薬理と治療

ICH E6 ガイドラインは，Guideline for Good Clinical Practice として1996 年に日米欧によって合意された「医薬品の臨床試験の実施の基準」である。本邦では，国内規制にICH E6 が取り入れられており，「医薬品の臨床試験の実施の基準に関する省令」および「「医薬品の臨床試験の実施に関する省令」のガイダンスについて」（以下，医薬品GCP ガイダンス）が制定されている。その後，リスクベースアプローチや技術革新への対応を目的としてICH E6（R2） が2016 年に合意された。さらに現在，臨床試験のデザインやデータソースの多様化に対応するためICH E6 （R3） として改定作業が進められている。ICH E6 改訂の背景，ICH E6 （R2） で導入されたリスクベースアプローチならびに品質マネジメントの考え方，および国内規制への実装について概説する。

「医療機関のQMS（Quality Management System，品質マネジメントシステム）」と盛んに言われるようになったのはここ3，4 年のことではないかと思われる。いま「QMS」と聞いて，何を思い感じるだろう。「なんかむずかしそう」「プロセスアプローチ，リスクアプローチ，PDCA，CAPA，英語ばかりでよくわからない」「もともと基本的な手順や流れは決めているし，逸脱の再発防止もちゃんと考えてるし……」「具体的に何をすればいいの？　何かしなきゃいけないんだろうけど」「これ以上仕事増やさないでほしい……」。現場で患者対応に当たっているCRC（臨床試験コーディネーター）の多くはこのような思いではなかろうか。否。むずかしく考える必要はまったくない。筆者が所属する国立がん研究センター東病院は2015 年に臨床研究中核病院，2017 年に特定機能病院の認証を受けている。全10 病棟のうち3 病棟は治験病棟であり，平均外来患者数1 日1200 名程度のうち治験患者数は外来約55 から65 名来院し，入院下では毎日約35 から40 名程度が治験治療を受けている。2020 年度の企業治験・医師主導治験の実施課題数は423 課題。いわゆるハイボリュームセンターである。これを言うとすぐに返ってくるのが「QMS は大規模施設で有効なアプローチなのでは？」「中核病院だからできるのでは？」「うちみたいな人数少ない組織じゃとても無理……」という言葉。これもまた否。2人以上いればそれは組織であり，QMS の原則さえ理解すれば，「品質のマネジメント」に組織の大小はまったく関係ない。それでは，臨床試験における「品質」とはなにか？　「品質をマネジメントする」とはどういうことか？　なぜ，それを取り入れる必要があるのか？　QMSを現場浸透させるためにものすごく大切なこと，これを外してしまったら確実にうまくいかないこととは何か？　本稿ではそれをQMS のシンプルな基本的原則に立ち返って考えていきたい。― WHY からはじめよう。

Background　Oropharyngeal candidiasis is an oral infectious disease caused by Candida bacteria, and the number of people susceptible to the infection is increasing due to the aging of society and the spread of advanced medical care in recent years. Thus, the importance of measures against oral candidiasis is increasing. The present study clarified the actual use of miconazole mucoadhesive tablets for oropharyngeal candidiasis at Fukuoka University Nishijin Hospital. Methods　We investigated the day 8 cure rate, the number of days required for improvement and medication adherence in inpatients who started miconazole mucoadhesive tablets（MCZ group）or amphotericin B syrup（AMPH-B group）for oropharyngeal candidiasis at our hospital from April 2019 to December 2021. Results　Twenty-one cases（MCZ group, 8 cases; AMPH-B group, 13 cases）were extracted during the survey period. The day 8 cure rate was 87.5％ in the MCZ group and 30.8％ in the AMPH-B group, which was significantly higher in the MCZ group（P＜0.05）. The number of days until improvement was 5.4±0.5 days in the MCZ group and 8.5±2.6 days in the AMPH-B group, which was significantly shorter in the MCZ group（P＜0.01）. In the MCZ group, where tablets were taken once daily, no patient was unable to comply with the dosage regimen. In the AMPH-B group, where syrup was taken two to four times a day, some patients were unable to comply with the dose regimen. Conclusions　Miconazole mucoadhesive tablets are considered effective for treating oral candidiasis by ensuring good medication adherence. （Jpn Pharmacol Ther 2022；50：977-82）

