薬理と治療

遺伝子治療は，遺伝子の導入や改変により疾患を治療する先端医療である。遺伝子治療では，遺伝子を人の体内・細胞内に導入するために，ウイルスがヒトに感染する仕組みを利用したウイルスベクター（病原性や増殖性を失わせ，治療用遺伝子を組み込んだウイルス）がおもに利用されている。また，腫瘍溶解性ウイルス（がん細胞内で選択的に増殖して細胞を破壊するウイルス）の臨床開発も進んでいる。遺伝子組換え技術を用いて作製されたウイルスベクターや腫瘍溶解性ウイルスは，「遺伝子組換え生物等の使用等の規制による生物の多様性の確保に関する法律（カルタヘナ法）」が規制する「遺伝子組換え生物等」に該当するため，これらを遺伝子治療に用いる場合はカルタヘナ法への対応が必要となる。

現在，多くの難治性疾患に対して，遺伝子細胞治療の研究・開発が行われており，その有効性から医薬品としての承認が進んでいる。一方で，その実施にあたっては，従来の医薬品とは異なった管理が必要である。今後の発展のためには，遺伝子細胞治療の本質的な安全性を理解・評価する必要があるが，これらを既存の医薬品における安全性の評価系で実施することはむずかしい。海外を中心にこれまでに行われた遺伝子細胞治療臨床試験の経験から，染色体へのベクター挿入による挿入変異の評価は必須であり，そのほか，遺伝子導入細胞やウイルスベクターの投与により惹起される免疫反応なども，開発時の非臨床試験では正確に評価できず，実際の患者管理の中で評価を行う必要がある。また，in vivo 遺伝子治療では，ウイルスベクターを患者体内へ直接投与することから，患者からのウイルス排出に対してカルタヘナ法第一種使用規定への対応が必要となる。このように，遺伝子細胞治療の開発や実施にあたっては，遺伝子細胞治療固有の特性に基づく安全性管理を正確に理解することがきわめて重要である。

遺伝子治療とは疾病の治療を目的として遺伝子または遺伝子を導入した細胞を人の体内に投与することである1）。遺伝子を直接投与する体内法（in vivo）の場合，プラスミドベクター，ウイルスベクター，腫瘍溶解性ウイルスなどの方法があるが，熊本大学病院（当院）ではプラスミドベクターと腫瘍溶解性ウイルスを用いた治験の実施経験がある。このうち，腫瘍溶解性ウイルス治験では，腫瘍溶解性ウイルスに特化したさまざまな調整が必要とされ，一概に遺伝子治療治験といっても，ベクターの種類によって治験実施体制は大きく異なることを実感した。本稿では，当院の腫瘍溶解性ウイルス治験における院内調整について述べたい。

再生医療や，ゲノム編集技術など遺伝情報改変技術等の臨床応用に関しては，従来の治療法開発にみられる倫理的課題にくわえて，それぞれの特性に鑑みた課題が検討されている。再生医療に関しては，たとえば細胞の由来にまつわる問題や，その細胞の持つ能力や可能性にかかわる新たな倫理的課題が示されており，研究が進捗するにつれて，倫理的課題は複雑さを増しているともいえる。遺伝子治療に関しては，ゲノム編集技術など遺伝情報改変技術等の飛躍的な向上が新たな治療の可能性を高めるとともに，その技術を人の生殖系列細胞に応用することへの次世代に受けつがれ得る倫理的な懸念に関する議論が続いている。遺伝子治療の概要等については当シンポジウムにおける専門の先生方に委ねるとして，本稿では，再生医療の概要と特性を概観したうえで再生医療における倫理的課題を示し，さらにゲノム編集技術をヒト受精胚に応用して臨床試験を実施したケースをもとにその倫理的課題について検討したい。

