薬理と治療

今回のシンポジウムのテーマである「治験を取り巻くお金」について考える際，いわゆる「研究費」については治験依頼者と実施医療機関のあいだだけの関係で考えることが可能であるが，実際には「医療費」も治験の実施に深くかかわってくる。そのため，治験にかかる費用（治験コスト）について考える際には，日本の医療を取り巻く現状と課題を正しく把握したうえで議論することが，今回のあり方会議のテーマである「本質を考える」うえでも重要であると考えている。

「医薬品の臨床試験の実施の基準（GCP）に関する省令（平成九年三月二十七日厚生省令第二十八号 )」が施行されて20 年以上が経過した。この間，わが国における治験実施体制は着実に整備が進んでいる。その一方で，被験者負担軽減費や治験診療に対する治験依頼者の費用負担については，見直しがほとんど行われていないのが現状である。国立国際医療研究センター病院（以下，当院）では，治験中の被験者の診療費については，「保険医療機関および保険医療養担当規則（以下，療養担当規則）」に従った運用を完全に行っていなかった。とくに，GCP 省令施行後まもない段階から，治験薬投与前および投与後の治験実施計画書に定められた検査・画像診断費用にかかる被験者自己負担分等の経費を治験依頼者と協議のうえ，治験依頼者に支払いを依頼していた。しかしながら，治験の受託数増加に伴い，各治験の内容に応じた請求や，包括医療費支払い制度導入後の費用負担の取り扱いが煩雑化するなど，医事課職員の負担が大きく，請求漏れが発生する等のトラブルが絶えない状況にあった。そのため，医事課職員より，療養担当規則の原則に従い，治験依頼者に通常診療請求を行いたいと相談を受けていた。そこでわれわれは，被験者の負担軽減費を見直すことで，法に定められた保険外併用療養費制度に従い運用することを目標とし，検討を行ったので報告する。

治験依頼者が医療機関に支払う委託研究費等の費用，いわゆる治験費用は，日本では1997 年の「国立大学附属病院における医薬品の臨床試験等の受託について（通知）」によってポイント算出表に基づいて算定することが一般的となり，現在では国立大学付属病院，私立大学附属病院，国立病院などのポイント算出表に基づいて算定されている。2011 年の「治験等の効率化に関する報告書」や2012 年の「臨床研究・治験活性化5 か年計画2012」およびそのアクションプランでは，「治験コストの適性化」が掲げられ，これまでも業務量に応じた適正な治験費用の算定や出来高払い方式の採用を目指した取り組みが進められている。一方で治験費用を取り巻く環境も変化しており，日本製薬工業協会（以下，製薬協）は2011 年に「企業活動と医療機関等の関係の透明性ガイドライン」を策定し，2013 年より委託研究費の公開を開始している。また，臨床研究法では研究資金等の提供に関する情報を公表することが定められており，治験依頼者が医療機関に支払う費用への透明性の確保が求められてきている。さらに，治験の国際化が進み国際共同治験がますます増加するなか，国際的に通用する考え方やルールへの適合が求められるとともに，各国の治験実施パフォーマンスがつねに比較されるようになってきており，治験費用もその一つである。

Background　Questionnaire surveys were conducted to investigate physiciansʼ and patientsʼ perceptions of informed choice（ICh）and a once-weekly oral hypoglycemic agent（OHA）in the treatment of type 2 diabetes（T2DM）. Methods　Patients with T2DM aged 20 years and older who were prescribed OHAs other than a once-weekly OHA were included in the questionnaire survey. Physicians treating more than 5 patients with T2DM each month were also included in the survey. The target number of questionnaires was set to 800 for the patient survey and 200 for the physician survey. Results　Data from 806 patients with T2DM and 200 physicians were analyzed. Of the patients, 75.6％ were male, the average age was 58.5 years and the average duration of diabetes was 12.4 years. The percentage of patients who“almost never miss a dose”was 7.5％ from the physiciansʼ responses, but 55.2％ from the patientsʼ responses. According to physiciansʼ responses, 51.4％ practiced ICh, while the patientsʼ responses showed only 23.1％ experienced ICh. Furthermore, according to the physiciansʼ responses, the average percentage of patients who wished to change to a once-weekly OHA even with just one drug was 43.0％, while the average of patientsʼ responses was 82.9％. Conclusions Physicians and patients were found to have different perceptions of various issues, such as ICh and a desire for once-weekly OHA. ICh, in which physicians share information about treatments with patients and patients choose their treatment, may reduce the cognitive gap between physicians and patients and help improve patient satisfaction in the treatment of T2DM. （UMIN000042598）