Background　Periostin is expressed in various kinds of cancer cells or surrounding tissue and is a factor that accelerates cancer metastasis. Our previous work reported that the herbal medicine juzentaihoto suppressed B16-F10 mouse melanoma cell lung metastasis. The study aims to examine the ability of mouse melanoma cells to secrete periostin, to ascertain the role of secreted periostin, and to determine whether periostin affects the suppression of cancer metastasis on juzentaihoto. Materials and Methods　C57BL╱6 male mice were intraperitoneally injected with B16-F10 mouse melanoma cells and given chow containing 1％ juzentaihoto. In subsequent in vivo experiments, we assessed tumor colony formation in the lung. Additionally, we determined if juzentaihoto suppressed cell migration. Results　Juzentaihoto significantly suppressed B16-F10 mouse melanoma cell metastasis and secretion of periostin in vivo and in vitro and B16-F10 mouse melanoma migration. Conclusions　These results suggested that periostin promoted B16-F10 mouse melanoma metastasis and showed that juzentaihoto suppressed periostin secretion and B16-F10 mouse melanoma metastasis. （Jpn Pharmacol Ther 2022；50：983‒91）

Background　The clinical symptoms of chronic fatigue syndrome（CFS）have been shown to include disorders in the neuroendocrine, autonomic, and immune systems. Cytokines produced in the brain play significant roles are known to develop central nervous system symptoms such as abnormally prolonged fatigue, pain, impaired thinking, depression, and sleep disturbance through neural-immune interactions. In Kampo, a traditional Japanese medicine, tonic formula herbal medicines called “hozai”, e.g. Juzentaihoto, has been traditionally used to treat against anemia, anorexia, particularly physical strength recovery for chronic disease, postoperatively, convalescents, aging or viral infections. 　Polyriboinosinic: polyribocytidylic acid（poly I: C）is frequently applied in immunologically fatigue animal experiments to mimic a condition of viral infection. Therefore, the purpose of this study was to examine the effect of juzentaihoto on an immunologically fatigue mouse model induced by intraperitoneal injection of poly I: C.Materials and Methods　5 weeks ages male ICR mice were randomly divided into four groups: control, poly I: C, juzentaihoto, and poly I: C＋juzentaihoto. Mice were administered juzentaihoto（1％）in their food（chow）. All mice were injected intraperitoneally on 2 alternate days（days 1 and 3）with vehicle（saline）or 20 mg╱kg poly I: C. Subsequently, the locomotor activity was measured once a day over 5 days. Furthermore, the expression of interleukin（IL）- 1β and IL-1 receptor antagonist（ra）mRNAs in the hypothalamus was measured using real-time polymerase chain reaction. Results　The results indicated a significantly increased locomotor activity and decreased mRNA expression of IL-1β in the juzentaihoto＋poly I: C groups compared with the hypothalamus of the poly I: C group. Conclusions　These results indicated that juzentaihoto reduced the poly I: C-induced physical momentum decrease, plausibly through the intracerebral anti-inflammatory effect of juzentaihoto. （Jpn Pharmacol Ther 2022；50：993‒1002）

