薬理と治療

ファーマコビジランスにおける世界と日本の現状について説明し，漢方製剤のファーマコビジランスにおける課題についても触れてみたい。

初めに漢方の市販後安全対策について説明し，その後，RMP の概要，事例，通知等について紹介していきたい。

薬物や薬物療法に内在するリスクが問題となることがある。わが国では，添付文書に基づいて正しい目的で正しく使われていたにもかかわらず，入院・治療や死亡に至るような重大な副作用が発生した際に請求が認められると，治療費や死亡給付金を受け取ることができる副作用被害救済制度がある。重大な副作用に遭遇してしまった患者にとって，薬物療法のベネフィット・リスク・バランスは成り立っていないことになる。一方，本日のテーマであるRMPは集団でのリスクを管理し最小化するという考え方の中に存在している。新薬が承認された段階では，5 too’s といって，限られた症例であったり，日本人の症例が少なかったり，治験では長期投与試験でも52 週程度のデータしかなく，すべてがわかっているわけではないという制約がある。そのなかで，医療現場の医師，薬剤師は患者さんの安全を守りながら，ベネフィット・リスクのバランスを成り立たせなければならない。本稿では，病院薬剤師としてチーム医療に参加し，医師と共に処方設計や患者の副作用モニタリングにかかわっている立場からRMP について述べてみたい。

日本漢方生薬製剤協会（以下，日漢協）では，医薬品のリスク管理として，リスク・マネジメント・プラン（RMP）の考えに沿った「医薬品安全性監視活動」および「リスク最小化活動」のさまざまな取り組みを行っている。ここでは，その取り組みを説明するとともに，企業で実施されている適正使用の推進に資する研究活動，ならびに日漢協が目指す更なる適正使用の確立として，「漢方の将来ビジョン2040」の一部を紹介する。

医療用漢方製剤は148 処方，一般薬は294 処方が添付文書情報として公開されている。一般薬では西洋ハーブや漢方製剤，医療用医薬品では漢方製剤等が市販，処方されているが，こうした生薬や漢方製剤は，これまでヒトにおける投与実績や有効性・安全性等のデータがあるものが開発されている。ヒトへの投与実績が十分にある生薬・漢方の製品開発は，既存のストラテジーに基づき，開発が進められる。また，既存の医療用医薬品の漢方製剤に効能を追加等していくストラテジーも考えられる。さらには，これまでに開発されていない生薬や漢方に関して，ヒトへの投与実績がないもの，投与実績が十分にないものを，新規に開発していくというストラテジーもあるかもしれない。本稿では，ヒトへの投与実績がない，または十分にない多成分系としての生薬・漢方製剤を新規に開発することを想定した際の毒性評価の留意点について述べる。なお，本稿で述べる見解は，医薬品医療機器総合機構（PMDA）の公式な見解ではなく，あくまでも個人的な見解であることに留意願いたい。

Objective　This study was conducted to verify the antioxidant effect and to confirm the safety profile of orally ingested unheated yuzu seed oil collected by cold-pressing method. Methods　A randomized, dose-controlled, parallel-group comparative clinical trial was conducted among healthy Japanese adults. The experimental treatment comprised daily oral administration of four, six, or eight gelatin capsules filled with 300 mg yuzu seed oil for 12 consecutive weeks. In order to assess efficacy, blood samples were collected before and at 4, 8, and 12 weeks after commencing the ingestion of the yuzu seed oil, and plasma lipid peroxide concentrations―an index of the antioxidant capacity―were quantified using the thiobarbituric acid method. Safety was evaluated by blood tests and clinical assessment after 4, 8, and 12 weeks. Results　Twelve weeks after commencing the ingestion of yuzu seed oil, lipid peroxide levels significantly decreased in all three groups compared to the lipid peroxide levels at the baseline. There were no adverse effects of the experimental treatment. Conclusions　Continuous ingestion of yuzu seed oil-for 12 weeks had an antioxidant effect in healthy adults and demonstrated good safety with long-term administration. UMIN ID: UMIN 000017543

