evaluate the safety of CFE. Results　Forty-two subjects completed the trial, and the per protocol set comprised 21 subjects in the CFE group and 21 subjects in the placebo group. JRQLQ scores for eye symptoms after the 8-week intervention were significantly lower in the CFE group than in the placebo group. Laboratory tests revealed no abnormalities to suggest any side effects of CFE. Conclusions　CFE（200 mg╱day）containing 20 mg of luteolin reduced allergic symptoms in the eyes. Therefore, CFE may be beneficial for attenuating hay fever symptoms. （UMIN000042583）

Objectives　In this study, we conducted a continuous intake test of foods containing aged garlic extract and investigated the mechanism of its effect of improving sleep quality and reducing fatigue. Methods　A randomized, double-blind, placebo-controlled, parallel study was conducted on 35 healthy adult volunteers（21 males, 14 females, 20-62 years old）. Subjects consumed a test food or placebo for 4 weeks. The quality of sleep was both subjectively evaluated, and objectively evaluated by an activity monitor. A d-ROMs test, BAP test, salivary melatonin measurement, and cold water load test as an evaluation for blood flow and body temperature, were also performed. In addition, a pharmacokinetic test of S-allylcysteine（SAC）, which is the main functional component of the extract, was conducted. We also investigated whether SAC affects the expression of clock genes. Results　Continued ingestion of the test food significantly improved sleep quality 3 to 4 weeks after ingestion compared to the placebo group, and decreased the number of awakenings and the wake after sleep onset. In the cold water load test, peripheral blood flow increased and peripheral body temperature increased in the test group 4 weeks after ingestion of the test food. The blood concentration of SAC peaked 30 minutes to 2 hours after ingestion of the test food, and decreased to a level that was not significantly different from the baseline 24 hours later. SAC promoted the expression of the clock gene Per2. Conclusions　As a result of this study, it was shown that peripheral blood flow improvement, body temperature rise, antioxidant action, and clock gene expression promotion may be involved as a mechanism for improving sleep quality and reducing fatigue by consuming the test food. Trial registration　UMIN-CTR: UMIN000042279, UMIN000042281

Objectives　This randomized, double-blind, placebo-controlled, crossover study aimed to evaluate the effects of Kaempferia parviflora extract on body temperature. Methods　Twenty five healthy subjects were selected and assigned to two groups: the test food group and the placebo group. The test food group ingested the test food containing K. parviflora extract（0.49 mg╱day in the form of tetramethylluteolin）, while the placebo group ingested foods without any extract but with 100 mL water. Core body temperature was measured before ingestion and 10, 20, 30, 40, 50, and 60 min after ingestion. Body surface temperature was measured before ingestion and 30 and 60 min after ingestion. Results　The test food group showed a significant increase in core body temperature compared with the placebo group（P＜0.05）. The change in body surface temperature was not significant in the test food group as compared with the placebo group. During the study period, no adverse events attributable to the test foods were observed. Conclusions　These results suggest that ingestion of K. parviflora extract may be useful for maintaining body temperature. （UMIN-CTR ID: UMIN000045227）

Objective　To examine the effects of foods containing sweet potato shochu lees extract with fat-soluble polyphenols（FSPs）on cognitive function in healthy Japanese adults. Methods　In this randomized, placebo-controlled, double-blind, parallel-group comparison study, twenty-two participants were randomly assigned to the FSP group or the placebo group using a computerized random number generator. One tablet of the test food that contained FSPs or placebo was taken daily with water at breakfast for 12 weeks. Evaluation items included cognitive function tests using Cognitrax, mood symptom assessment using the Japanese version of Profile of Mood States（2nd edition）, subjective cognitive function symptoms, and cognitive function-related biomarkers. Results　The efficacy analysis dataset was a per-protocol set（PPS）, and 20 participants per group were included in the analysis. Although there was no significant difference in the primary outcome of total memory between the two groups after the intervention, the FSP group showed a significant improvement in visual memory, which is a part of total memory, and other cognitive domains related to social cognition. In the womenʼs subgroup analysis, significant improvements were observed in the domains related to the neurocognitive index, total memory, total attention, and in the items that showed significant differences in the PPS. As for blood amyloid-β（Aβ）, analysis of the subgroup of the study subjects whose Aβ was below the mean value during the screening test showed the FSP group significantly suppressed increasing Aβ. The consumption of the test foods had no significant adverse effects. Conclusions　The 12-week intake of foods containing FSPs derived from sweet potato shochu dregs improved some cognitive functions in healthy Japanese adults. Trial registration　UMIN000041291 Foundation　Strategic Core Technology Advancement Program（Supporting Industry Program） and Satsuma Shuzo Co. Ltd.

