薬理と治療

GCP 省令では，治験審査委員会（以下，IRB）を共同，または団体等により設置し，中央審査することが可能となっているが，実情としては，治験実施医療機関ごとに設置されているIRBにて個々に審査されることが多い。欧米に目を向けると“One Study＝ Single IRB” が進むなか，日本においても変革が求められていないか危惧するところである。米国では，以前は日本と同様に治験実施医療機関ごとにIRB が設置されていたが，現在では審査の外部委託による中央化（脱施設化）が進んでいる。商業IRB も増えてきており，「質」といった面で一時期は懸念されていたようだったが，被験者保護プログラム認証協会（The Association for the Accreditation of Human Research Protection Programs, AAHRPP）による認証システムができたことにより，被験者保護に関する質の保証がされるようになった。中央化により，スピードや質だけでなく，研究のステークホルダーから確実に独立した立場で審査する透明性といった面でもメリットがあると考える。EU においては，2001 年に臨床試験指令が制定され，多施設臨床試験を一加盟国につき一つの審査機関にて審査している。各国，国の支援下にある審査機関で一括審査が原則となっており，一国一意見の原則である。日本では1998 年の新GCP 省令施行により，治験実施医療機関ごとにIRBが設置され独自の発展を遂げてきたが，一つの試験をさまざまなIRB で審査した場合，審査見解や質といった面で均一化されている保証はない。また，開発者側から見ても，試験運用にあたっての総合的な費用や労力に配慮されているとは言いがたい。グローバルリズムが席巻する時代において，現状に甘んじて良いものだろうか。これら背景をふまえ，日本におけるIRB の中央化について，小児治験ネットワーク中央IRB の事例をもとに効率的な活用方法を検討したい。

平成25 年6 月14 日，安倍政権は「日本再興戦略─ JAPAN is BACK ─」を発出した。そのなかの「医薬品・医療機器開発，再生医療研究を加速させる規制改革」の項に，整備すべきものとして以下の事項が列記されている。●日本版 NIH（現在のAMED）●臨床研究中核病院● 高度な専門家と十分な体制を有する中央治験審査委員会および中央倫理審査委員会● ARO（多施設共同研究を始めとする臨床研究・治験を実施・支援する機関）構築これらは着々と整備され，新規医療技術と最適医療開発に向けての道が整備されてきた。しかし，倫理審査に関しては，特定臨床研究の審査を行う認定臨床研究審査委員会が設置されたのみで，中央治験審査委員会や倫理指針対応下の臨床研究・臨床試験については制度としての中央化が十分に整備されないままに現在に至っている。一方，欧米は中央IRBの方向へ舵を切った。わが国においても，審査の質の向上に加え，審査の一本化は喫緊の課題である。

日本国内の臨床試験は，試験の目的，デザイン，介入内容，資金源などの実施体制等に応じて，適用される法令，指針などの品質管理基準が異なる。弥縫策的な改訂が過去20 年間続いたために，全体的に複雑な仕組みである。しかし，研究倫理に関する審査が必要であることは，すべてに共通している。治験は薬事承認申請という目的により定義される臨床試験である。1996 年のICH-GCP 合意を原点に治験のルールは法制化され，その後，企業・医療機関に20 年間以上かけて浸透している。関係者の世代交代も進んでいる。治験の審査は，原則施設ごとに設置される委員会で行うことで始まった。その後，審査の質・バラつきの問題，中央審査の導入（原則設置の廃止）と議論は推移している。一方で，IRB の目的は，ICH-GCP 改訂においても変更がない。その目的とは被験者の権利，安全，福祉の保護である。最近のCOVID19対応においても，多すぎる審査委員会とその反応・対応は，依頼者や責任医師の試験遂行に障害になったとも聞く。治験審査の中央化の遅れについては，スポンサーや日本臨床薬理学会から報告1，2）されているが，癌対象試験を受託するような比較的大きな医療機関において，審査効率が停滞している。