2006 年にマウス由来，2007 年にヒト由来の人工多能性幹細胞（iPS 細胞，induced pluripotent stemcells）が山中伸弥教授（現京都大学iPS 細胞研究所所長）らによって樹立されて以降，iPS 細胞の臨床応用への活用に対する期待は高い。その応用は，再生医療だけにとどまらず，疾患発症機構の解明や新薬あるいは既存薬の創薬スクリーニング系としてなど，世界各国でさまざまな研究が展開されており1～6），本邦でも臨床試験段階に進んだ研究が多く報告されるようになった2, 3, 6, 7）。一方，2013 年には再生医療等の安全性の確保等に関する法律，2014 年に再生医療等製品の臨床試験の実施の基準に関する省令（再生医療等製品GCP 省令）が公布され，再生医療の治験・臨床研究実施の基盤整備も進んでいる。しかしながら，iPS 細胞を再生医療に応用する研究の支援に必要な知識や経験の蓄積，ノウハウの共有などはいまだ十分とはいえない。本稿では，京都大学医学部附属病院にて実施した複数試験の経験を基に，iPS 細胞等を用いた再生医療の治験・臨床研究（以下，iPS 細胞の治験・臨床研究）においてCRC が確認すべき事項，院内実施体制構築のポイントをiPS 細胞の特徴も捉えつつ紹介する。

公益社団法人日本医師会　治験促進センター（以下，「当センター」）は日本国内における治験実施体制の整備および治験業務の標準化・効率化の促進を行うことを目的に活動している。とくに「臨床研究・治験活性化5 か年計画　2012」1）（平成24 年3月30 日文部科学省・厚生労働省）において“IT 技術の更なる活用等（企業主導治験，医師主導治験，臨床研究に共通）” の記載を受け，クラウドコンピューティングの推進として，IT システム開発と提供，電子化等にかかわるセミナー開催および教育コンテンツの提供等を行ってきた。活動当初は急速なIoT ツール等の登場に対し，医療機関等の導入現場では情報セキュリティポリシーの策定や教育等の体制が十分とはいえず，インターネット上で情報を取り扱うクラウドサービスに対しても懐疑的な質問が多数寄せられた。しかしながら近年，多くの医療機関でも電子化への理解も深まり，とくにペーパーレス等を足掛かりに当センターやベンダー各社が提供するさまざまなクラウドサービスが導入された。一方で，2020 年初頭のCOVID-19 の発生は，多くの医療機関業務へ影響を及ぼし，結果としてさらなる電子化や保管資料を電磁的記録とするいわゆる，電磁化，Web 会議・リモートSDV 等が進んだ。当センターではCOVID-19発生直後から医療機関のIoT ツールの導入状況や治験実施体制状況の調査を行ってきたので，これら調査結果について考察をする。なお，用語の混乱を避けるため以降IoT ツールも含めてIT システムと記載する。

Notorious COVID-19 caused the lock-down in many cities and led to a sedentary life-style in many people, resulting in“frailty”,“ sarcopenia”and bone loss in a senior generation. Generally, the aged bone loss has been treated by the dietary cure, athletic therapy and pharmacotherapy, that contains calcium drugs, active forms of vitamin D3, bisphosphonates, calcitonins, parathyroid hormones and the other drugs, which also include Chinese herbal（Kampo）medicines in Japan. One of them, Hochuekkito（HET）is composed of 10 herbal medicines and has been used for the treatment of fatigue and weakness from aging and the other diseases. Accordingly, we investigated the effects of HET on the experimental model, castrated rats. Eight-week administration of HET enhanced the bone mineral density, which was reduced by not only gonadotropin-releasing hormone agonist treatment but also ovariectomy, with a slight elevation of the serum estradiol. This fact may indicate that HET prevents not only the bone loss but also geriatric and menopausal disorders from aging and“frailty”in the aged. Anyway, Kampo medicines have wide-ranging efficacies in clinical medicine. Thus, there are many Kampo medicines as an antiosteoporotic drug such as Keishibukuryogan, Hachimijiogan, Goshajinkigan, Jyuzentaihoto and Ninjinʼ yoeito besides Hochuekkito. Taken together, the proper Kampo medicines can be selected and tried to prevent and/or cure sarcopenia and bone loss with frailty in increasing senior generation.

