薬理と治療

日本では，多くの臨床研究が行われているが，日本の医療機関では短期間に多数の症例を集積する必要があり，また，施設間，地域間のバイアスを失くす観点からも多施設共同での実施が必要である。多施設におけるデータの収集を簡便にするとともに，トレーサビリティを確保するツールとしてElectronicData Capture （EDC）を使用しているのが現状である。現在の具体的なEDC の入力と画像収集の方法の流れは図1 に示すとおりである。EDC を使用する場合，実施計画書にて定義したデータ収集項目を記載したデータシートを作成することが主流である。電子カルテからデータシート，データシートからEDC への転記作業では，これらの作業に多くの時間を要するだけでなく，それぞれの工程に入力漏れや転記ミスのリスクがある（図1上）。また，実際にこの業務を行うCRC や医師の立場では，電子カルテ，データシート，EDC 入力用PCと異なる媒体を行き来して利用する必要があり，こうした煩雑なプロセスにストレスを感じることも少なくない。また画像収集については，データセンターにすべての画像を集積し，画像中央判定を行うような研究モデルの場合，必要な画像を検索し，匿名化を行い，対応テーブルをつくり，記録媒体への書込みを行い，データーセンターへ郵送する，といった一連の作業の必要がある。そのため，EDC 入力と同様に多くの人的，時間的コストがかかるうえ，誤記や誤送といったリスクもある（図1 下）。こうした問題を解決すべく，臨床研究中核病院でもある大阪大学が中心となり構築した大阪臨床研究ネットワーク（OCR-net）で行う臨床研究では電子カルテと連動した臨床データ収集システム（Clinicalstudy Data Collecting System: CDCS）および画像収集システムを活用している。これらのシステムは情報通信技術（ICT）を活用したインフラを利用することで，上述したようなリスクやコストを軽減し，臨床研究の効率化と活性化を図り，安全性と信頼性を確保した臨床研究の実施を推進することを目的とている。本稿では，これらのシステムを用いて構築されたOsaka clinical research network for stroke（OCR-STROKE）研究を題材に，OCR-net の有用性について検証と考察を行った。ような研究モデルの場合，必要な画像を検索し，匿名化を行い，対応テーブルをつくり，記録媒体への書込みを行い，データーセンターへ郵送する，といった一連の作業の必要がある。そのため，EDC 入力と同様に多くの人的，時間的コストがかかるうえ，誤記や誤送といったリスクもある（図1 下）。こうした問題を解決すべく，臨床研究中核病院でもある大阪大学が中心となり構築した大阪臨床研究ネットワーク（OCR-net）で行う臨床研究では電子カルテと連動した臨床データ収集システム（Clinicalstudy Data Collecting System: CDCS）および画像収集システムを活用している。これらのシステムは情報通信技術（ICT）を活用したインフラを利用することで，上述したようなリスクやコストを軽減し，臨床研究の効率化と活性化を図り，安全性と信頼性を確保した臨床研究の実施を推進することを目的とている。本稿では，これらのシステムを用いて構築されたOsaka clinical research network for stroke（OCR-STROKE）研究を題材に，OCR-net の有用性について検証と考察を行った。

Background/Objectives　OPC-61815, a prodrug of the aquaretic drug tolvaptan, is being developed for administration as an intravenous infusion for patients with congestive heart failure（CHF）. We developed a population pharmacokinetic/pharmacodynamic（PK/PD）model to characterize the relationship between the PK of tolvaptan and the PD effect of an increase in urine volume in patients with CHF and fluid retention. Methods　Individual post hoc PK parameters were estimated and used to develop the model using a sequential approach. Goodness-of-fit and visual predictive check plots were generated to evaluate the adequacy of the final model. Interval urine volumes with varying OPC-61815 infusion durations were simulated and compared with oral tolvaptan. Results　The base PK╱PD model consisted of four compartments: water intake, water in edema, water in plasma, and urine. Relationships between tolvaptan exposure and urine volume on day 1 of administration of OPC-61815 and tolvaptan for all doses were adequately described; thereafter, urine volumes at OPC-61815 ≤16 mg and tolvaptan ≤15 mg doses were adequately predicted, but were under-predicted at higher tolvaptan daily doses. The maximum increase in urine volume occurred faster with an OPC-61815 infusion of ≤1 hour versus ≥6 hours, based on the simulation. Conclusions　The effect of tolvaptan on urine volume following OPC-61815 infusion and oral tolvaptan administration at clinical or lower doses was adequately described by a semi-mechanistic PK╱PD model incorporating circadian rhythm under the assumption that tolvaptan inhibits reabsorption of filtrated water. Based on the simulation with different infusion durations, an OPC-61815 1-hour infusion appears optimal. （Jpn Pharmacol Ther 2022；50：765‒79）

