薬理と治療

岡山大学病院（以下，当院）新医療研究開発センター 治験推進部（以下，当部）では，新型コロナウイルス感染症（以下，COVID-19）の感染拡大を契機に，リモートアクセスモニタリングの環境を整備した。当院では医療情報部との協議のもと，web カメラを利用してオンライン会議により原資料を閲覧する方式（web タイプ）を採用し，2020 年6 月から運用を開始している。今回，web タイプを導入した当院の運用を紹介するとともに， 2 年間の運用経験をふまえ，医療機関が感じるweb タイプのメリット・デメリットやリモートアクセスモニタリングの効果的な活用法について考察する。

Genistein（GEN）, a phytoestrogen found in leguminous plants such as soya bean may regulate ERK1/2/BDNF/TrkB signaling. For checking the same, primary cultures of cerebral cortices were prepared from embryonic day 18（E18）rats. Thereafter, neuronal culture cells（NCs） were placed into four group; Control NCs, GEN–treated NCs, K252a–treated NCs and K252a＋GEN–treated NCs（first TrkB activity was blocked with K252a and then GEN–treatment was done. After confirming condition of neurons, immunoblotting was performed to observe the expression of ERK1/2, BDNF and TrkB. In immunoblotting, expression of ERK1/2, mature form of BDNF（mBDNF）was high in GEN–treated NCs as compared to control, K252a–treated and K252a＋GEN–treated NCs. Further, expression of ERK1/2, mBDNF was high in K252a＋GEN–treated NC as compared to control and K252a group. The expression of full length TrkB（flTrkB）was high in K252a–treated NCs, K252a＋GEN–treated NCs and low in GEN–treated NCs as compared to other groups. Further, K252a did not block the GEN–induced increased expression of ERK1/2 and only minimally affect the expression of mBDNF expression. The exact possible mechanism of the above cascade is unknown. Such study is helpful to understand GEN–mediated enhancement in learning and memory through BDNF/TrkB/ERK1/2 or alternative signaling pathway.（Jpn Pharmacol Ther 2023；51：991‒1000）

In this study, we investigated the effects of persimmon fruit polyphenols for intoxication attenuation. In an animal test, oral administration of persimmon polyphenols（500 mg/kg）significantly suppressed blood alcohol concentration compared to the Control group（P＜0.01）. In a human trial, the polyphenol group ingesting 200 mg of persimmon polyphenols significantly suppressed the breath alcohol concentration compared to the placebo group（P＜0.05）. With flicker value evaluation, the flicker value was significantly reduced in the polyphenol group compared to that in the placebo group（P＜0.05）, suggesting intoxication attenuation. In addition, the degree of intoxication measured, as determined by using the Uchida–Kraepelin performance test, showed a downward trend（P＝0.06）in the polyphenol group compared to that in the placebo group. Furthermore, regarding subjective symptoms, the polyphenol group showed significant improvement in“tiredness”and“upset stomach”（P＜0.05）, as well as improved “drowsiness”（P＝0.06）.　　Conclusively, we posit that the intake of persimmon polyphenols reduced the degree of intoxication.（Jpn Pharmacol Ther 2023；51：1001‒11）

Objective　This study investigated the effects of consuming food product containing Krill Oil SUPERBA BoostTM for 12 weeks on skin function in healthy Japanese adults with normal to slightly dry skin（Transepidermal water loss; TEWL 15–30 g/m2/h）. Methods　The test product contained 70 mg docosahexaenoic acid and 150 mg eicosapentaenoic acid derived from Krill oil per capsule while the placebo contained vegetable oil. Participants were instructed to take 2 capsules of either test product or placebo per day. They were randomly assigned to either Krill oil or placebo group using a computer–generated randomization list, with stratified block random assignment using age（＜40 or ≥40）as the adjustment factor. Evaluation items included TEWL（the primary outcome）, elasticity and moisture content of skin on the inner right forearm, Omega–3 index, and facial microscopic observation. The evaluation time points were pre–intervention（0 w）, 6 weeks and 12 weeks post–intervention（6 w and 12 w）.Results　Two participants dropped out after allocation, and Intention To Treat（ITT）was used as the final dataset（26 in the Krill oil group and 28 in the placebo group）. The change of TEWL from 0 w to 12 w, the primary outcome of this study, was significantly lower in the Krill oil group compared to the placebo group. In addition, the lower eyelid pore size at 12 w was significantly improved in the Krill oil group, compared to the placebo group. Furthermore, the Omega–3 Index was significantly higher in the Krill oil group, compared to the placebo group at 6 w and 12 w, as well as all changes from 0 w. Conclusions　Consumption of food product containing Krill Oil SUPERBA BoostTM for 12 weeks significantly decreased TEWL, suggesting its ability to maintain skin function. Trial registration　UMIN000045734 Funding　AKER BIOMARINE ANTARCTIC AS（Jpn Pharmacol Ther 2023；51：1013‒29）

