薬理と治療

目的： 患者報告アウトカム尺度（patient reported outcome measure: PROM）のシステマティックレビューは，介入試験や診断検査の精度研究のレビューとは異なり複雑である。実際，1つ以上のPROMのレビューの実施は複数のレビュー（各PROM の各測定特性につき1 回のレビュー）からなる。測定特性のレビューのために特化して設計されたガイダンスがないことから，われわれの目的はPROM のシステマティックレビュー実施のためのガイドラインを開発することであった。方法：文献レビューおよび専門家の見解に基づき，既存のガイドラインに従いCOnsensus-based Standards for the selection of health Measurement INstruments（COSMIN）運営委員会はPROM のシステマティックレビューのためのガイドラインを開発した。結果：PROM のシステマティックレビューを実施するための連続的な10 ステップによる手順を提案する。ステップ1 ～ 4 は文献検索の準備および実施，ならびに関連研究の選択に関するものである。ステップ5 ～ 8は適格な研究の質，測定特性，解釈可能性および実行可能性の評価に関するものである。ステップ9 および10は推奨の定式化およびシステマティックレビューの報告に関するものである。結論：PROM のシステマティックレビューのためのCOSMIN ガイドラインは，測定特性に関する研究の方法論的質をPROM 自体の質（すなわち，その測定特性）と結び付ける方法論を含む。これにより，レビュアーが透明性のある結論を導き出し，PROM の品質に関するエビデンスに基づく推奨を行うことが可能となり，研究および臨床診療で用いるためのPROM のエビデンスに基づく選択をサポートする。

Background　Kuromoji（Lindera umbellata Thunb.）is a fragrant deciduous shrub belong to the Lauraceae family. Previous studies have shown that the hot water extract of Kuromoji has antiviral activity that inhibits the adsorption and invasion in infection of influenza virus. Methods　A macromolecular compound–containing fraction was obtained using a dialysis membrane with 3.5 kDa molecular weight cut–off from the aqueous ethanol–soluble fraction of the hot water extract of Kuromoji. Molecular weight of the components in the fraction was estimated by gel filtration HPLC and molecular structure was analyzed by acid hydrolysis and phloroglucinol degradation. Antiviral activity was evaluated using Madin–Darby canine kidney （MDCK）cells and an influenza virus infection. Viral infection was visualized by immunofluorescence staining for the virus nucleocapsid protein（NP）. To clarify the working point of the fraction, the amount of viral RNA in MDCK cells in time–of–addition analysis was quantified by real–time PCR. Results　Gel filtration HPLC showed that the peak molecular weight of the fraction was 8.7×103 Da. Phloroglucinol degradation generated that catechin and epicatechin. The fraction suppressed NP expression. The viral mRNA was significantly suppressed when the fraction was added simultaneously with virus infection. Conclusions　The macromolecular fraction of the hot water extract of Kuromoji is considered to be mainly composed of proanthocyanidins with catechin and epicatechin residues. This fraction showed antiviral activities that suppresses the expression viral NP and cytopathic effect shown by influenza virus. The suppressive effect is concluded to prevent the adsorption or entry of viruses into target cells. （Jpn Pharmacol Ther 2023；51：193‒201）

Objective　The efficacy of postprandial serum TG responses of the insoluble fraction from pulverized sesame seeds（LipiSmart®）was evaluated in rats. Furthermore, the mechanism of action of the insoluble fraction in the digestive tract was also investigated in vitro. Methods　After acclimation, the rats were randomly divided into two groups and fasted overnight prior to the High fat diet（HFD）challenge. The insoluble fraction was administrated at a dose of 45 mg/kg body weight using gastrostomy tubes 10 min prior to the administration of the HFD（0h）. Blood samples were collected from the tail vein at 0h, 1.5h, 3h, 4.5h, 6h and 7.5h. The bile acids and oleic acid and monoolein were mixed and homogenized for micellization. The purified insoluble fraction was added to the suspension of bile acid micelles and the supernatant（sup）was collected and lyophilized. After adsorption, oleic acids and monoolein in the sup were measured by LC–MS/MS. Results　Three hours after oral administration of HFD with/without insoluble fraction, the rats that received the insoluble fraction exhibited significantly reduced serum TG concentration compared to the vehicle group. After 4.5 hours, the postprandial serum TG concentration in the insoluble fraction group was still lower than that of the vehicle group. The insoluble fraction demonstrated significant adsorption ability for both micellized oleic acid and monoolein. Conclusion　The purified insoluble fraction was effective in suppressing the postprandial elevation of TG levels in rats following an oral fat load. Furthermore, insoluble fraction indicated high adsorption ability of oleic acid and Monoolein in vitro. （Jpn Pharmacol Ther 2023；51：203‒8）