Objectives　Duodenal low-grade inflammation has been implicated in the pathogenesis of functional dyspepsia（FD）. However, few studies have explored the therapeutic effects of drugs on duodenal low-grade inflammation. Effective treatment options for this condition have not yet been established. Therefore, this study aimed to investigate the effect of sucralfate on submucosal low-grade inflammation in a rat model of chronic stress-induced FD to determine whether mucosal protective agents would be a new treatment option. Methods　A suspension mixture containing 10％ sucralfate at 2 mL╱kg was administered to rats with FD once daily for 7 days. Occludin expression was quantified using Western blotting, and its localization was analyzed by immunostaining. Eosinophil infiltration was assessed by immunohistochemical staining with major basic protein as its identification marker. Results　Chronical stress caused persistent mucosal barrier disruption and duodenal low-grade inflammation in rats. Sucralfate restored not only occludin expression on the cell surface, which is responsible for mucosal barrier function, but also submucosal eosinophilic infiltration. Conclusions　These findings suggest that sucralfate may represent a helpful treatment for stress-induced chronic duodenal barrier disruption and low-grade inflammation. （Jpn Pharmacol Ther 2022；50：1003‒11）

Objectives　In humans, the antihypertensive effect of geniposidic acid via atrial natriuretic peptide（ANP）secretion is observed in Eucommia bark extract in which cyclic AMP phosphodiesterase（ cAMP-PDE）inhibitor coexists. On the other hand, the antihypertensive effect of geniposidic acid via ANP secretion is not observed in Eucommia leaf extract in which cAMP-PDE inhibitor does not coexist. 　For a long time（almost 20 years or more）, it has been believed that the antihypertensive effect of Eucommia leaf extract depends on the direct action of geniposidic acid to the parasymphasic nervous system, which results in the release of nitric oxide（NO）from the vascular endothelial cells, followed by the relaxation of vascular smooth muscle. However this mechanism is not correct since geniposidic acid does not act on the muscarinic acetylcholine receptor. 　The antihypertensive effect of Eucommia leaf extract in humans was considered from our previous and other reports. Methods　In order to determine the active ingredient in Eucommia leaf extract, each of the contents of iridoid compounds, phenolic compound and flavonoid compounds was measured by using the HPLC-UV method in the comparison with 85.0 mg of geniposidic acid（indicator component）in Eucommia leaf extract. Results　Geniposidic acid itself was also estimated to be the active ingredient showing the antihypertentive effect without the coexistence of cAMP-PDE inhibitor. Conclutions　Geniposidic acid is reported as a TNFα inhibitor. Therefore, it was suggested that the antihypertensive effect of the Eucommia leaf extract in humans might be dependent on the improvement of the vascular endothelial function by the suppression of the inflammation of blood vessels caused by TNFα. （Jpn Pharmacol Ther 2022；50：1013‒21）

Objectives　The aim of this study was to evaluate the effect of motor function after chewing gum. Methods　Eleven healthy subjects participated in a randomized, open, crossover trial. Subjects measured for motor function before and after ingestion of two grains xylitol gum or nothing on different day. Results　Grip strength and static balance before and after chewing gum increased significantly compared to no chewing but dynamic balance and vertical jump showed no change. Conclusions　In conclusion, chewing gum for 10 minutes before the measurement suggested improvement in maintaining grip strength and static balance. （UMIN 000045850）（Jpn Pharmacol Ther 2022；50：1023‒8）

Objectives　The purpose of this study was to verify that the food consisting of rice bran fermented product containing 3-（4-hydroxy-3-methoxyphenyl）propionic acid（HMPA）has theeffect of reducing visceral abdominal fat in healthy adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 90 healthy volunteers（Aged 20-64, BMI 23 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, physical measurement, and safety assessment. Abdominal visceral fat area was the primary outcome, and physical measurements, abdominal subcutaneous and total fat area, and blood parameters were the secondary outcomes. Results　Abdominal visceral fat area at 12 weeks was significantly lower in the test food group than in the placebo food group. Moreover, waist circumferences at 8 and 12 weeks were significantly lower in the test food group than in the placebo food group. Conclusion　The food consisting of rice bran fermented product containing HMPA reduced abdominal visceral fat area and waist circumference. This study findings indicate that the food consisting of rice bran ferment containing HMPA have an effect of reducing abdominal visceral fat in healthy men and is useful functional food for controlling visceral fat（. UMIN-CTR ID: UMIN000044727）（Jpn Pharmacol Ther 2022；50：1031‒40）