To assess the safety of burdock sprout extract（GSE）, single and repeated dose toxicity studies by oral administration were performed. Male and female 6-week-old Crl: CD（SD）rats were administered orally with single dose of 2000 mg/kg of GSE. During 14 days after the single administration, neither mortality nor abnormal symptom was observed in any animals administered with GSE. Subsequent 91/day repeated dose toxicity study, maximum dose was set at 2000 mg╱kg which is the same dose as used in the single dose toxicity study, and dose levels of 1000 and 500 mg╱kg for middle and low dose were set with a proportionality factor of 2. Male and female 6-week-old Crl: CD（SD）rats were administered orally by gavage for 91 days. During the treatment period, the treatment caused no deaths, and no toxicological effect related to the treatment was observed for the general condition, body weight, food consumption, water consumption, urinalysis and ophthalmology. At necropsy, incidence of dilatation of the cecum was increased in the male and female 2000 mg╱kg. As to the post-mortem examination, no alteration in hematology, clinical chemistry, organ weights or histopathological examination was observed. Dilatation of the cecum was not considered adverse effect since the dilatation was considered to be caused by dextrin which was included in GSE. In conclusion, the no observed adverse effect level（NOAEL）of GSE for male and female was judged to be 2000 mg╱kg under the experimental conditions here reported.

Objectives　Asperuloside is one of iridoid glucosides contained in Eucommia （Eucommia ulmoides Oliver）leaves. The oral administration of asperuloside to high-fat diet-fed rats resulted in anti-obesity effects. Recently it is reported that the oral administration of asperuloside increases Akkermansia muciniphila bacteria in gut which has a beneficial effect to the obesity. It is also reported that the oral administration of metformin increased the bile pool in the gut by the reduction of ileal absorption of bile acid, accompanied by a marked increase of A. muciniphila in the gut. From the comparison with the mechanism of metformin, possible mechanism on the increase of A. muciniphilla in gut by asperuloside was considerated. Methods　Hydrolysis reaction of asperuloside was respectively examined in the artificial gastric solution and in the artificial small intestinal solution adding amond-derived β-glucosidase and rat small intestinal acetone powder. Results　Asperuloside was not affected in the gastric solution. Asperuloside was also not affected in small intestinal solution by almond-derived β-glucosidase. Prior research indicated that the iridoid glucosides in the gut are only hydrolyzed into the unstable aglycone at ileum by the intestinal bacteria-derived β-glucosidase. So definitely asperuloside might be hydrolyzed into unstable aglycone at the ileum by the intestinal bacteria-derived β-glucosidase. Conclusions　Metformin increases the bile acid pool in the gut predominantly through reduced ileal absorption. It has been known that the unstable aglycone from asperuloside binds easily with proteins. Therefore, the increase of the bile acid pool in the gut by asperuloside administration in rats might be attributable to reduction of ileal absorption of bile acid by the transporter bound with the aglycone of asperuloside at ileum. We concluded that the increase of the bile acid pool in the gut by asperuloside resulted in a marked increase of Akkermansia muciniphila bacteria in the gut.

Objective　Athletes are under physical and mental stress on a daily basis such as high intensity exercise, game stress, etc., and the importance of maintaining good condition has been mentioned. Euglena gracilis EOD-1 is a kind of microalgae, contains over 50 kinds of various nutrients and 70％ to 80％ of β-1,3-glucan called paramylon which is unique component in Euglena species. EOD-1 strain contains more paramylon than other Euglena sp., so it is gathering attention as functional food. Recent studies suggest that salivary and blood of human contain the immunoglobulins which react the paramylon from EOD-1 strain, thus EOD-1 strain is expected to contribute to human immune function. Methods　We evaluated the effect of EOD-1 strain intake on rugby players during the season. Thirty-six male rugby players were subjected to the tests in open-label trial. They were given the supplement contain EOD-1 strain dried powder（500 mg）daily for the season. Results　By intake of the supplement contain EOD-1 strain dried powder was significant increased salivary testosterone compared with before ingestion and reduced a physical fatigue feeling. The rate of immunoglobulin secretion was maintained during the top league. Conclusions　It was suggested that the intake of Euglena gracilis EOD-1 strain is useful for athletes who exercise vigorously on a daily. （UMIN ID: UMIN000028531）