Objectives and method　A blood glucose level of 140 mg/dL or higher is considered to be high blood glucose, a blood glucose level of 80 mg╱dL or less is considered to be hypoglycemia, and a difference between postprandial high blood glucose（Max BS）and subsequent hypoglycemia（Min BS）≳60 mg╱dL is defined as glucose spike. The glucose spike group（S group）found by FreeStyle Libre Pro was loaded with 75 g OGTT, and then a 4-week administration experiment of the study drug was conducted（90 final analysis subjects）. Healthy group （H group）and S group were compared. The study drug administration group was divided into 4 groups（healthy group; H group, placebo group; P group, LAB4 alone administration group; L group, glucomannan-added LAB4 administration group; GL group）and compared. All were done by RCT, and the effects of LAB4 and glucomannan-added LAB4 on glucose spikes were examined. We also compared subjective symptoms and laboratory test values. Results and discussion　In 75gOGTT, hyperglycemia immediately after and hypoglycemia were observed in group S, and excessive insulin secretion was observed. LAB4 suppressed hyperglycemia and also suppressed insulin secretion. It can be seen that the mechanism of action involves the autonomic nervous system of the pancreas and liver （particularly the pancreatic parasympathetic nerve）. In the study drug administration, the improvement of glucose spike was superior in the order of GL group＞L group＞P group. There were no side effects other than loose stools. The subjective symptoms improved, and there were no cases of abnormal laboratory test values. LAB4 and glucomannan-added LAB4 are considered to be meaningful substances as glucose spike improvers.

Objectives　Abelmoschus esculentus（Okra）is a plant of the genus Abelmoschus manihot. It is a slimy plant that is often eaten in summer. We evaluated the efficacy of okra from Ibusuki on postprandial blood glucose levels. Methods　The subjects were healthy adult volunteers with a fasting blood glucose level of less than 126 mg╱dL and a postprandial blood glucose level of 140-200 mg╱dL after 120 minutes. A randomized, placebo-controlled, double-blind, crossover study was conducted in 30 subjects （7 males and 23 females aged 21 to 64 years）. Subjects were fed a placebo with either a low or high dose of the test food containing okra powder, followed by a carbohydrate-loaded diet. Blood glucose and insulin levels were measured 30 to 120 minutes after ingestion. Results　Ingestion of the test food in the low-dose group tended to lower the postprandial blood glucose level compared to the placebo group, and the increase in the value was significantly suppressed in the high-dose group. In the high-dose group, the value at 30 minutes after ingestion of the test food（128.1±5.0 mg╱dL）was significantly lower than the placebo value （137.4±5.7 mg╱dL, P＝0.005）. Total area under the curve of blood glucose level was 13,950 ±730 mg・min╱dL in the test group and 14,784±743 mg・min╱dL in the placebo group（P＝0.011）, showing a significant difference between the two groups. Conclusions　These results suggested that Abelmoschus esculentus（Okra）would be a viable prevention tool for type 2 diabetes.

Objectives　The aim of the present study was to examine the effect of a food product containing rare sugar syrup（RSS）on the body fat reduction and its acceptability in humans. Methods　Ninety-six healthy Japanese adults（25≲BMI＜30）were participated in a randomized, double-blind, placebo-controlled, parallel-group trial. Participants were divided into two groups; one group to consume one test beverage containing RSS 20 g（350 mL）per day for 12 weeks, and another group to consume one isocaloric control beverage（containing high-fructose corn syrup instead of RSS）as a placebo beverage. The visceral fat areas（VFA）using bioelectrical impedance analysis was measured on the start day and every 4 weeks along with the medical and physical examinations by a doctor and the collection of fasting blood and urine samples. Additionally, the measurement of VFA using computed tomographic scanning was performed on the first and last day of the trial. Results　After 12-week consumption of test or control beverage, VFA, body fat percentage and body fat mass in RSS group were significantly lower than those at baseline. Body fat percentage and body fat mass were also significantly lower in RSS group compared to control group. There was no adverse event reported nor observed for both groups during the trial. Conclusions　The beverage containing 20 g RSS per day were able to reduce body fat percentage and body fat mass without any adverse events in humans. The beverage was well-accepted.

Objectives　In this study, we aimed to clarify whether the beneficial effects of soy peptide as a functional food component are affected by a personʼs regular exercise or social participation habits. Methods　Seventy-three older adults（aged 71.7±5.5 years）were randomly assigned to either the control group（n＝35）or soy peptide intake group（n＝38）. Participants in the nutritional intervention group ingested a beverage containing soy peptide（4000 mg╱day as soy peptide） for 3 months. Body composition, physical performance, and cognitive function were measured at baseline and post-intervention. Results　After the 3-month regimen, physical performance（Timed Up & Go Test）and cognitive function（Recognition Memory Test for Words）were significantly improved, and the skeletal muscle index score tended to improve more for the soy peptide group compared with the control group. In addition, stratified analysis demonstrated that active people with regular exercise or social participation habits showed improved body composition, physical performance, and cognitive function in response to the nutritional intervention. However, non-active people remained unchanged in both groups. Conclusions　Soy peptide intake may be an important tool in reducing sarcopenia and cognitive decline in older adults with regular exercise and social participation habits.（ UMIN ID:UMIN00044966）