Objective　The purpose of this study was to investigate serum and saliva cytokine profiles of healthy subjects in the heat stress. Methods　An open-label, crossover study was conducted in healthy male adult subjects. The subjects were seated rest for 120 minutes in climate chamber（36℃, 50％ relative humidity）. Ten minutes after entering the climate chamber, the subjects ingested 7.5 g╱kg body mass of control beverage（28℃）or ice slurry（－5℃）for 25 minutes. Serum and saliva samples were collected before entering（Pre）and 15 minutes after leaving the climate chamber（Post）for analysis of 45 cytokines. Results　Serum TGF-α, CXCL8 and OSM were significantly increased, and IL-27, FLT3LG, IL-10, MMP-12 and IL-17C were significantly decreased in the Post as compared with the Prein the control beverage trial. In addition, TGF-α was also significantly increased in saliva. Whereas there were no significant changes in serum cytokines in the ice slurry trial. Conclusion　The findings suggest that the changes in cytokines due to heat stress might be vital as an early response to heat stroke and TGF-α may be a useful biomarker for heat stroke. （Jpn Pharmacol Ther 2022；50：1041‒8）

Objective　The purpose of this study was to evaluate the effects of continuous gum chewing on stress, autonomic nervous system, and immunity. Research methods　A total of 50 healthy subjects were enrolled, with 25 being allocated to the chewing gum group and 25 being allocated to the control group. The chewing gum group masticated gum 3 times daily for 2-weeks and there was no intervention in the control group. Subjects had their mood state（POMS Ⅱ）, autonomic indices, and salivary components measured before and after the intervention. Results　After the 2-week intervention period, the chewing gum group showed significantly improved Total Mood Disturbance, Confusion-Bewilderment and Vigor-Activity on POMS Ⅱ, and a significant increase in lnHF and a significant decrease in LF╱HF on the autonomic index compared with the control group. The chewing gum group also showed a significant increase in the concentration of the immune substance S-IgA in saliva. Conclusions　The results suggest that continuous gum chewing affects oral immune function by improving stress and autonomic function in healthy subjects. （ID: UMIN000045372）（Jpn Pharmacol Ther 2022；50：1049‒54）

Background　Nutrients found in food can have pronounced effects on skin health. Lacto-fermented foods have been reported to afford many benefits to the skin. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparison study in healthy Japanese individuals with generalized skin dryness, sagging skin, and skin irritation to investigate the effects of Lactobacillus gasseri strain N320（N320）-containing foods on skin conditions. Methods　Subjects consumed foods containing heat-sterilized N320 or containing a placebo for 8 weeks. Efficacy was assessed by skin measurements（transepidermal water loss（TEWL）, skin moisture, and in vivo three-dimensional wrinkle analysis）and physicianʼs finding scores. Results　The reduction in skin moisture on the leg was lower in the N320 group than in the placebo group at 8 weeks after intake. Four weeks after food intake, there was a lower increase in neck dryness and overall average wrinkle depth in the N320 group than in the placebo group. A stratified analysis of subjects with skin moisture transpiration values of 15 g╱h╱m2 or higher showed different trends. The reduction in skin moisture on the leg was lower in the N320 group than in the placebo group at 4 and 8 weeks after intake. The increase in the neck dryness was lower in the N320 group than in the placebo group at 4 weeks after intake. Overall, the increases in the percentages of wrinkled area, total wrinkle volume, and ISO standard surface roughness parameters were lower in the N320 group than in the placebo group at 8 weeks after intake. No side effects or adverse events arose from the intake of N320-containing food. Conclusions　Our results suggest that the intake of N320-containing food is safe and helps improve skin conditions（. UMIN000030349）（Jpn Pharmacol Ther 2022；50：1055‒64）