Objectives　The flavedo of shiikuwasha（Citrus depressa Hayata）, a fruit grown in Okinawa, is rich in polymethoxyflavonoids（PMF）, especially nobiletin, in comparison with other kinds of citrus. Recent in vitro and in vivo studies have shown that PMF has an effect of improving lipid metabolism and liver function. That is why we conducted an exploratory clinical trial using a hydrous ethanol extract of a Shiikuwasha peel, which includes flavedo, and we were able to confirm that it is also effective on humans. Therefore, this time, we evaluated it by a randomized, double-blind, placebo-controlled, parallel-group comparison study for verification purposes. Methods　The subjects were 44 men and women between the ages of 20 and 74 who are developing fatty liver. The test food was in a capsule shape and it contained 20 mg/day of Shiikuwasha extract（2 mg/day was PMF）. During the ingestion period of 12 weeks, physical examinations, blood tests, medical interviews, etc., were performed before ingestion as well as 6 and 12 weeks after ingestion. This study was conducted with the approval of the institutional review board. Results　43 people were subject to analysis（PMF group: 21, placebo group（P group）: 22）. In all cases, triglyceride, total cholesterol, arteriosclerosis index and non/HDL cholesterol were significantly decreased in the PMF group compared to the P group. In γ-GTP, in the subgroup of healthy subjects（PMF group: 16 persons, P group: 18 persons）, which excluded 9 persons exceeding 80 U╱L, the PMF group significantly decreased compared to the P group. In the safety assessment, there were no adverse events or abnormal changes in test values due to the test food.Conclusions　This study suggested that the Shiikuwasha extract improves lipid metabolism as well as liver function due to the effects of PMF, and the safety of continuous ingestion was also confirmed. （UMIN Trial ID: UMIN000021816）

Background　Issues in the knee joint is one of the major problems for elderly people. Labdane, which is contained in Japanese white turmeric leaf, has demonstrated to inhibit degradation of hyaluronic acid（HA）. Since HA is important for lubricating joints, Labdane is expected to have a role to maintain good joint health. Objectives 　For the purpose of applying to be considered as a functional food, we investigated the effect of Labdane intake with healthy adult men and women who feel discomfort in the knee joints. Methods　In a randomized, double-blind, placebo-controlled, parallel-group comparative study, 40 healthy subjects（ages 41 to 68 years）with discomfort in the knee joint received 0.11mg of Labdane per day for 12 weeks. The discomfort of the knee joint was measured from the start of intake until 12 weeks using Japanese Knee Osteoarthritis Measure（JKOM）and Visual Analogue Scale （VAS）. Results　Changes in the VAS assessment of JKOM knee pain（pain during knee flexion and extension）at weeks 0 and 12 showed a statistically significant improvement in knee flexion and reduction in extension pain in the intervention group compared to the control group.（ P＝0.01）.Conclusions　This study concluded that taking 0.11 mg/day of Labdane for 12 weeks in healthy adult men and women with a discomfort in the knee joint is significantly effective at improving knee flexion and reducing pain during extension. （UMIN-CTR ID: UMIN000040804）

Objectives　In our previous study, we confirmed the anti-hyperglycemic effect of Aloe vera gel and identified five minor plant sterols, named Aloe sterols, as active ingredients. This study was conducted to evaluate the effects of Aloe sterols on glucose metabolism. Methods　In total, 123 healthy adults with slightly elevated blood glucose levels participated in a randomized, double-blind, placebo-controlled, parallel-group trial. Subjects were allocated to an Aloe sterol group or a placebo group. The Aloe sterol group received 3 capsules daily containing 40μg Aloe sterol and the placebo group received 3 capsules daily containing no Aloe sterol for 12 weeks. An oral glucose tolerance test was carried out and blood glucose AUC was calculated at 0 and 12 weeks. Results　During the experimental period, no significant differences in fasting blood glucose levels were observed between Aloe sterol and placebo groups. However, the changes at 0 and 12 weeks in blood glucose levels at 60 minutes after OGTT and blood glucose AUC were significantly lower in the Aloe sterol group than placebo group, even though there was no difference in blood insulin levels. In addition, the Matsuda Index was significantly different in the two groups on subgroup analysis. No serious adverse events related to test foods ingestion were observed in the two groups. Conclusions　This study indicated that dietary supplementation with Aloe sterol has the beneficial effect of lowering postprandial blood glucose levels by improving insulin sensitivity in healthy subjects. （UMIN000037132）

