薬理と治療

患者や家族，市民と研究者がパートナーシップのもとに研究開発を進める動きが，国内でも広まりつつある。本稿では，その代表的な取組みである医学研究・臨床試験における研究への患者･市民参画（Patient and Public Involvement, PPI）について，PPIを牽引してきた英国と日本医療研究開発機構（AMED）の「患者・市民参画（PPI）ガイドブック～患者と研究者の協働を目指す第一歩として～」（PPI ガイドブック）の考え方を軸にPPI の基本を紹介し，円滑で有意義なPPI の実現に向けた課題と展望を述べる。なお筆者はPPI ガイドブックの草案作成者の1 人であるが，本稿は私見に基づいている。

近年，臨床研究への患者・市民参画（Patient &Public Involvement, PPI）の必要性がさまざまな場面で叫ばれるようになってきた。2021 年4 月現在，ステップ3 に進んでいるICH-E8（R1）（臨床試験の一般原則）のなかにも「患者からの情報の試験デザインへの反映」という項目が設けられており，とくにデザイン段階でのPPI の必要性が強調されている。また，AMED「臨床研究等における患者・市民参画に関する動向調査」委員会からPPI ガイドブックが公表され，日本でも学会や臨床試験グループ，医療機関など，さまざまな場面でPPI の取り組みがなされつつある。シンポジウム10 では，国立がん研究センター中央病院や日本臨床腫瘍研究グループ（JCOG）で行ったPPI の実体験をもとに，研究者目線でのPPI の必要性と事例について発表を行った。

臨床研究コーディネーター（以下，CRC）はつねに患者に寄り添い，治験や臨床試験の支援を行っていると感じる。その意味で「患者中心」ではあるが，その実践のためにはいくつかの工夫が必要である。実践の背景となる業務上のジレンマの一つとして，治験終了後の患者に対し，関連情報をどのように伝えるかという問題があった。英国における「患者・市民参画」1）で示されている参加（participation），エンゲージメント（engagement），参画（involvement）のなかでは，エンゲージメントに関する話題である。CRCの立場からは治験薬の割付け結果やその後の開発に関する情報を伝えたい想いを抱える反面，治験薬に治療効果を期待している患者に対して，割付けがプラセボであったこと，治験薬の有効性・安全性が認められないことや開発中止を伝えることは大きな負担になると思われた。そこで，われわれは2011 年に治験参加後の情報還元に関する患者の意識に関して質問紙調査を行った。今回は，その調査の結果をもとにした治験・臨床試験の結果の患者への還元を中心に，取り組みの状況を紹介したい。

Background　In September 2009, the first biosimilar received market authorization, and 15 ingredient biosimilar products for the originators have been approved by May 2021. The number of products that can be self-injected is also increasing, and those products are dispensed at community pharmacies. It is important for community pharmacists to understand biosimilars in order to promote their usage. We conducted a questionnaire survey on the awareness of biosimilars for pharmacists. Methods　The questionnaire survey was conducted on the web for the supervising pharmacists working in the pharmacies as the member of Japan Pharmaceutical Association or in the pharmacies as the member companies of Nippon Pharmacy Association. Results　2887 responses were obtained. 67.1％ of pharmacies received prescriptions related to biosimilars, and 69.0％ of prescriptions were specified the biosimilar brand. When a prescription without tick mark on the field of non-substitutable was received, 46.3％ of pharmacists dispensed originators without confirming prescribed doctor, and 31.0％ asked prescribed doctor whether they could dispense an originator or a biosimilar. A relatively large number of respondents concerned about substitution of biosimilars for originators compared to other items regarding concerns on biosimilars. The highest percentage of the respondents pointed out that substitution rules are important for promoting use. Conclusions　It is important for regulatory authorities to disseminate information and implement training program on biosimilars, and it was considered necessary to establish standards for substitution rules. The medical fee schedule should be designed in consideration of inventory burden of biosimilars and required time for consultation with patients.

