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）