Recently, a report was published that extract of the health food natto prevents infection by viruses such as severe acute respiratory syndrome coronavirus 2（SARS-CoV-2）and bovine herpes virus 1（BHV-1）, and we sought to elucidate the actual antiviral action of this extract. In this study, we assumed that Nattokinase（NK）was the actual factor responsible for the major degradation activity in natto extract. For this purpose, NK contained in natto was first purified from the culture medium of Bacillus subtilis natto. When this purified NK was used to act on recombinant SARS-CoV-2 spike protein in vitro, we proved that the viral protein was hydrolyzed by electrophoresis and Western Blot method using anti-SARS-CoV-2 spike protein antibody. It was also found that recombinant SARS-CoV-2 mutant strain S1 RBD（N501Y）was degraded. On the other hand, NK lost its viral degrading effect after heat treatment（HI-NK）at 100℃ for 10 min. Even in the presence of the serine protease inhibitor AEBSF, its degradation was specifically inhibited. Viral HA, which is involved in influenza virus infection, was also degraded similarly by NK, and its degradation was inhibited by HI-NK treatment. From these findings, it was inferred that NK has antiviral activity to prevent not only novel coronaviruses but also influenza virus infection. （Jpn Pharmacol Ther 2022；50：781‒7）

Objectives　The purpose of this study was to investigate the effects of food consisting of rice bran fermented product containing 3-（4-hydroxy-3-methoxyphenyl）propionic acid（HMPA）on postprandial blood glucose control in healthy adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 30 healthy volunteers with elevated postprandial blood glucose. Volunteers were randomly assigned to receive either test food or placebo. Daily intake of the test food for 4 weeks. After 4 weeks, volunteers performed a glucose tolerance test without the test food ingestion and evaluated changes in postprandial blood glucose levels. Results　All 30 volunteers completed this study. In the test food group, blood glucose levels 2 hours after the glucose tolerance test were significantly lower than in the placebo food group（P＜0.05）. Moreover, maximum concentration time（Tmax）of blood glucose in the glucose tolerance test was smaller in the test food group than the placebo group. During the study period, no adverse events attributable to the test food were observed. Conclusion　The study revealed that the consumption of the food containing rice bran ferment lowers postprandial elevated blood glucose levels by improving glucose metabolism, rather than by inhibiting glucose absorption in healthy adults.（UMIN-CTR ID: UMIN000044481）（Jpn Pharmacol Ther 2022；50：791‒9）

Objective　The goal of this study was to assess the effects of food containing matured red ginseng extract（MRGE）on sleep quality in healthy Japanese adults with sleep quality problems. Methods　Fifty-six participants were randomly assigned to two groups via a computer program in a 1：1 ratio. Furthermore, they were asked to take two tablets of the test food（MRGE-containing food）or the placebo at any time for 12 weeks with water. The assessment items were the OSA Sleep Study MA（OSA-MA）, subjective symptoms using the Likert scale, and objective sleep evaluation. Results　The efficacy analysis data set was a per protocol set, and 27 subjects were included in the analysis for each group. The primary outcome, which was the sleepiness on rising of OSA-MA, was significantly improved in the MRGE group compared with the placebo group. Further, some of the sub-items of sleepiness on rising（concentration, and feeling of freedom）were improved. In the evaluation of subjective symptoms, it was confirmed that worries at the time of falling asleep were significantly reduced. Moreover, in the evaluation of sleep, there was a significantly deeper sleep in the MRGE group than the placebo group. There were no adverse events or side effects found to be causally related to the test food. Conclusions　The 12-week intake of a food containing MRGE was found to improve sleep quality in healthy Japanese adults with sleep quality problems. Trial registration　UMIN000042444 Foundation　KIMʼs Korean Ginseng Co., Ltd. （Jpn Pharmacol Ther 2022；50：801‒15）