Recently, the “gut–brain axis”, the interaction between the gastrointestinal tract and the nervous system has been clarified. Thus, prebiotics may affect the nervous system via the gastrointestinal tract. Therefore, the aim of this study was to examine the effects of inulin, a type of prebiotic, especially Fuji FF, which is produced from sugar using the enzyme, on sleep, stress, and mucosal immune function, which is related to sleep and stress. The study was conducted in a randomized, double–blind, placebo–controlled, parallel–group trial（UMIN–CTR ID: UMIN000045370）. Eighty healthy participants who had a poor quality of sleep and a constipation tendency consumed 5 g of Fuji FF or maltodextrin（placebo）each day for 6 weeks. Sleep quality was assessed by the Pittsburgh sleep quality index（PSQI）. The intensity of daily stress was assessed by a stress questionnaire. Mucosal immune function was assessed by salivary sIgA secretion rate. Fuji FF significantly improved Sleep quality, Sleep disturbances, Daytime dysfunction, and PSQI total score compared to Placebo. Fuji FF also significantly reduced the number of days of severe stress compared to Placebo. On the other hand, the rate of secretion of sIgA increased in the inulin compared to Placebo but did not change significantly. The present study indicated that inulin intake was shown to improve sleep quality and mitigate stress.（Jpn Pharmacol Ther 2023；51：1031‒9）

Objectives　This study aimed to verify that the effect on serum LDL cholesterol amd non–HDL choresuterol level of the quercetin–tri–glycoside–A–rich green tea extract intake. Methods　A randomized, double–blind, placebo–controlled, parallel–group study was conducted in 40 participants（Age 20–65, the LDL cholesterol levels were between 120 mg/dL and 139 mg/dL）. Participants were randomly assigned to receive either the test product or placebo daily for 12 weeks. Daily intake of the test product contained quercetin–rich green tea extract. The primary outcome measure was the change from baseline of serum LDL cholesterol（Friedewald Equation）levels and the secondary outcome measures were total cholenterol, non–HDL cholesterol, serum triglyceride, waist circumference, body fat percentage, blood sugar and blood pressure. Results　In analysis of total evaluable population, there was no significant change in primaly and secondary outcomes between test product group and placebo group. However, analysis of non–HDL cholesterol levels were under 150 mg/dL participants revealed that significant decrease of non–HDL cholesterol in the test product group compared with the placebo group. Conclusions　The result suggested that ingestion of the quercetin–tri–glycoside A from green tea leaf improves non–HDL cholesterol levels in healthy adults whose non–HDL cholesterol level is within standard.（UMIN ID: UMIN000040740）（Jpn Pharmacol Ther 2023；51：1041‒52）

Objectives　We conducted a randomized, double–blind, placebo–controlled, parallel–group trial to evaluate the effects of young barley leaf powder which can improve the gut microbiota, on general health conditions, such as secretion rate of salivary secretory immunoglobulin A （sIgA）, physical health, and stratum corneum water content. Methods　We selected 38 healthy adults and randomly assigned them into two groups: test food group（which consumed 1.17 g young barley leaf powder every day as dietary fiber）and placebo group（which did not consume young barley leaf powder）for four weeks. The primary outcome of the trial was salivary sIgA secretion rate and the secondary outcomes were evaluation of participantsʼ physical conditions based on a questionnaire survey and stratum corneumʼs water content. Results　The test food group had a significant increase in the secretion rate of salivary sIgA and stratum corneum water content（P＜0.01, P＜0.05, respectively）compared to the placebo group. Additionally, the test food group had a significantly lower cumulative incidence of cold–like symptoms（P＜0.05）. No adverse events attributable to the test food were observed during the study period. Conclusions　These findings indicate that young barley leaf powder affects the secretion rate of salivary sIgA, onset of cold–like symptoms, and stratum corneum water content in healthy subjects. （UMIN–CTR ID: UMIN000043386）（Jpn Pharmacol Ther 2023；51：1053‒60）