医療機関ごとの治験審査委員会（IRB）設置原則が2008 年に廃止され12 年が経過した。現在は，治験の国際化が進み，遺伝子治療や再生医療，希少疾患といった専門性の高い治験が増加し，バイオマーカー戦略やIoT（Internet of Things）の進化に伴い臨床試験デザインも格段に高度化，複雑化している。そのような臨床試験環境変化においても，適切に被験者保護，データの信頼性を確保するためにIRB が担う役割は大きい。むしろより重要になったと言えるかもしれない。検討が開始されたICH E6（R3）においても，IRB の役割，重要性は揺るぎのないものとして議論されている。一方で，非効率なIRB 手続きは課題とされており，その解決手段の一つとしてIRB のセントラル化が叫ばれてきた。製薬企業にとってセントラルIRB（C-IRB）活用における課題は何なのか，日本における望ましいC-IRB とはどのようなものなのか考えてみたい。

Background　In January 2018, esomeprazole（Nexium® capsules/granules for suspension） received additional approval for treating reflux esophagitis, gastric ulcer, duodenal ulcer, and non-erosive reflux disease in pediatric patients. We describe the results of a specified drug-use survey in Japanese pediatric patients. Methods　Between May 2018 and March 2020, patients aged ≥ 1 to ＜15 years who had been treated for the first time with esomeprazole for gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, non-erosive gastroesophageal reflux disease, or Zollinger-Ellison syndrome were registered and observed for 4-8 weeks. Results　Of 240 patients registered, safety and efficacy were analyzed in 212 and 184 patients, respectively. The mean age was 9.3 years, body weight was ＜ 20 kg in 24.1％, and mean disease duration was 10.1 months. Adverse drug reactions occurred in 1.4％ of patients. Iron deficiency anemia, abdominal pain, diarrhea, alanine aminotransferase increased, aspartate aminotransferase increased, and γ-glutamyltransferase increased occurred in 0.5％（n＝1）of patients each; none were serious. The subjective and objective symptoms improved in ≥ 90％ and deteriorated in ≤ 5％ of patients at the final evaluation point for heartburn, acid regurgitation, epigastric pain, and upper abdominal discomfort. Heartburn, acid regurgitation, epigastric pain, and upper abdominal discomfort were eliminated in ＞ 80％ of patients. Symptoms were eliminated in ≥ 83％ of patients. Endoscopic cure was achieved in both patients with peptic ulcer and endoscopic findings before and after treatment. Conclusions　This study detected no new safety concerns for esomeprazole in children, with high rates of symptom improvement and elimination in actual use. （ClinicalTrials.gov: NCT03562026）

Bexarotene has been used for the clinical treatment of cutaneous T-cell lymphoma （CTCL）in many countries. Though this FDA︱approved selective RXR agonist is known to inhibit the proliferation of CTCL cells in culture, the anti-tumor effect of bexarotene have not been investigated in CTCL-animal models. In this study, we examined the inhibitory effect of bexarotene on cell growth of variant cells derived from patients with CTCL in vitro and tumor progression in CTCT cell-xenografted mice. Bexarotene inhibited the proliferation of HuT 78 and HH cells but not MJ cells with a double-sigmoid curve. Tumor progression in HH cell-xenografted mice was significantly suppressed from day 11 to day 28 by daily oral treatment with bexarotene at 30 mg/kg or 100 mg/kg. In addition, bexarotene significantly upregulated the expression of mRNA encoding p21 but not Rb in tumor after 2 weeks. Furthermore, the mRNA for RXRα in tumor was markedly induced by bexarotene at 100 mg╱kg after 2 weeks. Bexarotene also enhanced the expression of RXRα protein after 2 and 4 weeks. 　　We have demonstrated for the first time that bexarotene treatment can inhibit tumor growth in a CTCL animal model, and suggest that the mechanism may involve upregulation of RXRα and╱or p21 expression.