Objective　The objective of this research was to investigate the effectiveness of daily ingestion of food containing soy isoflavone and lactobionic acid on the viscoelasticity of skin and the stratum corneum hydration in healthy adult women who were aware of skin dryness. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 70 participants aged 31 to 65 years. Participants were randomly assigned to receive a test food containing soy isoflavone and lactobionic acid or a placebo once daily for 12 weeks. Hydration of stratum corneum, trans-epidermal water loss, skin viscoelasticity, subjective evaluation of skin conditions and urinary equol and isoflavones levels were evaluated. Results　The test product significantly inhibited the decrease in hydration of stratum corneum, the increase in trans-epidermal water loss, and the deterioration of skin viscoelasticity compared to placebo. And, the test product significantly increased urinary equol and isoflavones concentration. In ad-hoc analysis focusing on equol-producing ability, equol-producing ability did not affect the results. Conclusion　It was suggested that ingestion of soy isoflavone and lactobionic acid-containing foods for 12 weeks in healthy adult women who are aware of dryness increased skin hydration and maintained skin viscoelasticity due to the promotion of absorption of soy isoflavones. In addition, under the conditions of this test, it was not affected by the equol-producing ability. （UMIN ID: UMIN000042493）（Jpn Pharmacol Ther 2022；50：817‒33）

Objective　We found that mature okra seeds extract had an inhibitory effect on fibroblast-derived elastase activity. In this study, we examined the effect of mature okra seeds extract on improving skin elasticity in a clinical study. Methods　A randomized, placebo controlled, double-blind, paralleled study was conducted for 23 healthy subjects（11 males and 12 females aged from 30 to 65 years）. Subjects consumed either placebo or test food（300 mg╱kg of mature okra seeds extract, containing OF4949-Ⅱ）for 12 weeks. The elasticity of the skin was measured with a Cutometer® DUAL MPA, and the parameters of R2, R5, and R7 were evaluated. Results　Ingestion of mature okra seeds extract significantly improved R2 and R7 values compared to the placebo group. Conclusion　These results suggest that mature okra seeds extract, which inhibits fibroblast-derived elastase activity, improves skin elasticity in healthy subjects. （Jpn Pharmacol Ther 2022；50：835‒41）

Purpose　We conducted an open-label, single-arm study on healthy Japanese subjects（aged 20-59 years）who were aware of thinning hair to investigate the effects of the intake of food containing Lactiplantibacillus plantarum subsp. plantarum N793（N793）on thinning hair. Methods　The subjects consumed heat-sterilized N793-containing food for 24 weeks. Efficacy was assessed via hair evaluation using a digital microscope, the number of hair loss, and the Visual Analogue Scale（VAS）questionnaire. Safety was evaluated using blood and urine tests. Values of each item were compared between before intake and 12 or 24 weeks after intake using Dunnettʼs test. Results　For hair evaluation using a digital microscope, a significant improvement was observed at 24 weeks after intake compared to before intake for the total number of hairs, mean diameter, number of non-vellus hair, non-vellus hair percentage, number of vellus hair, and vellus hair percentage. For the evaluation of the number of hair loss, although the number of hair loss decreased at 12 and 24 weeks after intake compared to before intake, the difference was not significant. The scores of hair loss in the VAS questionnaire significantly improved at 24 weeks after intake compared to before intake. Similarly, the scores of hair thickness, hair volume, and hairline and part significantly improved at 24 weeks after intake compared to before intake. Regarding safety, although significant differences were observed in several items, they fluctuated within the reference values and were considered to be within the range of physiological fluctuations caused by lifestyle habits. Conclusion　These results suggest that the intake of N793 improves thinning hair. Additionally, the intake of food containing N793 was demonstrated to be safe. （Jpn Pharmacol Ther 2022；50：843‒54）

Objectives　The aim of this study was to elucidate the effects of banana intake on obese participants on their blood biochemical markers, body composition and visceral fat volume. Methods　A randomized parallel-group comparison study was conducted on 36 obese adults between ages 25 to 44. Participants were randomized into two groups; one group took 120 g of banana every day; another group with no banana nor banana ingredients added to their everyday food, for four weeks. Visceral fat, body composition, serum biomarkers including inflammatory markers were evaluated before and after the intervention term. Results　16 participants were in the banana group, and 15 participants were in the control group. Serum iron showed significant decrease in the control group, ferritin resulted in significant decrease in the control group in intergroup comparison analysis. MCV showed significant decrease in both groups, MCHC resulted in significant increase in both groups. Visceral fat did not show statistical difference in the two groups after intervention. Alkaline phosphatase showed significant decrease in both groups. Conclusions　The results suggested that taking banana for a long term may contribute in lowering the risk of iron deficiency anemia in obese people. As obesity is a global pandemic, with recent studies showing anemia risk in that population, and that iron deficiency is the most common nutrient deficiency globally, banana intake may contribute to alleviating iron deficiency in obese population. UMIN ID: UMIN000045655 （Jpn Pharmacol Ther 2022；50：855‒63）