Objective　The objective of this study was to examine the effects of continuous consumption of a beverage made from black soybean seeds on mood and sentiment state in healthy Japanese women. Method　This randomized, double–blind, placebo–controlled parallel study included 24 healthy volunteers（n＝24）who consumed either a placebo or test beverage made from black soybean seeds for six weeks. Participantsʼ subjective mood（fatigue）was evaluated using the visual analogue scale（VAS）, and the profile of mood states questionnaire（POMS）and stress arousal checklist（J–SACL）were administered. The stress states, such as α–amylase activities and peripheral blood flow, were also measured. Results　The elevation of mood state score on total mood disturbance（TMD, POMS）was significantly improved after six weeks of consuming the test beverage compared to the placebo （P＝0.04）. The scores of anger–hostility（AH）and depression–dejection（DD）were significantly lower compared to the placebo（AH, P＝0.01; DD, P＝0.03）. In addition, feeling of vitality score（SACL）in the test beverage group was higher than that in the placebo group（test group, 11; placebo group, 6, P＝0.07）. Conclusions　Continuous consumption of the beverage made from black soybean seeds has been shown to improve mood states and lead to better mental health. （UMIN ID: UMIN000044948）（Jpn Pharmacol Ther 2023；51：1061‒70）

Activation of the mineralocorticoid receptor（MR）is involved in the pathogenesis of hypertension, cardiovascular（CV）disease and diabetic kidney disease（DKD）. Inhibition of MR overactivation with MR antagonist（MRA; Aldosterone antagonist）is, therefore, anticipated to provide cardio–renal protection. 　　Over the past decades, the RALES, EPHESUS and EMPHASIS–HF trials have provided evidence of the beneficial effects of steroidal MRAs, spironolactone and eplerenone, on CV events. Recently, a study of a newly–developed non–steroidal MRA, esaxerenone, showed that it lowered blood pressure（BP）in the ESAX–HTN and improved albuminuria in the ESAX–DKD. More recently, the FOGARO–DKD and FIDELIO–DKD studies with another non–steroidal MRA, finerenone, have shown renoprotective effects, thereby newly extending its clinical indication to DKD. 　　The mechanisms by which MRAs exert cardio–renal protection are diverse and include blood pressure lowering, natriuresis, cardioprotection and inhibition of renal fibrosis/inflammation in the heart and kidney. In addition, intraglomerular hypertension in CKD could be optimized by MRA via the tubuloglomerular feedback system（TGF）. 　　In this narrative review, we discuss how to incorporate these new MRAs into our daily clinical practice, gaining a new insight into the pathogenesis of MR–related hypertension and DKD.（Jpn Pharmacol Ther 2023；51：1071‒87）

The improvement effect of asperuloside, one of main active components in Eucommia leaf extract, on dextran sodium sulfate–induced ulcerative colitis in mice was reported. However, this mechanism of the improvement remains unclear. 　　Asperuloside hydrolyzate inhibits the bile acid transporter in the ileum. As a result, it has been shown that the bile acid pool in the gut increases and alters the intestinal gut bacteria flora. It has also been reported that the intestinal gut bacteria produces short–chain fatty acids such as butyric acid and acetic acid etc from the dietary fiber. 　　Recent research has demonstrated that butyric acid in the colon acts on naive T cells to promote the differentiation into Treg cells. The increase of the Treg cells by butyric acid improved the symptoms of mice suffering from colitis. From these findings, it was suggested that the mechanism of the improvement effect of asperuloside in Eucommia leaf extract on ulcerative colitis in mice might depend on the increase of the Treg cells due to butyric acid produced by the intestinal gut bacteria, Akkermansia muciniphila. （Jpn Pharmacol Ther 2023；51：1089‒91）