薬理と治療

心理的安全性という概念は,1965 年に心理学者のベニスとシャインが初めて提唱した.以降,さまざまな研究者がこの概念に関する研究を行っているが,近年,もっとも有名な研究者の一人が,エイミ-・C・エドモンドソンである.エドモンドソンは,心理的安全性を集団やチ-ムの特性として再定義した.組織やチ-ムの心理的安全性は,リ-ダ-の影響を大きく受ける.本稿では,まず心理的安全性という概念と高める目的について論述する.次に心理的安全性を基盤とした新しい働き方を導くリ-ダ-に参考にしてもらうために,心理的安全性を高めるための仕組みや方法を提示する.

はじめに岡山大学病院(以下,当院)の治験実施体制を紹介する.当院は,治験を年間約280 件受託しており,治験推進部には22 名の院内CRC およびSMO 所属のCRC が在籍している.SMO 所属のCRCを除く院内CRCはCRC部門長も含めて3 チ-ムに分かれ,各チ-ムにはチ-ムリ-ダ-が1 名配置されている.チ-ムリ-ダ-の任期は1 年であり,毎年新たなリ-ダ-が部門長より指名される.チ-ムリ-ダ-の役割はおもに,①チ-ムメンバ-の状況把握,欠勤者の業務の配分,②新規治験の担当決めの取りまとめ,③必要に応じてチ-ムメンバ-のサポ-トやその他のメンバ-へサポ-トを依頼するなどである.リ-ダ-は組織やチ-ムを円滑に動かすために必要な存在である.筆者は,看護師としてもCRC としても,リ-ダ-という役割をこれまで担ってきた経験がなかった.本稿では,そんな筆者が,チ-ムリ-ダ-に任命された1 年を振り返り,リ-ダ-のあるべき姿や理想とされるリ-ダ-像とは何か,リ-ダ-として「やるべきこと」と「気を付けること」の答えを自分のなかで模索し試行錯誤した経験を紹介する.

職場におけるコンフリクトは避けられない現象ではあるが,しばしば厄介で避けたいものとみなされがちである.とくにリ-ダ-にとって,その対応が組織全体の雰囲気や生産性に直結するため,非常に重要な課題の一つである.臨床試験を実施する医療機関内で,多職種を巻き込み全体をコ-ディネ-トする専門家であるCRC は,日常的に直面することが多い.これらのコンフリクトは,一見するとネガティブなものであるが,適切に対処することで職場環境を改善し,組織の成長につながることがある.本稿では,職場でのコンフリクトの種類とその影響,リ-ダ-の役割について考察し,コンフリクトが適切に管理されれば組織の成長や改善に寄与する可能性があることを論じる.

The “drug loss” issue has been attracting attention in Japan. The Ministry of Health, Labour and Welfare defines drug loss as “drug lag” refers to events that are approved in the United States and Europe but not in Japan, and “drug loss” refers to events in which development has not begun in Japan. There were noticeable delays in dealing with emerging fields such as biopharmaceuticals and gene therapy drugs. This has led to further discussion as a social issue. Measures to eliminate drug losses are being actively discussed in various collegial bodies. On the regulatory front, eliminating drug losses and providing rapid access to innovative new drugs is a central goal. Since 2004, we have been studying compassionate use( CU) of unapproved drugs. The goal of CU is to allow exceptional access to promising unapproved drugs for patients who cannot wait for approval due to life-threating diseases. It is a public system that began in the United States and in Europe in the 1980s. There is a common denominator between the goal of CU and achieving rapid access to innovative drugs. Efforts to turn CU’s goal into reality have been ongoing globally and are yielding positive results. We believe that the lessons learned from these efforts will be useful for addressing the challenges of eliminating drug losses and realizing a system of rapid access to innovative new drugs. So far, CU has not been mentioned in the discussions of the collegial bodies. We hope that CU will be included in these discussions and that the experiences of CU will contribute meaningfully.

Background　Osteoarthritis(OA)is accepted to be the common chronic joint disorder in older individuals. Aging and obesity are recognized to be the important triggers of joint pathological changes, which are mainly mediated by inflammatory factors, especially adiponectin, secreted from adipocytes in white adipose tissues. Long–term treatment with glucosamine hydrochloride(GH)and chondroitin sulfate, classified into symptomatic slow–acting drugs for OA(SYSADOA), favorably modifies the clinical conditions of OA. However, the therapeutic mode of action of SYSADOA is still unclear. Therefore, this study was carried out to examine the effect of GH on adiponectin production from adipocytes in vitro. Materials and Methods　Adipocytes from mouse 3T3–L1 cell line were cultured in the presence or absence of GH. The adiponectin concentrations in the 24 h–culture supernatants were measured by ELISA. The influence of GH on transcription factor, Akt, activation and gene expression level of adiponectin in adipocytes cultured for 24 h were assessed by ELISA and real time RT–PCR, respectively. Results　GH inhibits the ability of adipocytes to produce adiponectin through the suppression of Akt phosphorylation and mRNA expression for adiponectin. The minimum concentration of GH causing statistically significant inhibition was 1.0μg/mL. Conclusions　The present results suggest that glucosamine may have some, albeit partial, effect on the pathogenesis of OA via suppression of adiponectin production.(Jpn Pharmacol Ther 2024;52:1303‒10)