Backgrounds　Androgenic alopecia（AGA）occurs as a result of the contraction of the anagen through the action of androgen on hair follicles. Transforming growth factor-β（TGF-β）is up-regulated in hair follicles of AGA patients, and TGF-β enhances the transition from the anagen to the catagen. TP0427736 is an inhibitor of the TGF-β type I receptor ALK5 and suppressed the signal transduction of TGF-β. Our previous study showed TP0427736 reduced TGF-βinduced growth inhibition of human outer root sheath cells. Objectives　To investigate the in vivo efficacy of TP0427736 on alopecia, two studies were conducted on the transition from anagen to catagen in normal mice and testosterone-treated mice with accelerated hair follicle transition to the catagen as in AGA pathology. Methods　The dorsal hairs of C57BL╱6 mice were depilated with depilatory wax. From day 10 after depilation, TP0427736 lotion or vehicle were applied topically to the depilated dorsal area. After the application for several days, the change of anagen hair region ratio were histologically analyzed. In the pathological model, testosterone solution was additionally applied. Results　In normal mice, TP0427736 significantly increased the anagen hair region ratios after depilation. Additionally, TP0427736 inhibited the testosterone-induced hair cycle transition of the anagen to catagen in an AGA mouse model. Conclusions　These results provide the first evidence demonstrating an ALK5 inhibitor can suppress the catagen transition in a mouse model resembling the pathology of human AGA. TP0427736 would be a new therapeutic option for AGA treatment.

Globin peptide（abbreviation“GD”, also known as“Globin digest”, registered trademark “METAP®”）, is a commercially available oligopeptide mixture derived from edible proteins developed to effectively lower serum triglyceride levels and to regulate dietary fat metabolism. In this study, the effect of GD and its active ingredient valine-valine-tyrosine-proline（VVYP） equivalent to GD content on blood glucose in the oral glucose tolerance test of ICR mice, was examined. GD and VVYP suppressed the elevation of blood glucose in the oral glucose tolerance test of ICR mice. The suppressive effect of VVYP on the glucose value in the area under the curve during the 2 h after administration was the same level as that of GD. These results indicate that VVYP may be the main active ingredient in GD that has the suppressive effect on the elevation of blood glucose.

Objective　The subcritical water revealed a more effective solvent than alcohol and hot water, as it quickly extracted the flavonoids hesperidin and narirutin from whole fruits. In previous studies, we reported the effects of unripe mandarin（Citrus unshiu）extract powder（UMEP） treated with subcritical water on allergic diseases using animal models. This study aimed to investigate the effects（efficacy and safety） of repeated oral intake of UMEP on the allergen-induced allergic reactions and subjective symptoms in Japanese adult males and females who complained of discomfort in eyes and nose. Methods　A randomized, placebo-controlled, double-blind parallel group study was conducted in 68 subjects（20-65 years old）with allergic symptoms of pollinosis. The subjects were daily given either UMEP or the control product（vehicle）for 18 weeks. Before and after the start of the product intake, the scores of Japanese Rhino-conjunctivitis Quality of Life Questionnaire（JRQLQ）with other tests were examined in each subject. Result　During the 18 weeks continued intake of the UMEP-containing supplement, several scores of JRQLQ, QOL questions including allergic symptoms such as nasal discharge, sleep disorder were significantly improved in the UMEP-containing supplement group compared to the placebo group. And easing of mental nervousness and anxiety was also observed. Little notable adverse effects were noted throughout the study. Conclusion　The results indicated that oral repeated intake of UMEP might be effective for the reduction of some allergy symptoms derived from pollinosis.（UMIN-CTR: UMIN000039243）

Objectives　The study aimed to verify the efficacy on blood flow and cold sensitivity and safety of dietary supplement containing NMN. Methods　The study was conducted as an open study in which 23 participants who were aware of poor circulation orally taken a test food containing 125 mg of NMN daily for 4 weeks. Results　Analysis by Laser Doppler Velocimeter revealed that 4 weeks of ingestion of the test food increased palm blood flow. As the blood flow increased, the surface temperature of the palm also increased by thermography. Furthermore, the questionnaire of the subjects revealed that the dissatisfaction with cold sensitivity was significantly resolved. Conclusion　From the above results, it was strongly suggested that the intake of foods containing NMN may contribute to the elimination of cold sensitivity. （UMIN-CTR ID: UMIN000042012）