Objective　The aim of this study was to examine the efficacy and safety of caffeine treatment for premature infants who have apnea attacks according to the blood caffeine concentration. Methods　Blood was collected before the administration of caffeine, and on days 1, 5 and 10 of caffeine administration. Using collected blood, blood caffeine concentrations were measured by an LC-MS/MS analysis. Regarding gestational age, birth weight, corrected age╱body weight╱days after birth at the start of the administration, and Apgar scores at 1 and 5 minutes, blood caffeine concentrations were compared between two groups. In addition, we investigated the relationship between the blood caffeine concentration and the improvement of apnea attacks, or adverse events. Results　There were no significant differences in the blood caffeine concentrations for any of the items in the seven items listed above. The investigation of the improvement of apnea attacks revealed that the blood caffeine concentrations were significantly lower in the improved group, the total molecular concentrations, including caffeine metabolites, were also significantly lower than in the unimproved group. In addition, the blood caffeine concentration in one patient with a suspected adverse event caused by caffeine was within the therapeutic range. Conclusions　It was suggested that the effect of caffeine is more likely to be obtained when the degree of growth is larger and the administration is started earlier. Moreover, we found that the more developed infants may have faster metabolism and excretion.

Background and Objectives　A long-term post-marketing prospective study was conducted to evaluate the safety and efficacy of the DPP-4 inhibitor anagliptin （brand name: SUINY®）in real-world clinical settings. Methods　Patients with type 2 diabetes mellitus who were newly treated with anagliptin were included in this study. Adverse events, efficacy endpoints and others were surveyed using a central registry system. The observation period was three years from the start of anagliptin administration. Results　According to the safety analysis set in 6324 patiets, the incidence of adverse drug reactions was 9.49％（600 patients）, including hypoglycaemia（1.08％）, constipation（0.81％）, hepatic function abnormal（0.51％）, hypertension（0.33％）, renal impairment（0.28％）, weight increased（0.25％）, dizziness and blood urea increased（0.24％ each）, cerebral infarction and blood creatinine increased（0.21％ each）. The incidence of serious side effects was 1.85％ （117 patients）, including cerebral infarction（0.21％）, death（0.09％）, myocardial infarction （0.08％）, gastric cancer and cerebral haemorrhage（0.06％ each）, pneumonia and colon cancer （0.05％ each）, appendicitis, breast cancer, decreased appetite, angina pectoris, atrial fibrillation, cardiac failure acute, cardiac failure congestive, interstitial lung disease, gastrointestinal haemorrhage and liver disorder （0.03％ each）. The efficacy of this drug was maintained up to three years, and the mean change in HbA1c at the final evaluation was －0.70±1.42（SD）％. onclusions 　No new safety or efficacy issues were observed during three years of use, suggesting that anagliptin is a useful treatment option for patients with type 2 diabetes mellitus.

Objectives　Kaempferia parviflora（KP）was discovered in Thailand. It has been used widely as a herbal medicine for centuries. KP and its various components have been suggested to exhibit beneficial effects such as anti-obesity, anti-inflammatory, and antioxidant effects. We aimed to focus on its effect on the brown adipose tissue （BAT）, which consumes energy due to thermogenesis. We examined the effect of intraduodenal（ID）administration of a KP extract （KPE）on the activity of the sympathetic nerve innervating BAT in urethane-anesthetized rats. We also identified one of components from KPE responsible for the effects on BAT-sympathetic nerve activity（BAT-SNA）and investigated the effects of this component on BAT-SNA and BAT-temperature（BAT-T）in rats. Methods　The present study examined the effects of ID administration of KPE and fractions on autonomic neurotransmission in anesthetized rats by electrophysiological method. We did fractionation of the fractions containing methoxyflavones from KPE using high-performance liquid chromatography. We measured of BAT-T using by thermistor implantable telemetry system. Results　ID administration of original KPE significantly elevated the BAT-SNA in urethane-anesthetized rats. Among the six fractions of methoxyflavones isolated from KPE, ID administration of fraction 2 containing 5,7,3′,4′-tetramethoxyflavone and 3,5,7,3′,4′- pentamethoxyflavone caused an increase in BAT-SNA in rats. Moreover, ID administration of 5,7,3′,4′-tetramethoxyflavone resulted an increase temperature in the subcutaneous space above the interscapular BAT in conscious rats. Conclusions　These findings suggest that 5,7,3′,4′-tetramethoxyflavone, a component of KP, stimulates thermogenesis via excitation of the sympathetic nerve innervating BAT.