Objective　To investigate the effects of eicosapentaenoic acid（EPA）-containing food on low-density lipoprotein（LDL）cholesterol in healthy subjects with high-normal blood LDL cholesterol levels. Methods　A randomized double-blind placebo-controlled parallel-group trial was conducted in 28 healthy subjects with high-normal blood LDL cholesterol levels（120-139 mg╱dL）. The subjects were randomly allocated into the intervention（427 mg╱3 capsule of EPA）or placebo groups（n＝28 per group）. They consumed 3 capsules╱day of either EPA-containing food or placebo for 12 weeks. The primary outcome was LDL cholesterol level at 12 weeks, whereas the secondary outcomes were blood cholesterol levels（LDL, HDL, and total）, angioendothelial function, blood flow measurements, and subjective symptoms Results　Twenty-six subjects from the intervention group and 27 from the placebo group were analyzed. LDL cholesterol level at 12 weeks and the measured values and changes in the distance between the blood vessels from the baseline to 4 weeks significantly decreased in the intervention group compared to those in the placebo group（P＜0.05）. In the subgroup of females aged ≥50 years, the blood flow velocity at 8 weeks was significantly higher in the intervention group（P＝0.025）than that in the placebo group. Furthermore, no adverse events were reported.

Objectives　The purpose of this study was to determine the effects of single or long-term ingestion of a hotrienol-containing tablet on psychological stress and salivary biomarkers. Methods　A randomized, placebo-controlled, double-blind, crossover study was conducted with 42 healthy adults. The subjects ingested two tablets containing 0.03 mg of hotrienol or a placebo. Chronic Stress levels were measured using SCL30 and effects on the endocrine system were measured using salivary biomarkers. Secretory immunoglobulin A（s-IgA）, cortisol （Cor）, chromogranin A（CgA）and oxytocin（OT）were measured as biomarkers in saliva. Results　Out of the 42 subjects, 41 completed this study. Single ingestion of the hotrienol-containing tablet significantly increased salivary s-IgA and OT concentrations compared to the placebo. Although the SCL30 score was not significantly different compared to placebo, it decreased slightly in the group ingesting the hotrienol-containing tablet. In the subjects having high psychological stress as indicated by SCL30-score baseline（11-20 points）, long-term（2 weeks）ingestion of the hotrienol-containing tablet significantly decreased salivary Cor concentration compared to the placebo. Conclusions　This study confirmed that intake of hotrienol increased salivary s-IgA, which has been reported to increase in a relaxed mood; and salivary OT, which is associated with anti-anxiety effects and feelings of comfort. These results therefore suggest that single ingestion of hotrienol not only temporarily reduces psychological stress and anxiety, but also heightens pleasant feelings such as“relaxation”,“comfort”, and“emotional attachment”. 　　Further, it was confirmed that long-term ingestion of hotrienol reduced salivary Cor, which is an anti-stress hormone, indicating that hotrienol is effective in relieving chronic stress. UMIN ID: UMIN 000044060

Objectives　The aim of this study was to evaluate the effect of sugar-free chocolate on postprandial blood glucose in healthy people. Methods　Thirty-two healthy subjects participated in a randomized, single-blind, crossover trial. Subjects ingested normal milk chocolate or sugar-free chocolate containing maltitol. Blood glucose, blood insulin, blood triglyceride, and blood active glucagon-like peptide 1（GLP-1）levels were measured before and 30, 60, 90, 120 minutes after ingestion. Results　Blood glucose and blood insulin levels at 30, 60 minutes after ingestion of sugar-free chocolate were significantly lower than after ingestion of normal chocolate. Blood triglyceride level was not significantly different between both chocolates. Blood active GLP-1 level at 30, 60, 90, 120 minutes after ingestion of sugar-free chocolate was significantly higher than after ingestion of normal chocolate. Conclusions　In this study, blood glucose and blood insulin levels after ingestion of sugar-free chocolate were significantly lower than after ingestion of normal chocolate. Additionally, blood active GLP-1 level after ingestion of sugar-free chocolate was significantly higher than after ingestion of normal chocolate. Thus, sugar-free chocolate has less effect on postprandial blood glucose than normal chocolate. UMIN-CTR ID: UMIN 000045667