Background　Discomfort of the nose and eyes due to allergic rhinitis is one of the factors that negatively affects the quality of life（QOL）. Therefore, unripe Japanese mandarin orange（Citrus unshiu）fruit was investigated as a functional food candidate for improving the QOL of those with nose and eye discomfort. Methods　The effects of food containing the dried powder of unripe Japanese mandarin orange（CUP）, which contains 215 mg of hesperidin and 48 mg of narirutin, were evaluated for 8 weeks in a randomized, double-blinded, placebo-controlled, parallel-group comparative study. Eighty healthy adults with nose and eye discomfort were randomly selected as subjects. Results　The intake of CUP significantly improved nasal symptoms compared with the placebo. In particular, the decrease in“nasal discharge”by CUP was significantly larger than that by placebo according to symptom diaries. Regarding the decrease in“nasal discharge”, the difference between groups at the endpoint of 8 weeks was larger than that at 7 weeks. In addition, there were no adverse events caused by the intake of these foods for 8 weeks. Conclusion　CUP alleviated nasal symptoms of allergic rhinitis in healthy adults with nose and eye discomfort. （UMIN ID: UMIN000041584）

Objectives　A randomized, double-blinded, placebo-controlled, crossover study was conducted to evaluate the effect of consuming food containing an extract of Terminalia bellirica on the elevation of postprandial serum uric acid（SUA）level. Methods　Sixty male participants with fasting SUA levels of ≤7.9 mg╱dL were recruited. The participants were randomly divided into two groups. Along with the loading diet, the experimental group consumed food containing an extract of T. bellirica（with 20.8 mg gallic acid）and the control group consumed the placebo food. The levels of SUA and urinary uric acid were measured before and after food consumption. Results　Consumption of food with the T. bellirica extract significantly decreased postprandial SUA levels compared with consumption of the placebo food. T. bellirica significantly lowered the incremental area under the curve and tended to lower SUA levels after the loading diet in the experimental group than in the placebo group（P＜0.05）. Moreover, during the study period, no adverse events were observed that could be attributed to consumption of the food containing the T. bellirica extract. Conclusions　Consumption of food containing the T. bellirica extract significantly decreased postprandial levels of SUA.

Background　Sea buckthorn has been used for medical treatments since ancient time, and effect of the products on inflammation have been well known, but few studies have reported the effect on skin hydration. Objectives　The aim of the present study was to assess the efficacy of intake of sea buckthorn juice compared with the placebo over 4 week period on skin-moisturizing, using trans epidermal water loss（TEWL）scores as the primary endpoint. Methods　We conducted a clinical parallel, double-blind, placebo-controlled trial study to assess the efficacy of the sea buckthorn on skin-moisturizing. 30 healthy women were divided by age and body mass index（BMI）at baseline, into the sea buckthorn group, in which the subjects consumed the sea buckthorn juice, and the placebo group, in which the subjects consumed a placebo juice. Results　At week 4, the improvement of score from baseline（week 0）in TEWL score was observed only in the sea buckthorn group （P＝0.001）. A tendency of decrease of skin hydration was also observed in the placebo group（P＝0.059）. Conclusions　The study indicated the intake of sea buckthorn juice improves the skin-moisturizing in healthy women. （UMIN000041444）