Objectives　The purpose of this study was to investigate the effects of food consisting of rice bran fermented product containing HMPA on human abdominal fat in healthy adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 30 healthy males（Aged 20-64, BMI 25 or more and less than 30）. Subjects were randomly assigned to receive either test food or placebo. Daily intake of the test food for 12 weeks. Subjects were assessed on abdominal fat area（primary outcome）, physical measurement, and safety assessment. Results　Abdominal fat area and subcutaneous fat area were significant lower in the test food group than in the placebo food group（P＜0.05）. During the study period, no adverse events attributable to the test food were observed. Conclusion　The study findings indicate that the food containing rice bran ferment have an effect of reducing abdominal fat in healthy men. （UMIN-CTR ID: UMIN000041225）

Objectives　The high-protein yogurt with higher protein content than regular yogurts is processed fermented milk by centrifugation. The aim of this study was to assess whether the high-protein yogurt consumption will increase postprandial plasma amino acid levels and improve protein absorption. Methods　In a randomized crossover study, 12 males（20-29 years）were randomly assigned to ingest the high-protein yogurt, or non-fermented control milk with identical protein content. Postprandial plasma amino acid levels were measured before, and at 15, 30, 45, 60, 90, 120 and 180 minutes after consumption. The incremental area under the curve（ΔAUC0-180）and the incremental maximum plasma concentration（ΔCmax）were compared between both crossover periods. Results　The ΔAUC0-180 and ΔCmax value of essential amino acid after the consumption of the high-protein yogurt was higher than non-fermented control without and with significance（P＜0.1 and P＜0.05, respectively）. The leucin ΔAUC0-180 and ΔCmax values were also significantly augmented after the high-protein yogurt（both P＜0.05）, and similar results were found in the BCAA values（both P＜0.05）. Conclusions　This study shows that consumption of the high-protein yogurt increases plasma essential amino acid levels, such as BCAA and leucine levels, as compared to control milk. Our results indicate that the high-protein yogurt administration improves protein absorptions through fermentation and condensing process. When considering the important role of leucine in muscle protein synthesis, the high-protein yogurt may stimulate postprandial muscle protein accretion more effectively than regular yogurts. （Trial registration UMIN-CTR：UMIN000035055）

Objectives　This clinical study aimed to evaluate the bioavailability of ellagic acid in human plasma after ingestion of Irvingia gabonensis extract. Methods　Ten healthy Japanese participants were enrolled in the study and randomly divided into two groups: one group served with low-dose test food（containing 3 mg of ellagic acid）and the other with high-dose test food（containing 24 mg of ellagic acid）. Plasma ellagic acid levels were measured immediately before ingestion and 30, 60, 120, and 240 min after ingestion of the test food. Results　Plasma ellagic acid levels were significantly elevated in the high-dose group 60 min post ingestion（P＜0.05）; in contrast, no significant increase was observed in the low-dose group. No adverse events associated with the test food were observed throughout the study period. Conclusions　The results of this study suggest that at least 24 mg of ellagic acid may be required for its functional bioavailability in healthy participants. （UMIN-CTR ID: UMIN000038596）

Objectives　Black-vinegar-mash-garlic containing inulin-type fructan is suggested to improve immune system and useful for various physical conditions. The aim of this study was to evaluate the effects of food containing black-vinegar-mash-garlic on the feeling of fatigue, decreased vitality and sleep quality in daily life. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 30 participants（Age 20-64, the Profile of Mood State 2nd Edition （POMS2）T-score ≲50）. Participants were randomly assigned to receive either the test product or placebo daily for 8 weeks. Daily intake of the test product contained black-vinegar-mash-garlic. Participants were evaluated using POMS2, OSA sleep inventory for middle age and aged（OSA-MA）and 36-Item Short Form Survey（SF-36）. Results　Sleeping on rising score of OSA-MA and role physical score of SF-36 was significantly improved in the test group than the placebo group at week 4. In a post hoc analysis of subgroup without T-score of Fatigue-Inertia on POMS2 ≳70, significantly improvement was observed in initiation and maintenance score of sleep of OSA-MA and general health score of SF-36 in the test group at week 8. Conclusions　The result suggested that ingestion of the test product reduces feeling of fatigue and decreased vitality and improves sleep quality in daily life. （UMIN ID: UMIN000041751）