Objectives　This randomized, placebo-controlled, double-blind, parallel-group trial aimed to determine the effects of raw shark liver oil on healthy Japanese adults. Methods　Healthy Japanese subjects（n＝56）were included and randomly allocated into two groups（n＝28, each）using a computerized random number generator. The active group consumed four capsules that contained raw shark liver oil daily for 12 weeks, whereas the control group consumed four placebos. The primary outcome was the comparison of the vitality（VT） scale of Medical Outcomes Study Short-Form 36-Item Health Survey（SF-36）between the two groups. Secondary outcomes were SF-36 scales（excluding VT）, visual analog scale of fatigue, immunological assessment, skin moisture, Japanese rhino-conjunctivitis quality of life questionnaire individual scores, questionnaire assessment using the practical guideline for managing allergic rhinitis in Japan, and salivary immunoglobulin A. Results　In each group, 28 subjects were analyzed as per-protocol datasets. In the active group, VT values at 8 and 12 weeks, and the general health of SF-36 values at 12 weeks afterintervention were significantly higher than those in the placebo group（P＜0.05）. In the sub-group analysis of the age of ≥ 50 years or ≥ 60 years, some immune indexes significantly improved in the active group in comparison with the placebo group. Furthermore, in the subjects with improved SF-36 at 12 weeks after intervention, the number of cases with improved immune index was significantly higher in the active group than in the placebo group. No adverse events related to the test products were reported. Conclusions　We found that raw shark liver oil consumption enhances immunity, improves subjective health status, energy, and VT, and reduces fatigue in healthy Japanese adults. Trial registration　UMIN-CTR: UMIN000040492 Foundation　EGAO CO., LTD.

Background　Sesame lignan and vitamin E（VE）are known to have protect lipids from oxidative stress. Objective　This study aimed to evaluate whether sesame lignan（10 mg sesamin/episesamin） and low dose VE（55 mg α-tocopherol）（SVEX） supplementation alleviates the oxidative susceptibility of LDL and erythrocyte membranes in healthy middle-aged and elderly people. Methods and Study design Fifty-seven subjects（aged 40-69 years, 26 men and 31 women） received either SVEX or placebo for 4 weeks. LDL oxidation lag time and the accumulation of 2-thiobarbituric acid reactive substances（TBARS）in erythrocytes were measured upon oxidation. Results　LDL oxidation lag time increased and TBARS in erythrocytes decreased in the SVEX group compared with those in the placebo group. The results from in vitro studies of VE-treated LDL suggested that the prolongation of LDL oxidation lag time by SVEX could not be explained only by VE intake. Conclusion　Our study indicates that SVEX supplementation may be an effective approach to protect middle-aged and elderly people from excess oxidative stress.

Objectives　We previously reported the efficacy of citrus juice fermented with Lactiplantibacillus plantarum YIT 0132（LP0132）in the management of Japanese cedar pollinosis（JCPsis）. This post hoc analysis evaluated symptoms and quality of life（QOL）in adults with mild JCPsis. Methods　Participants from our previous study who had relatively mild JCPsis as defined by the Guideline on Notification of Foods with Function Claims were selected. Data of participants in the primary intention-to-treat analysis（n＝50 per group）who met the guideline criteria were used in this post hoc analysis. Symptom scores, impaired QOL scores, and allergy-related blood parameters were compared to evaluate the efficacy of citrus juice fermented with LP0132. Results　From the intention-to-treat analysis, data were selected for 44 participants in the LP0132 group and 49 in the placebo group who met the guideline criteria. The increase in symptom scores during the early part of pollen season was significantly suppressed in the LP0132 group compared with the placebo group. Impairment of QOL scores was also significantly suppressed in the LP0132 group compared with the placebo group and was positively correlated with total symptom score. A significant decrease in regulatory T cells was observed from enrollment to late March in the placebo group but not in the LP0132 group. These results were supported by propensity score matching analysis adjusted for medication score during the study period. Conclusions　Citrus juice fermented with LP0132 alleviated JCPsis symptoms and impairment of QOL during the pollen season in participants with relatively mild JCPsis. （UMIN000025924）