Background/Objectives　This study aimed to investigate the effect of water-soluble Candida utilis cell wall（TPF）on postprandial blood glucose levels in adult men and women, including those with borderline diabetes. Methods　To test the effects of TPF intake, we conducted a randomized double-blinded crossover study on 30 healthy adults. The subjects ingested a solution containing 800 mg of TPF with 200 g of rice. Blood samples were taken before and 15, 30, 45, 60, 90, and 120 min after ingestion, and blood glucose was measured. Results　The analysis of all subjects showed that TPF intake tended to suppress the increase in postprandial blood glucose levels, but the difference was not significant. In a stratified analysis of subjects with fasting blood glucose levels of 100︱125 mg╱dL at screening, postprandial blood glucose levels at 60 and 90 min（P＝0.033 and 0.040）and glucose area under the curve （AUC）（P＝0.037）were significantly lower after TPF ingestion. The analysis of subjects with maximum postprandial blood glucose levels above the median showed that TPF ingestion induced significant suppression of postprandial blood glucose levels at 45, 60, and 120 min （P＝0.005, 0.006, and 0.042）and glucose AUC（P＝0.004）. Conclusions　These results indicate that water-soluble dietary fiber from C. utilis is useful for the prevention of lifestyle-related diseases such as diabetes mellitus and is considered as supplementary means of dietetic therapy. （UMIN000043321）

Objective　The aim of this study was to establish the functionality of oral ingestion of Laurus nobilis leaf extract（LAURESH®）-containing food on continuous and single ingestion. Methods　The study was conducted from September to December 2020. A randomized, double-blind, placebo-controlled parallel-group comparison study was performed on 44 healthy Japanese adults（22 males and 22 females）. All subjects were randomly allocated into the test food group（n＝22）or the placebo group（n＝22）using a computerized random-number generator. The subjects ingested either the placebo or the test food including 108 mg╱day LAURESH® for 4 weeks, and the effects on the oral environment（the ratio of Tannerella forsythensis to total bacteria count as the primary outcome, gingival index（GI）, gingival bleeding（the number of spontaneous bleeding points on the gums）, plaque index（PlI）, the number of Streptococcus mutans, halitosis, and serum high-sensitivity CRP concentration）, the condition of saliva（oral moisture values, volume of saliva, salivary pH, and salivary IgA）, and subjective symptoms were examined. Furthermore, the effects of a single ingestion of test food including 108 mg LAURESH®（3 tablets╱day）on halitosis, oral moisture value, volume of saliva, salivary pH and subjective symptoms were evaluated at the start of the trial. Results　Forty-one subjects completed the trial, 21 subjects in the test food group and 20 subjects in the placebo group were analyzed. As a result, the ratio of T. forsythensis to total bacteria was significantly lower in the test food group than in the placebo group after 4 weeks of ingestion of the test food（P＝0.03）. There was an improving trend in the number of spontaneous bleeding points on the gums（P＝0.05）. No significant improvement was observed in the other endpoints. In a subgroup analysis, GI was significantly reduced in the female test food group（P＝0.04）. Next, a single ingestion showed a significantly higher salivary pH in the test food group than in the placebo group but within the normal range（P＝0.03）. No significant improvement was observed between the groups in halitosis, volume of saliva, and subjective symptoms. In the safety study, no adverse events caused by the test food ingestion were observed during 4 weeks of ingestion. Conclusion　The test food reduced the ratio of T. forsythensis to total bacteria in healthy subjects and improved GI in female. Furthermore, a single ingestion of this test food improved the saliva buffering within the normal range. Taken together, the data suggest that ingestion of this test food improved the oral environment and condition of saliva. In addition, the test food appeared to be safe under the conditions employed in the present study. Trial Registration　UMIN-CTR: UMIN000041594 Funding　Tokiwa Phytochemical Co., Ltd.

Objectives　This trial was conducted to evaluate the effectiveness of proteoglycan derived from salmon nasal cartilage on discomfort in the knee joints in healthy individuals. Methods　In a randomized, double-blind placebo-controlled intergroup trial, the subjects were randomly allocated to receive a 10 mg╱day of proteoglycan or placebo for 16 weeks. The primary outcomes were scores on JKOM and VAS at rest, at walking, at going up and down stairs, and standing up and sitting down, and at 10-minute standing. The secondary outcomes were scores on 10-time-repeated exercise tests and the levels of biomarker sCPⅡ, uCTX-Ⅱ, and sC1, 2C. The subjects were confirmed whether to have arthritis by biomarker testing. Results Each group consisted of 25 subjects. The proteoglycan group showed a significant difference in the changes from week 0 to week 16 in the VAS score at walking as compared with the placebo group（P＜0.00）. In hierarchical analyses in the ≥50-year-old population, Proteoglycan showed effectiveness in the scores on VAS at going up and down stairs（P＝0.04 for the week 16 score and P＝0.04 for the changes）and the squat score of 10-time-repeated exercise tests（P＝0.00 for the change）in the between-group comparison. The levels of biomarkers were decreased without showing significant between-group differences, and suggested that the subjects were healthy individuals. Conclusions　It is indicated that the intake of proteoglycan derived from salmon nasal cartilage can ameliorate or prevent knee discomfort caused by walking in healthy individuals and by bending and stretching of the knee joints, such as using stairs and doing squat, in healthy individuals aged 50 years or older.