Background　Taste disturbances experienced by patients with cancer undergoing anticancer drug therapy can reduce quality of life and hinder treatment continuation, but the underlying mechanisms remain unclear. In this study, we conducted a pathological examination using rats to elucidate the mechanism of taste disturbances experienced with the oral multi–kinase inhibitor drug sunitinib, which has frequently been associated with taste disturbances in clinical practice. Methods　Wistar rats were divided into sunitinib groups(1 mg/kg, 5 mg/kg, 10 mg/kg)and a control group. Taste disturbances were confirmed using the two–bottle preference test (TBPT). Tissue sections including fungiform papillae of the rat tongue were prepared and examined using immunostaining and hematoxylin–eosin staining. Results　At the third week of the TBPT, the quinine water drinking rate was significantly higher in the sunitinib 5 mg/kg and 10 mg/kg groups. The number of unclear taste buds was significantly higher in the sunitinib 10 mg/kg group than in the control group. Conclusions　In a rat model of sunitinib administration, taste disturbances may manifest in over a concentration 5 mg/kg, and in over 3weeks, with observed unclear taste buds as a potential mechanism. Further investigations are needed to explore this phenomenon in more detail.(Jpn Pharmacol Ther 2024;52:1311‒7)

Objective　Ergothioneine is a hydrophilic amino acid that is abundantly contained in mushrooms, and reported to have an antioxidant effect, a neurogenic effect, and a memory improvement effect. The purpose of this study is to evaluate the effect of ergothioneine on stress in humans. Methods　We conducted a randomized, placebo–controlled, double–blind, parallel–group study for 52 healthy individuals who experience stress on a daily basis and feel physical discomfort( not chronic or disease–related), such as sleep quality and fatigue(27 men and 25 women). Subjects consumed either a drink containing 5 mg ergothioneine as the test food(provided by LS Corporation Co., Ltd.)or a drink not containing ergothioneine as the placebo. Stress responses after mental load and during daily life were evaluated before, 4 and 8 weeks after consumption of the test food. Results　The stress effects of ergothioneine ingestion after mental load were significantly improved compared to placebo in POMS2(anger–hostility, friendship)after 8 weeks and in POMS2(vitality–energy)after 4 weeks. In addition, ergothioneine intake significantly improved OSA–MA(Sleepiness on rising)at week 4 as an anti–stress effect during daily life compared to the placebo group. No adverse events attributable to the test food were observed in any subjects during the study. Conclusion　These results indicate that continuous intake of ergothioneine has an anti–stress effect on stressed healthy subjects.(UMIN000049989)(Jpn Pharmacol Ther 2024;52:1319‒35)

Objective　AQUASOLITA® Jelly(AQSJ)is a jelly–like liquid derived from AQUASOLITA® solution(AQS), formulated to aid in water and electrolyte replenishment during dehydration. Both AQSJ and AQS have identical concentrations of key ingredients such as Na, K, Cl, and glucose. This study evaluated the clinical equivalence of AQSJ and AQS for water and electrolyte replenishment in healthy adult men with sauna–induced dehydration. Method　A randomized, crossover comparison study was conducted with 30 healthy men. Participants stayed in a dry sauna for 10–minute periods. After three sauna sessions and a 30–minute rest, they ingested an amount of AQSJ or AQS equivalent to their weight loss due to dehydration. Measurements of fractional excretion of Na(FENa), body weight, serum and urinary electrolyte concentrations, hematological parameters, and blood chemistry values were taken before sauna bathing and up to 240 minutes after consuming AQSJ or AQS. Equivalence was determined if the 90% confidence interval(CI)for the estimated mean value ratio of the two groups was within 80% to 125%. Result　Participants showed mild dehydration after sauna bathing. The peak value of FENa, serum electrolyte concentrations, hematological parameters, and blood chemistry values were considered equivalent for the two groups, although FENa and urinary electrolyte concentrations at each timepoint were not considered equivalent due to different water absorption rates by the different forms. Conclusion　Although the water absorption of AQSJ was slightly slower than that of AQS, the effectiveness of water and electrolyte replenishment by AQSJ and AQS was clinically equivalent in healthy adults with sauna–induced dehydration. (UMIN ID: UMIN000054163)(Jpn Pharmacol Ther 2024;52:1337‒53)

Objective　This study was performed to examine the effects of foods containing apple pectin on defecation frequency and the skin environment in healthy adults. Methods　This randomized, double–blind, placebo–controlled, parallel–group study involved 38 healthy men and women in their 20s. The participants were randomly assigned to either a placebo group or a pectin group. The study consisted of a 2–week pre–test period followed by a 4–week test diet intake period. The participants recorded their daily bowel movements, and stool samples and skin conditions were assessed before and after the test diet period. Results　After 4 weeks of continuous study diet intake, the pectin group showed a significant increase in the frequency of defecation and improved satisfaction with bowel movements based on the defecation status records. Additionally, the skin condition measurements showed a significant improvement in the stratum corneum moisture score. No adverse events related to the study diet were reported. Conclusions　These results suggest that consuming pectin–containing foods over time can increase the frequency of defecation, improve satisfaction with bowel movements, and enhance skin moisture levels.(UMIN–ID: UMIN000051306)(Jpn Pharmacol Ther 2024;52:1355‒64)