Objectives　The aim of this study was to investigate the effect of oral intake of Amazake using the sake lees and rice koji on cold symptoms on slight constipation patients and healthy subjects. Methods　This placebo-controlled group comparison study included 82 subjects. Subjects ingested 190 g of amazake containing sake lees and rice koji, or 190 g of a control beverage containing starch degradation products instead of sake lees and rice koji, one bottle per day for 90 days. And they also record the days when they felt cold symptoms（cough, sore throat, fever, fatigue and lethargy, runny nose, diarrhea）during the consumption period. Results　Comparing the number of days of cold symptoms during the ingestion period for the 37 subjects in the amazake group and 18 subjects in the control group, the average number of days per subject was significantly lower in the amazake group than in the control group for the total number of symptoms, fever, and diarrhea. Conclusions　The fact that the consumption of amazake suppressed the occurrence of common cold symptoms suggests that the bacterial components in the sake lees and rice koji materials, the rice-derived components that have undergone fermentation, or the bacteria itself may have exerted an effect to maintain and enhance the bodyʼs immune response, thereby suppressing viral infection itself or the occurrence of symptoms of viral infection. （UMIN000044117）

Objective　The aim of this study was to evaluate the safety of salmon roe oil, astaxanthin and soy lecithin in healthy adult human. Methods　Non-randomized, open-labeled trial were conducted in healthy adult subjects. 30 subjects were assigned to 3 groups: five（n＝20）, two（n＝5）and one（n＝5）times the recommended amount consumption. All subjects were given test products for 4 weeks. Results　There were no adverse events associated with the test products during the study. 29 subjects complete the study without abnormal change in physical examinations, hematological analyses, blood biochemical tests or urinary analyses in two weeks. Conclusions　This study suggests that the excessive dose of salmon roe oil, astaxanthin and soy lecithin is safe for healthy adults.（UMIN ID: UMIN000039269）

Objective　The aim of this study was to evaluate the safety of salmon roe oil, astaxanthin and soy lecithin in healthy adult human. Methods　Non-randomized, open-labeled trial were conducted in healthy adult subjects. 10 subjects consumed the 5 times as much as usual consumption. All subjects were given test products for 4 weeks. Safety was evaluated every 2 weeks. Results　There were no adverse events associated with the test products during the study. 9 subjects complete the study without abnormal change in physical examinations, hematological analyses, blood biochemical tests or urinary analyses. Conclusions　This study suggests that the excessive dose of salmon roe oil, astaxanthin and soy lecithin is safe for healthy adults. （UMIN ID: UMIN000041528）

Objective　Early detection and early intervention are important in the prevention and treatment of dementia. Previously, we reported the results of randomized controlled trial on the effectiveness of supplement containing ferulic acid and others in the elderly with mild cognitive impairment（MCI）. In this study, we verified the usefulness of test foods in MCI of middle-aged and elderly people. Method　Subjects were recruited at 2 clinics. Those who were enrolled met the MCI criteria of DSM-5 and the age at registration was from 55 to 74 years old, MMSE score was from 24 to 27. Subjects were given supplements containing ferulic acid, α-glycerophosphocholine, Ginkgo biloba extract and vitamin C for 180 days. MMSE, ABC dementia scale and POMS2 shortened version was evaluated. Results　MMSE score improved significantly from 26.3±0.4 to 28.2±1.1（180 days, P＝0.049）. ABC dementia scale, no changes were observed in ADL or BPSD, cognitive function. In the evaluation of mood by POMS, the Total Mood Disturbance（TMD） score showed positive change from 49.2±1.8 to 43.8±1.6（180 days, P＝0.049） significantly. There were no particular problems with safety. Discussion　In this study, cognitive function and psychological improvement were observed in subjects with MCI by ingestion of the test food. Together with the previous reports, it was expected that this test food would improve cognitive function and mood in middle-aged and elderly people with MCI, and contribute to the prevention of conversion to dementia. （UMIN ID: UMIN000036381）