Objectives　This study aimed to evaluate the efficacy of the food containing EGCG and L-theanine from green tea on immune responses and maintenance of physical conditions. Methods　A randomized, double placebo-controlled, parallel-group study was conducted in 124 participants aged 20 to 64 years. Participants were randomly assigned to receive a test product containing EGCG, L-theanine or placebo for 12 weeks. Primary endpoints were evaluated by life survey questionnaire including cumulative incidence days of cold-like symptoms and s-IgA secretion rate, and second endpoints were evaluated by 36-Item Short Form Survey （SF-36）, Profile of Mode States 2nd Edition（POMS2）, Visual Analog Scale（VAS）of fatigue. Results　Cumulative incidence days of cold-like symptoms such as“runny nose”,“stuffy nose”, throat pain”,“voice sickness”,“general malaise”and“sputum buildup”during the intake period were significantly lower in the EGCG and L-theanine group compared to the placebo group. After 12 weeks, IL-4 in the EGCG and L-theanine group was significantly lower compared to the placebo group. No clinically significant adverse events were reported during the study. Conclusions　The results suggested that the ingestion of EGCG and L-theanine improved maintaining physical conditions and could have positive effects of immune responses. （UMIN ID: UMIN000042600）

Background　We previously reported that the intake of Lactoplantibacillus pentosus strain b240（B240）decreased the severity of the subjective physical symptoms dose-dependently. However, the time of effect onset had not been assessed. Therefore, we investigated the time of effect onset with╱without limiting to common cold. Methods　Additional analyses for the efficacy against subjective physical symptoms were conducted using data obtained from a previously reported randomized, double-blind, placebo-controlled study of 300 healthy elderlies, which suggested the reduction in common cold incidence by the intake of B240. Results　In this study, the average severity of runny nose symptoms in common cold episodes was reduced after the fifth week of consumption of both 2 billion B240 as well as the intake of 20 billion B240. Moreover, the efficacy on the average severity of runny nose symptoms after the fifth week of consumption of B240 was also confirmed without limiting to sufferers of common cold. Conclusions　We confirmed that the efficacy on the average severity of runny nose symptoms was revealed after the fifth week of consumption of B240. The onset of effect coincided with the rise in salivary IgA reported previously. Trial registration：UMIN000005398

１年時のイベント率（いわゆるイベント年率）を求めたいとき，生存率解析で用いるカプラン・マイヤー法（Kaplan-Meier method）を使うかもしれません。その一方で，年率でのイベント率のことなので， 人年法（person-yearmethod）で計算しようとするかもしれません。今回は，これら二つの手法の違いと使い分けについて考えてみます。

本誌では，医薬品をはじめ健康食品に関する臨床試験が報告されている。臨床試験には比較試験と単群試験とがあるが，本誌で報告される臨床試験の多くは比較試験である。そのなかでも，被験薬（食品）と対照薬（食品）への割り振りをランダム（無作為：「むさくい」と読む）に行ったRCT （ランダム化比較試験）が大多数を占めている。このようなRCTを報告する際にはCONSORT声明1）という著名なチェックリストがあるため，これに準拠して論文を執筆すればよいわけだが，準拠していない論文も散見される。そこで，本稿では報告された論文の不備を指摘し，よりよい報告になるための説明をしたい。その項目として表1に示した15 項目を取り上げる。