Objectives　This randomized, double-blind, placebo-controlled, parallel-group study aimed to evaluate the effects of young barley leaf powder on the human gut microbiome, physical conditions, and fecal characteristics. Methods　In this study, 60 healthy subjects were randomly divided into two groups: the test food group and the placebo food group. The subjects consumed either test food containing young barley leaf powder （daily dietary fiber consumption through young barley leaf powder in each test food group subject: 0.7 g）or placebo food for four weeks. Gut microbiome composition（primary outcome）, and physical conditions and fecal characteristics（secondary outcomes） were evaluated. Results　The test food group showed a significant increase in the occupancy rate of Faecalibacterium, Roseburia, Lactobacillus, and Paraprevotella and a significant decrease in the occupancy rate of Anaerotruncus, as compared to the placebo food group（P＜0.05）. The test food group showed a significantly lower cumulative incidence of days of cold-like symptoms, as compared to the placebo food group. No significant difference was found in the fecal characteristics of the two groups. During the study period, no adverse effects attributable to the test food were observed. Conclusions　The findings of this study indicate that intake of food containing young barley leaf powder contributes to the improvement in enteric environment balance and suppresses cold-like symptoms in healthy subjects. （UMIN-CTR ID: UMIN000043006）

Objectives　This randomized, double-blinded, placebo-controlled, parallel-group study aimed to evaluate the effects of young barley leaf powder on skin health parameters including stratum corneum water content, trans-epidermal water loss, and skin viscoelasticity. Methods　Fifty healthy adult women experiencing dry skin were selected for this study and were randomly assigned into two groups: a test food group and a placebo group. Participants consumed either test foods containing young barley leaf powder（0.7 g/day as dietary fiber）or placebo（similar foods, unsupplemented with young barley leaf powder）, for 8 weeks. Stratum corneum water content（primary outcome）, transepidermal water loss, skin viscoelasticity, skin condition scoring by a dermatologist, and a questionnaire survey on skin condition（secondary outcomes）were evaluated. Results　The test food group showed a significant increase in stratum corneum water content （P＜0.05）relative to the placebo group. No significant differences between groups were found in other measured outcomes. During the study period, no adverse events attributable to test foods were observed. Conclusions　These findings indicate that the foods containing young barley leaf powder could increase stratum corneum water content in healthy adult women experiencing dry skin. （UMIN-CTR ID: UMIN000043067）

Objective　We evaluated the effects of cocoa on skin blood flow, skin temperature, and subjective measures in healthy adults. Methods　A randomized, double-blind, placebo-controlled crossover comparison study was conducted in healthy subjects. After resting for at least 30 minutes at room temperature of 23± 1℃ and humidity of 40±5％, the subjects ingested a single dose of cocoa containing 30 mg of flavanols or placebo, which does not contain flavanols. Blood flow and skin temperature were measured every 10 minutes from 0 to 60 minutes after ingestion of the test food. Coldness of the hand was assessed by the visual analogue scale （VAS）scores every 20 minutes from 0 to 60 minutes after ingestion of the test food.Results　In the analysis of 24 subjects, cocoa intake significantly increased skin blood flow, and skin temperature at 40 to 60 minutes after ingestion of the test food compared to placebo. The VAS analysis showed a significant improvement in“hand coldness”60 minutes after cocoa intake compared to placebo. Conclusions　In healthy adults, the ingestion of cocoa containing 30 mg of flavanols significantly increased skin blood flow and skin temperature, and improved hand coldness by VAS score. （UMIN ID：UMIN000044542）