Objective　This study investigated the effects of a dietary supplement containing enzymatically modified isoquercitrin（EMIQ）on physical function and blood parameters in middle-aged and elderly adults. Methods　A randomized, double-blind, placebo-controlled parallel-group, comparison study was conducted with 24 healthy middle-aged and elderly subjects. The subjects were randomized into two groups and given either capsules with EMIQ（42 mg EMIQ per day）or the placebo capsules, for 12 weeks. Physical function, daily activity, blood pa-rameters, body composition, and food consumption were evaluated. Results　The time taken to complete a 10-meter walking test was significantly reduced in the EMIQ group compared to the placebo group. The cadence and speed in the EMIQ group also improved. Daily activities and blood parameters in the EMIQ group improved. A nutrition survey revealed higher caloric intake in the EMIQ group than the placebo group without body composition change. Conclusions　These results suggest that daily intake of EMIQ can improve the quality of life of middle-aged and elderly adults by improving walking speed and blood parameters. （UMIN-CTR ID：UMIN000038020）

Objectives　To investigate the effects of lactoferrin（LF）on gene expression of type Ⅰ interferon（IFN）in HT-29 cells and subjective symptoms related to physical condition in healthy adults. Methods　HT-29 cells were incubated with bovine LF, followed by stimulation with poly Ⅰ:C, a Toll-like receptor 3 agonist, then we examined the gene expression of IFN-α/β. 　　In addition, we investigated how LF intake could affect subjective symptoms related to physical condition as a secondary analysis of a previous randomized, double-blinded, placebo-controlled trial. Healthy adults ingested placebo or LF（200 mg╱day）for 14 weeks, and subjective symptoms were analyzed to evaluate the effects on physical conditions. Results　LF enhanced the IFN-α/β gene expression in poly Ⅰ: C-stimulated HT-29 cells. 　　In the human study, from the 207 subjects（placebo, n＝104; LF, n＝103）, 13 subjects were lost to the follow-up, leaving 194 for a full analysis set（n＝99, n＝95）. The cumulative incidence days of lip and mouth swelling, sore throat, cough, headache, and fatigue were significantly lower in the LF group than in the placebo group. The adverse events were similar in each group and none had a causal relationship with test food intake. Conclusions　These results suggest that LF enhances IFN︱α/β production in the intestinal tract upon viral stimulation, and the intake of 200 mg╱day of LF is beneficial for physical condition maintenance. （UMIN000027405）

Objective　We evaluated the effects of ingesting Ramune Soda Candy（Ramune）, a compressed tablet candy, on blood glucose and acetaldehyde levels after drinking alcohol in healthy adults. Methods　A randomized, placebo-controlled, double-blind cross-over, comparison study was conducted in healthy subjects. The subjects were given either the test product（29 g Ramune containing 26 g hydrous crystal glucose, Morinaga & Co., Ltd., Tokyo）or the placebo（controlled candy not containing glucose）after an hour of drinking 25 of alcohol. The outcomes were blood acetaldehyde, ethanol and glucose levels, exhaled ethanol levels, and visual analog scale（VAS）scores. Results　In the VAS analysis of all 15 subjects, fatigue, dullness, and stagger were significantly improved. Two subgroups were set by the median value of the difference between the blood glucose level of Ramune and placebo 2 hours after drinking. In the high blood glucose subgroup of 7 subjects, the blood acetaldehyde level of the subjects 3 hours after drinking, was significantly lower than those of placebo. No significant difference was observed in the low blood glucose subgroup of 8 subjects. Conclusions　In healthy adults, ingesting Ramune after drinking significant improved drunkenness. No significant effects were observed in blood acetaldehyde level, blood and exhaled ethanol levels. The high blood glucose subgroup was significantly decreased blood acetaldehyde level compared with those of placebo. These results suggested that there is a correlation between the decrease of blood acetaldehyde level and maintenance of blood glucose level.（UNIN000044158）

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