Objective　To examine the effects of foods containing broccoli extract（Brolico）on the immune function in healthy Japanese adults. Methods　In this randomized, placebo-controlled, double-blind, parallel-group comparison study, subjects were randomly assigned to the Brolico group or the placebo group using a computerized random number generator（n＝50 each）. Subjects took six tablets of Brolico or placebo at breakfast for 8 weeks. Evaluation items included common cold symptoms, immune function, and SF-36. Results　The efficacy analysis data were set as a per-protocol set for 47 subjects in the Brolico group and 49 in the placebo group because four subjects withdrew from the study for personal reasons in the intervention period. The primary outcome, the cumulative number of days of common cold symptoms per study subject during the study period was significantly lower in the Brolico group than in the placebo group. Furthermore, the number of total days and cumulative days of common cold symptoms per group during the study period and the ratio of cumulative days of common cold symptoms to total days were significantly lower in the Brolico group than in the placebo group. Moreover, the Brolico group showed significantly higher CD8＋CD28＋T-cell count scores in the immune function test compared with the placebo group, and the CD8＋CD28＋T-cell counts were marginally higher in the Brolico group than in the placebo group. The consumption of the test food had no significant adverse effects. Conclusions　These results revealed that Brolico consumption affects the immune function and reduces common cold symptoms in healthy Japanese adults. Trial registration　UMIN000044913 Foundation　Imagine Global Care Corp （Jpn Pharmacol Ther 2022；50：1065‒78）

Background　The fruit of sea buckthorn contains various nutrients and bioactive compounds. It has a long history used as a traditional medicine and the various effects to human health have been studied, such as anti-inflammatory, anticancer, antioxidant effects. However, its effects to the human immune functions have been still unclear. Methods　In this study, we performed a randomized, placebo-controlled, double-blind, parallel -group comparative study to evaluate the improvement of the immune functions by taking sea buckthorn fruit beverage for 4 weeks. Thirty-seven healthy subjects were allocated into two groups; 18 subjects in the test group took 60 mL sea buckthorn fruit beverage in a day and 19 subjects in the placebo group took same amount of the placebo juice. The changes in the immune functions of these subjects were examined by the blood and saliva tests, and health conditions, including cold symptoms, were evaluated by multiple questionnaires. Results　The blood test showed that the numbers of T helper cells increased statistically significantly only in the test group, and the activity of NK cells marginally increased after 4 weeks of the trial in the test group. The concentration of sIgA in saliva was also larger in test group than in the placebo group. Several questionnaires suggested that the intake of the sea buckthorn beverage reduced fatigue and shorted the duration of cold symptoms. Conclusion　These results suggest that the regular intake of the sea buckthorn fruit beverage can enhance both innate and acquired immunities, and contribute greatly to our healthy life. （UMIN ID: UMIN000043112）（Jpn Pharmacol Ther 2022；50：1079‒94）

Objective　This study aims to verify the effects of consuming sugarcane stem extract（SSE）-containing p-coumaric acid and ferulic acid on improving cognitive function in healthy Japanese adults who feel a memory decline. Methods　This was a randomized, double-blind, placebo-controlled, parallel-comparison study involving 99 healthy Japanese adults. Using a random number generator, subjects were assigned to one of three groups: regular-SSE（500 mg╱day）, low-SSE（250 mg╱day）, or placebo（n＝33）. For 12 weeks, subjects took five capsules per day of regular-SSE, low-SSE, or placebo. Cognitive function tests（Cognitrax）, subjective symptom-related cognition, and cognitive　function-related biomarkers were used to assess the effects of SSE-consumption. Results The number of subjects analyzed as per the protocol set was 30 in each group. Although composite memory after the 12-week intervention, which was set as the primary outcome, did not show a significant difference between the regular-SSE and the placebo group, the low-SSE group showed a significant improvement compared to the placebo group. Furthermore, when compared to the placebo group, the low-SSE group improved significantly in visual memory, psychomotor speed, and overall cognitive function after a 12-week intervention. There were no medically significant changes observed as a result of the test foodʼs continued consumption. Conclusions　The 12-week intake of SSE-containing foods was found to improve overall memory performance in healthy Japanese adults aged≥40 years who feel a memory decline, particularly with SSE 250 mg╱day（p-coumaric acid 35.8 mg╱day, ferulic acid 16.3 mg╱day）. Trial registration　UMIN000044305 Foundation　Mitsui Sugar Co., Ltd. （Jpn Pharmacol Ther 2022；50：1095‒110）