Objectives　We investigated the effects of continuous ingestion for 28 days of the supplement containing black ginger（Kaempferia parviflora）extract as a main ingredient, black pepper extract, black sesame extract, fermented black onion powder, and black soybean seed coat extract on cold intolerance. Methods　Fifty seven female volunteers with a subjective symptom of cold participated in a randomized, double-blind, placebo-controlled, parallel-group comparative study. Subjects consumed the test food containing black ginger extract, black pepper extract, black sesame extract, fermented black onion powder, and black soybean seed coat extract, or the placebo food for 28 days. The skin surface temperatures of fingertip and toe were measured by infrared thermography. The changes in sensation of cold whole body, cold limbs, shoulder stiffness, fatigue, quality of sleep, and defecation were evaluated by using subjective scale, visual analog scale（VAS）. Results　Continuous ingestion for 28 days of the supplement containing black ginger extract, black pepper extract, black sesame extract, fermented black onion powder, and black soybean seed coat extract significantly raised the toe skin surface temperature in subjects with low surface temperature and/or with a BMI of 22 or higher, and increased the fingertip skin surface temperature in subjects over 40 years old. Continuous feeding of the supplement reduced the VAS scales for cold limbs, fatigue, and defecation feeling. Conclusions　These results showed that continuous ingestion of the black ginger supplement improves cold intolerance, fatigue, and defecation feeling. （UMIN-CTR: UMIN000042764）

Objectives　Urolithin A, an intestinal metabolite of ellagic acid contained in nuts, pomegranate and berries is a component that has been reported to have an autophagy/enhancing effect and is attracting attention. In this study, a double-blind, parallel-group comparative study was conducted to investigate the effects and safety of ingestion of fermented pomegranate extract（containing 10％ urolithin A） on vascular endothelial function. Methods　We conducted a placebo/controlled, randomized, double-blind, parallel-group study using 36 patients with impaired vascular endothelial function. They were divided to 3 groups, high dose group（50 mg/day of urolithin A）, low dose group（10 mg/day）and placebo group for 12 weeks. Vascular endothelial function was evaluated by measuring flow-mediated dilation（FMD）. In addition, a blood test was conducted to examine safety. Results The low dose group showed a tendency to improve vascular endothelial function 8 weeks after ingestion（P＝0.078）. In addition, no safety problems were observed with the intake of supplement containing urolithin A for 12 weeks. Conclusion These results suggested that ingestion of urolithin A 10 mg╱day is expected to improve vascular endothelial function and that it is safe after 12 weeks of ingestion. （UMIN-CTR ID: UMIN000042014）

Objectives　The constipation improving effect of jelly containing yuzu juice and β-glucan was evaluated in healthy subjects with a constipation tendency. Methods　A jelly containing 5 g of yuzu juice and 20 mg of β-1,3-1,6-glucan per packet（18 g）was ingested for 3 months. Group 1 ingested one packet of jelly per day while group 2 ingested two packets of jelly per day. The Japanese version of the Constipation Assessment Scale（CAS）and the Bristol stool form scale（BSFS）of stool property score were used to evaluate the improvement of constipation. Doctorʼs diagnosis, blood pressure measurements, and blood tests were performed before, 1 month, and 3 months after the start of jelly intake. Results　CAS score decreased significantly in both groups after 1 month and 3 months compared to the value before ingestion. In addition, BSFS significantly increased in the group with normal stool cases. However, one month after the end of ingestion, both CAS and BSFS tended to return to their values before ingestion. Furthermore, no problem was found in the results of doctorʼs diagnosis, blood pressure, and blood tests after 1 month and 3 months. Conclusions　Jelly, which contains yuzu juice and β-glucan, was found to improve constipation, and the improvement was dependent on ingestion. In addition, results confirmed that there was no problem with safety during long-term ingestion. （UMIN-CTR ID：UMIN000027857）