Objective　In this study, we examined the variation in postprandial blood glucose(PBG)levels after consumption of white rice cooked in a carbohydrate–cut rice cooker. Methods　Twenty–four Japanese men and women without disease were included in the study. They were randomly assigned to the rice–cooker–cooked–first group and the conventional–cooked–first group(n=12 each). In each period, the subjects received a single intake of white rice(150 g)cooked in either a carbohydrate–cut rice dish or a normal rice dish. Blood glucose, blood insulin, and blood triglycerides were measured before, 30, 60, 90, and 120 minutes after consumption of white rice, and the corresponding rice cooker–cooked group was compared with the conventionally cooked group. Results　The area under the blood glucose curve(iAUC)was lower in the rice cooker group than in the conventionally cooked group in 23 subjects, excluding 1 subject whose blood glucose level after food intake was at the diabetic threshold. In the subgroup analysis, iAUC was significantly lower in the rice cooker group than in the conventionally cooked group. Under the conditions of the study, there were no safety issues with the test foods. The post–meal questionnaire showed no significant differences in sleepiness, taste, consistency, texture, or satiety between the two groups. Conclusion　White rice cooked with carbohydrate–cut rice was not found to suppress the increase in postprandial blood glucose levels, but it was suggested that it may be effective in suppressing the increase in postprandial blood glucose levels for those with normal fasting blood glucose levels.(UMIN ID:UMIN000050004)(Jpn Pharmacol Ther 2024;52:1365‒74)

Objectives　A randomized, double–blind, placebo–controlled, parallel–group study was conducted to evaluate the impact of foods containing Garcinia indica extract on body fat in healthy participants. Methods　One hundred healthy participants(25≤body mass index[BMI]<30)were enrolled and randomly divided into two groups: the test food group, which consumed food containing G. indica extract(18.0 mg/day of garcinol)for 12 weeks, and the placebo group, which consumed food without G. indica extract for the same duration. The primary outcome, visceral fat area, along with secondary outcomes including subcutaneous fat area, total fat area, body weight, BMI, body fat percentage, body fat mass, waist circumference, and a questionnaire on bodily sensations, were evaluated. Results　The test food group showed a statistical significance in visceral fat area, total fat area, body weight, body mass index(BMI), body fat percentage, and body fat mass(P<0.05)compared to the placebo group. No adverse events attributable to the test foods were observed during the study period. Conclusions　Overall, these findings indicate that foods containing G. indica extract exert an anti–obesity effect in healthy participants(25≤BMI<30).(UMIN–CTR ID: UMIN000053493)(Jpn Pharmacol Ther 2024;52:1375‒83)

Objectives　We conducted a randomized, double–blind, placebo–controlled, 12–week continuous intake study and an excessive intake open study to confirm the safety of food containing Levilactobacillus brevis subsp. coagulans FERM BP–4693(Labre®). Methods　In the 12–week intake study, 40 healthy Japanese females ingested one capsule of the test food containing 100 billion cells of Labre® or one capsule of placebo daily for 12 weeks. In the excessive intake study, 20 healthy Japanese volunteers(10 males and 10 females), including 6 subjects prone to constipation, ingested 5 capsules of Labre® per day for 4 weeks. Safety observation then continued for another 2 weeks. Results　In the 12–week intake study, there were some significant differences in the measured values of physical examinations and blood tests at the 8th and 12th week visits compared to the values at screening for both groups. Although some significant differences were found, these values were within the facilityʼs normal ranges and were judged by the investigator not to be medically meaningful changes. In the excessive intake study, no changes in physical examinations, blood data, and so on that would raise safety concerns were observed. Although minor adverse events were observed in both studies, the food containing Labre® could be continuously consumed without any problems. It was shown that there were no safety issues. Conclusion　No obvious safety concerns were found when taking Labre® daily for a long period of time(12 weeks)at the recommended daily dose of 100 billion cells, or for excessive consumption at 5 times the recommended daily dose for 4 weeks.(UMIN–CTR:UMIN000052449, UMIN000052722)(Jpn Pharmacol Ther 2024;52:1385‒98)

じつはクロスセクショナル研究なのに,ケ-スコントロ-ル研究と誤っている人がいることに気づいたので,その違いを整理したいと思います.臨床研究でケ-スコントロ-ル研究はほとんどありません.その多くは疫学研究です.目的は病因(Etiology),すなわち疾病の原因(危険因子,Risk factors)を明らかにすることです.副作用の原因を見つけるための疫学研究でも,ケ-スコントロ-ル研究はよく使われます.記憶に新しいところでは,タミフルTM と小児異常行動の因果関係について,ケ-スコントロ-ル研究が実施されました.