Objectives　The aim of this study was to evaluate the effects of combined oral supplements of sesame lignans and astaxanthin on feeling of daily fatigue. Methods　A ramdomized, double-blind, placebo-controlled, parallel-group comparison study was conducted with subjects feeling fatigue with aging and on daily. Two hundred seventy-two Japanese volunteers were randomly assigned to 2 groups and ingested either placebo or the test foods containing 10 mg sesame lignans（including sesamin and episesamin）and 6 mg astaxanthin daily for 8 weeks. Subjects reported feeling of fatigue and quality of life were examined using the Visual Analogue Scale（VAS）. Results　The per-protocol analysis revealed significant improvements in the VAS scores of the fatigue feeling at 4 weeks in the test food groups compared to the placebo food groups（P＜0.05）, and these scores tended to be lower in the test food groups than the placebo food groups at 8 weeks（P＜0.1）. Conclusions　The results suggested that the intake of combined supplements of sesame lignans（including sesamin and episesamin）and astaxanthin reduced feeling of daily fatigue. （UMIN ID: UMIN000041552）（Jpn Pharmacol Ther 2022；50：1111‒9）

Objective　The study aimed to evaluate the effect of Salacia extract and naringin on blood glucose. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 60 healthy volunteers. The subjects were randomly divided into two groups and took placebo food or test food containing Salacia extract and naringin for 12 weeks. The primary outcome was HbA1c and the secondary outcome was fasting blood glucose, insulin, HOMA-IR, 1,5-AG, body weight, BMI and triglycerides. Results　The test food didnʼt suppress HbA1c significantly than placebo, but significantly increased 1,5-AG. Additionally, in the subgroup analysis with higher BMI, the test food significantly suppressed HbA1c than placebo. Conclusion　These results suggest that the ingestion of Salacia extract and naringin suppresses HbA1c in healthy subjects with higher BMI（. UMIN-CTR ID: UMIN000044429）（Jpn Pharmacol Ther 2022；50：1121‒9）

Objectives　This study aimed to evaluate the efficacy of the food containing garlic and ginger for body surface temperature and sensory perception under cold conditions on healthy women. Methods　A randomized, double-blind, placebo-controlled, crossover study was conducted in 16 healthy women who were aware of cold. They took test food containing both garlic（7 mg of Alliin）and ginger（600μg of ginger-derived polyphenols）or placebo. Body surface temperature, sensory perception and autonomic nerves under cold conditions were measured. Results　In analysis of total evaluable subjects, there was no significant change in area under the curve（AUC（0-60 min））of body surface temperature and other evaluation items between test food and placebo. However, ingestion of test food containing ginger and garlic significantly suppressed the decrease in body surface temperature of non-thin subjects with BMI 20 or higher with placebo. Conclusions　This study suggests that the food containing garlic and ginger maintained the body surface temperature of the peripheral site of healthy non-thin women in cold conditions. （UMIN ID: UMIN000044513）（Jpn Pharmacol Ther 2022；50：1131‒9）

自身が特任教授になったことで，英語名刺をどう書こうかと思ったのがきっかけでした。いろいろ調べると，「Specially appointed professor」が多そうでした。ただ，直訳だし何のことがわかりません。国際的にも通じないので，これはだめだと思いました。少しましなものに，「Project professor」がありました。何らかのプロジェクト専任の教授なので，これはありかなと思いました。しかし，国際的には聞いたことがありません。そこで思いついたのが，「Research professor」です。Research は研究のことでもあり，しかも国際的にもよく使われていたため，これが正解と思ったわけです。私のいたノースキャロライナ大学にも，ほぼ40 年前すでに，「Research professor」というポストがありました。