Objective　The study investigated the effects of supplements include composite functional ingredients on obesity. Methods　A randomized, double–blind, placebo–controlled, parallel–group study was conducted. Healthy subjects aged 20 to 65 years with a body mass index of 23 to below 30, and without change in body weight for half a year were selected. They were randomly assigned into three groups, and ingested either supplement A, B or placebo. Result　The abdominal fat area, body weight, BMI and waist circumference were significantly reduced by ingestion of both supplements. Furthermore, both supplement improved gut microbiota. No adverse effects were observed in this study. Conclusion　Supplements containing multiple ingredients indicated anti–obesity effects on healthy overweight subjects whose body weight are difficult to change. （UMIN ID: UMIN000046535）（Jpn Pharmacol Ther 2023；51：209‒21）

Objectives　In this study, we reanalyzed the results of our previously reported paper to see if there were more useful odorant combinations that could test for cognitive decline. Methods　The resulting olfaction scores of 223 subjects were used for reanalysis, with changes in the number of odorant varieties and the allocation of each odorant component, to exploratory analysis of conditions for higher sensitivity and specificity. Results　Six odorants were selected: toothpaste, butter, India ink, apple, soap and Hinoki. When toothpaste was scored 2 points, butter 2 points, and India ink 3 points out of a total of 10 points, the sensitivity was 0.75, 0.85, 0.76, the specificity was 0.69, 0.99, 0.79, the AUC was 0.78, 0.97 and 0.84 for healthy control vs MCI groups, healthy control vs AD groups, and MCI vs AD groups, respectively. Conclusions　The combination of odorants found in this study may discriminate between healthy individuals and those with MCI or AD, thus facilitating early screening for cognitive decline among Japanese patients at high risk of cognitive decline and dementia.（UMIN ID: UMIN000041794）（Jpn Pharmacol Ther 2023；51：225‒33）

Objective　The purpose of this study was to verify the effect of propolis on lower urinary tract symptoms（LUTS）and clarify its mechanism of action. Method　This was an open–label study conducted on 26 healthy women with frequent urination. The participants took propolis–containing food daily for 8 weeks. Voiding and related items were assessed using voiding diaries and questionnaires（overactive bladder symptom score, nocturia–quality of life, Kings health questionnaire, visual analog scale questionnaire, Oguri–Shirakawa–Azumi sleep inventory MA Version sleep questionnaire）. The pharmacological action of propolis was verified using rat bladder smooth muscle model. An in vitro study verified the protective effect of propolis and propolis–containing components against oxidative stress. Results　The frequency of 24–h urination, urinary urgency, frequency of urinary incontinence, and urine volume were significantly decreased compared to before propolis–containing food administration. The volume per urination increased significantly, and the time from sleep onset to the first morning void was significantly longer. Furthermore, pharmacological evaluation revealed that propolis suppressed the contraction of rat bladder smooth muscle and showed protective effects against oxidative stress in cell assays. Conclusion　This study demonstrates that the continuous intake of propolis may mitigate LUTS. Inhibition of bladder smooth muscle contraction and protection against oxidative stress may improve bladder function. Trial resistration　UMIN–CTR: UMIN000046266 （Jpn Pharmacol Ther 2023；51：235‒47）

Objective　A randomized, double–blind, placebo–controlled, parallel–group study was conducted to determine the effect of food containing tea flower extract standardized for chakasaponin content on human body fat. Methods　Eighty–one disease–free male and female adults with a body mass index（BMI） between 23 and 30 were fed food with 100 mg of tea flower extract, food with 300 mg of tea flower extract, or control food without tea flower extract per day for 12 weeks. The measurements of body fat area（subcutaneous fat area and visceral fat area）by computed tomography scan, BMI, body fat percentage by the impedance method, waist circumference, and blood tests were obtained. Results　Five of 81 patients dropped out of the study because of personal reasons, and 76 patients completed the study. After reviewing the cases, all subjects who completed the study were included in the analysis. After 12 weeks of intake, the total fat area, visceral fat area, and subcutaneous fat area of the 100 and 300 mg tea flower extract groups significantly decreased compared with that of the placebo group. In addition, BMI and waist circumference were significantly reduced in the 100 and 300 mg tea flower extract groups compared with the placebo group. In terms of body fat percentage by the impedance method, the 100 mg tea flower extract group showed a significant decrease compared with the placebo group after 12 weeks of intake, and the 300 mg tea flower extract group showed a significant decrease compared with the placebo group after 8 and 12 weeks of intake. The 300 mg tea flower extract group showed a significant increase in adiponectin levels after 8 and 12 weeks of intake compared with the placebo group. Adiponectin significantly increased in the 100 and 300 mg tea flower extract groups after 12 weeks of intake compared with the placebo group. Conclusion　The results showed that food with tea flower extract was effective in reducing body fat and as a health–promoting food.（UMIN–CTR: UMIN000047267）（Jpn Pharmacol Ther 2023；51：249‒56）