Objectives　This study aimed to evaluate the efficacy of a supplement product containing proteoglycan extract from salmon nasal cartilage on knee movement and walking function in healthy adults. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 54 participants aged 43 to 73 years with anxiety about falling. Participants were randomly assigned to receive a test product containing proteoglycan or placebo for 12 weeks. Primary endpoints were evaluated by Timed Up and Go（TUG）test and 6 min walk test. Secondary endpoints were evaluated by the score of Japanese Knee Osteoarthritis Measure （JKOM）, Tinettiʼs Fall Efficacy Scale（FES）, 2 step test, knee extension muscle strength and 30 sec chair stand test. Results　In analysis of the total evaluable population, there was no significant change in primary and secondary outcomes between test product group and placebo group. However, analysis of locomo level 1 participants revealed that significant decrease of time taken to stand and pre-turn time on TUG test in the test product group compared with the placebo group. In addition, the score of“Reach into cabinets or closets?”on FES in test product group was significantly lower compared with the placebo group. Conclusions　These results suggest that the ingestion of proteoglycan extract from salmon nasal cartilage improves knee movement and walking function in healthy adults whose mobility is beginning to decline with aging. （UMIN ID: UMIN000043053）

Objectives　This study investigated the associations of 30-min postload plasma glucose（30-mPG）levels during an oral glucose tolerance test（OGTT）with characteristics, lifestyles, and habits in Japanese adults without diabetes. Methods 　Participants comprised 1,085 healthy Japanese individuals（age, 20-64 years）who underwent 75-g OGTTs. Blood glucose and insulin levels were measured at 0, 30, 60, 90, and 120 min. Participants were classified into four categories based on the following conditions: Class 1, 30-mPG≤135 mg/dL; Class 2, 30-mPG 136-156 mg╱dL; Class 3, 30-mPG 157-177 mg╱dL; and Class 4, 30-mPG≥178 mg╱dL. Results　Proportions of participants in Class 4 were as follows: 20 s, 5.5％; 30s, 8.5％; 40s, 8.3％; 50s, 17.9％; 60s, 27.6％; BMI＜18.5, 13.3％; BMI 18.5-25, 11.7％; and BMI＞25, 17.3％. Conclusions　High levels of 30-mPG, a risk factor for type 2 diabetes, were found in a certain percentage of the general healthy population, as well as in younger individuals and those at low risk of lifestyle-related diseases. （UMIN ID: UMIN000037674）

Objectives　In previous paper, we reported the sleep improvement effect of Kwanso-deriverd Hypnocallis®（Hemerocallis fulva var. sempervirens）using OSA sleep questionnaire. In this paper, we analyzed electroencephalogram of Hypnocallis® using electroencephalography （EEG）recordings during sleep, and conduct a randomized, double-blind, placebo-controlled, crossover study for the purpose of examining a sleep improvement effect. Methods　A total of 45 individuals participated in the study. Among 35 otherwise healthy volunteers, 20 individuals with sleep disorder were selected according to the criteria for selection. Ten participants each were randomized to either ingest food containing Hypnocallis 2000 mg, or placebo over a period of 2 weeks. During 2 weeks of ingestion, the sleep EEG and the OSA sleep inventory score was measured. Results　All 20 participants completed the study. As a result of analysis of the sleep EEG, it significantly decreased（P＜0.05）at sleep latency and nocturnal awakening as compared with the placebo intake period for Hypnocallis® intake period. Also, ratios of non-REM sleep significantly increased（P＜0.05）as compared with the placebo intake period for Hypnocallis® intake period. Analyses of OSA sleep inventory score showed significant differences in sleepiness on rising（factor Ⅰ）, initiation and maintenance of sleep（factor Ⅱ）, dreaming（factor Ⅲ）, and relieving fatigue（factor Ⅳ）for Hypnocallis 2000 mg versus placebo. The adverse event to assume intake of the study food origin during an intake period did not occur, and there was not the safe problem to intake of the Hypnocallis extract. Conclusion　In Hypnocallis® including uncinoside A which was standardized extract derived from Kwanso improved quality of the sleep, and sleep latency and nocturnal awakening decreased by sleep EEG analysis, then increase of the non-REM sleep. （UMINID: UMIN000042200）