Objectives　To investigate the effects of ubiquinol（reduced form of coenzyme Q10）on cognitive performance in healthy middle-aged and elderly individuals, a randomized, double-blinded, placebo-controlled trial was conducted. Methods　The 90 residents（20 men, 70 women, aged 50-83 years）of Niihama-city, Ehime prefecture were randomized into Ubiquinol group（n＝45）and Placebo group（n＝45）. The participants of Ubiquinol group consumed soft capsules including 100 mg ubiquinol after meal for 34 weeks, whereas Placebo group consumed placebo capsules for 34 weeks. At baseline and after 28 weeks, Memory Performance Index （MPI）was evaluated. At baseline and after 34 weeks, Trail Making Test（TMT）and Digit Symbol Substitution Test（DSST）were conducted. Results　In MPI score, TMT times, and DSST score, significant differences were not observed between the two groups. However, regarding the rate of improved participants, Ubiquinol group （62.2％）showed high tendency compared to Placebo group（44.4％）（P＝0.09）. In addition, within the participants who were diagnosed “normal” in MPI score at baseline, the improved rate of Ubiquinol group（62.8％）was higher than Placebo group（41.0％）significantly（P＝0.049）. Further, in Per-protocol analysis, TMT-A time of Ubiquinol group after 34 weeks was significantly faster than that of Placebo group（P＝0.0498）. Conclusions　The present study indicated that ubiquinol intake could improve memory, attentiveness, and work processing ability in healthy middle-aged and elderly residents. （UMIN000038014）

Objective　This randomized, double-blinded, placebo-controlled, parallel-group study was conducted to evaluate the effect of food containing pine bark extract on platelet aggregation. Methods　Sixty healthy participants were enrolled in this study and were randomly assigned into two groups: the test food group and placebo group. The participants consumed either the test food containing pine bark extract（PBE）or food not containing pine bark extract（placebo） for 12 weeks. Platelet aggregation with 2.0μM ADP（primary outcome）was evaluated by light transmission aggregometry, which was performed before ingestion and at 8 and 12 weeks after ingestion. Results　In the PBE group, the maximal ％ aggregation and the ％ aggregation at the end of the monitoring period were reduced significantly compared with those in the placebo group（P＜0.05）. During the study period, no adverse events attributable to the test foods were observed. Conclusions　Ingestion of food containing pine bark extract could result in reduced platelet aggregation.（UMIN-CTR ID: UMIN000042940）

This randomized, double-blind, placebo-controlled, parallel-group study was conducted in healthy men and women between the ages of 20 and 64 years old who were aware of dryness and sagging of the skin on their whole body. They ingested Trapa japonica and tomato extracts for 12 consecutive weeks. The specific aim was to confirm improvement of barrier function caused by improvement of skin moisture using skin transepidermal water loss as an index, effects on skin color measured by colorimeter and skin image analysis, and effects of anti-glycation, anti-carbonylation, and anti-oxidation using AGEs and glycoxidants as indices. Skin moisture and skin barrier function was improved by decrease of skin transepidermal water loss, and skin color measured by colorimeter and skin image analysis was improved. Also, anti-glycation and anti-carbonylation effects were observed by decrease of pentosidine, a glycation and arbonylation reactive substance. In terms of safety, no adverse reactions or adverse events were observed during the study period. These results indicate that intake of supplements containing Trapa bispinosa Roxb. and tomato extracts can be expected to improve skin color, skin barrier function, and skin moisture through their anti-glycation and anti-carbonylation effects. （UMIN ID: UMIN000042220）

Objectives　It is said that the number of chews of modern people has decreased significantly compared to the past. In this study, we searched the number of chews in 10 g of local specialties or local foods of each prefecture in Japan for the purpose of raising awareness of mastication. Methods　10 subjects ingested 10 g of each test food and the number of chews was measured by video observation. Results　For all tested foods, the number of chews per mouthful was over 30, as recommended by the government. Conclusions　This study may help to raise awareness of the number of times people chew, thereby raising awareness of dietary education, and may also help to prevent oral frailty by using foods that increase chewing and chewing frequency in meals.（UMIN000044454）

関係はないようにみえる2 つのテーマですが，取り違えていると思われる投稿論文を目にしたので少し解説をします。どうみてもサブグループ解析だと思われるものを，PPS（per protocol set）解析と称していた例がありました。