Background　Panax ginseng is one of the most popular herbal medicine since ancient time. Generally, it has been used as a nutritional supplement or an analeptic. In addition to these benefits, ginseng is also considered to affect the nervous system and improve the cognitive functions. However, its scientific evidence for the cognitive function of healthy subjects has been still uncertain. Methods　In this study, we performed a randomized, double-blind, placebo-controlled parallel-group comparative study to evaluate the improvement of the cognitive functions by taking supplements made from Panax ginseng grown in Korea for 6 weeks. The changes in the cognitive functions of 30 healthy subjects over 60 years of age were evaluated by three cognitive tests: Benton visual retention test, modified Stroop test Ⅱ, and mini mental state examination （MMSE）. Results　Thirty subjects were allocated into two groups of 15 subjects. Each subject took either 2 packages of ginseng supplements or placebo in a day for 6 weeks. Two ginseng packages contain 7.8 mg of ginsenosides. Statistically significant improvements in the ginseng group were found by Benton visual retention test, however, no significant changes were observed in the placebo group. Mild cognitive improvements were also found only in the ginseng group by the modified Stroop test Ⅱ; while no significant changes were detected in the both groups by MMSE. Conclusion　These results suggest that the daily intake of the supplement of Panax ginseng has beneficial effects especially in the visual cognitive function and the selective attention. We speculate that the ginseng supplement has great possibilities to improve our health-related quality of life（QOL）.

Objectives　The aim of the present study was to investigate effects of whey protein containing soy-derived peptide（SOYLAX®）on responses to stresses and self-rated health in athletes. Methods　In this two-weeks-trial, 26 healthy volunteers who belonged to a university baseball team were recruited and divided into two groups. Test articles（whey protein containing 1000 mg of SOYLAX®）were administrated to one group（SOYLAX® group）and placebo whey protein were administered to another one（placebo group）before the practice every day. Concentration of salivary cortisol, Visual Analogue Scale（VAS）, Profile of Mood State 2nd Edition-Adult Short, 12-item General Health Questionnaire, Mood Check List-Short form.2 were repeatedly evaluated. Results　SOYLAX® group showed lower concentration of salivary cortisol than placebo group after the practice on the last day of the trial. The VAS score of satisfaction about physical function in SOYLAX® group was higher than in placebo group on the day after the game. Mental stresses test showed no significant differences between two groups. Conclusions　Drinking whey protein containing SOYLAX® could alleviate stresses after sports and improve the satisfaction about physical function in athletes. SOYLAX® would support athletes to show the best performances of them.

Objects　The aim of this study was to assess whether the ingestion of drinkable yogurt containing Lactococcus lactis subsp. cremoris YRC3780（YRC3780）can alleviate the symptoms of perennial allergic rhinitis. Methods　In a randomized, double-blind, placebo-controlled trial, 58 adults with perennial allergic rhinitis consumed 100 g of drinkable yogurt containing YRC3780（4⊠108 cells/day） or placebo for 8 weeks. The primary endpoints are the QOL questionnaire self-recorded their symptoms of eyes and nose at before, 4th and 8th week of the intake period, and the diary of discomforts of eyes and nose from the pre-observation period to the end of the intake period （total 9 weeks）. Secondary endpoints are specific IgE（house dust and mites）, salivary S-IgA concentrations and secretion rate, medical examination for check subjects nasal condition at before, 4th and 8th week of the intake period. Results　There was no significant difference between the two groups in QOL questionnaire for nasal and ocular symptoms, specific IgE（house dust and mites）, salivary S-IgA concentrations and secretion rate, medical examination for check subjects nasal condition. Discomfort score of eyes and nose during the intake period were grouped into 4 consecutive periods of 2 weeks each, and average values were compared between periods. In the YRC3780 group, itchy eyes score was significantly lower than scores in the placebo group during 2nd week of intake periods（P＜0.05）. Conclusions　This study suggests that the continuous intake of drinkable yogurt containing YRC3780 is a safe and effective approach to relieve the discomfort of the eye of perennial allergic rhinitis. （UMIN000041755）

コロナウイルス感染症の特効薬として，ワクチン開発が進んでいます（Box 1）。すでにいくつかのワクチンは承認済みですが，まだ数多くのワクチンが開発中です。国産のワクチンも早いものでフェーズII/III の最終段階ですが，聞くところによると症例数は500 人のようです。欧米で開発されたワクチンは，すべて4 万人近くの症例数で実施されました。それが500 人で済むとは到底思えません。それにしても，どうして何万人もの被験者が対象にならないといけないのでしょうか。今回はこれについて考えてみたいと思います。