Objectives　This randomized, double-blinded, placebo-controlled, parallel-group study aimed to evaluate the effect of Lagerstroemia speciosa leaf extract and exercise on gait function, posture, and quality of life（QOL）. Methods　Forty participants were included in this study and were randomly assigned into two groups: the test food group and placebo group. The participants consumed either food containing L. speciosa leaf extract （test; 2.2 mg╱day as corosolic acid）or food not containing corosolic acid（placebo）for 8 weeks. The participants were also instructed to exercise 4-5 times a week, during the study period, and the exercise load was gradually increased. Primary（gait function） and secondary（posture assessment using X-rays and questionnaire using SF-36 and visual analogue scale （VAS））outcomes were evaluated before, and after 4 and 8 weeks following food administration. Results　The test food group showed significant improvements in gait speed, timed up and go test, lumbar lordosis angle, physical component summary in SF-36, and VAS（P＜0.05）than the placebo food group. During the study period, no adverse events were attributed to the test foods. Conclusions　Overall, the findings indicated that L. speciosa leaf extract and the exercise can improve gait function, posture, body-related concerns, and QOL in adult men and women. （UMIN-CTR ID: UMIN000043824）

Objective　We evaluated the effects of coffee-derived chlorogenic acids on postprandial serum triglyceride（TG）levels in this randomized, double-blind, placebo-controlled, crossover study. Methods　24 healthy subjects with fasting serum TG levels ≥100 mg╱dL and ≤149 mg╱dL were randomly divided into two groups. Subjects ingested test food（containing 350 mg coffee- derived chlorogenic acids）or placebo food（not containing coffee-derived chlorogenic acids） together with a high fat meal（lipid: 49 g）. Serum TG levels was measured before and 1, 2, 3, 4 and 6 hours after ingestion. Results　In the analysis of all subjects, postprandial serum TG levels did not differ significantly between the test food and the placebo food. However, in the subgroup with the maximum serum concentration（Cmax）of TG ≥200 mg╱dL when ingested placebo food, in comparison with the placebo food, the test food significantly lowered the delta TG at 6 hours after ingestion and the Cmax of delta TG（each P＜0.05）. In addition, the test food lowered the incremental area under the curve（iAUC）values of TG（P＜0.10）. No adverse events attributable to the test food were observed throughout the study period. Conclusion　These results suggest that ingestion of coffee-derived chlorogenic acids suppresses the elevation of postprandial serum TG levels in subjects with relatively high postprandial serum TG levels（UMIN ID: UMIN000044733）.

Objectives　A randomized, double-blind, placebo-controlled, crossover study was conducted to evaluate the effect of food containing Apocynum venetum leaf extract（AVLE）on daytime sleepiness, psychological stress in daily life, and concentration. Methods　Forty healthy subjects were enrolled and randomly assigned to two groups. The subjects ingested either the food containing AVLE（with 1 mg╱day hyperoside and 1 mg╱day isoquercitrin）or the unmodified food as placebo for 4 weeks. Epworth sleepiness scale（ESS）, visual analogue scale（VAS）for psychological stress, and correct answer rates of performance tests were evaluated. Results　The consumption of food containing AVLE significantly reduced the scores of ESS and VAS for psychological stress versus those of the placebo group（P＜0.05）. In the subgroup whose VAS scores for psychological stress were more than average, the consumption of the food containing AVLE significantly improved the correct answer rates of discrimination response tests and psychomotor vigilance tests versus those of the placebo group（P＜0.05）. During the study period, no adverse events attributable to the test food were observed. Conclusions　The results indicate that the ingestion of food containing AVLE can relieve daytime sleepiness and psychological stress in daily life and can improve concentration in healthy individuals. （UMIN-CTR ID: UMIN000043948）

高校のときに数学が得意だった人なら，帰納法も背理法も聞いたことがあるかもしれません。じつは，統計学はこの二つの思考法を取り入れています。そんな言葉は聞いたことがないという人も，避けずに読んでもらえればと思います