薬理と治療

「医師の祖」と言われる古代ギリシャの医師ヒポクラテスは，「いかなる患者を診るときもそれはただ患者に益するためである」と言っている。これはある意味では非常に古典的な患者中心主義であり，しかしながらこの考え方は，われわれ現代の医療者にとっても成立する重要な使命であるとされる。これに対して，患者の意向が反映された形で治験（開発）が実施されること，患者自らが参画すること，Digital Transformation（Dx）を利活用することといったことは，いま治験に求められる新患者中心主義ともいえる新たなコンセプトである。そして2020 年，われわれは新型コロナパンデミックを経験した。14世紀のペストパンデミックでは封建社会から近代市民社会へ移行した。20 世紀のスペイン風邪パンデミックでは5 億人が感染し第一次世界大戦が終結した。そして21 世紀の新型コロナパンデミックでも価値観の大きな転換が起きようとしている。それは治験の実施方法においても同様である。おそらく社会のあるべき未来を示す羅針盤のようなものだ。この新患者中心主義と新型コロナパンデミックの経験，これら二つの潮流によりもたらされる治験のあり方の大転換がまさにリモート治験である。

リモートSDV の推進が「臨床研究・治験活性化５か年計画2012」において提言されたことにより，話題に上ることはあったが，その実施まで至る医療機関はあまり多くない状況が続いていた。その状況が一変したのは，2020年春に発生したCOVID-19の感染拡大，それに伴う緊急事態宣言の発出であり，リモートSDV・モニタリングの必要性が一気に高まった。そのような背景のもと，当社では，多様なモニタリング業務へ対応すべく，医療機関，治験依頼者・CRO との協議を重ねてきた。その結果，多数のケースにおいて，リモートSDV・モニタリングの実施を進めることができた。本稿では，当社で実施しているテクノロジーを活用したリモートSDV・モニタリングの取り組みおよびテクノロジー活用だけでは解決できない課題に対するプロセス面での検討事例について紹介する。加えて，ポストCOVID-19 も見据えた持続可能なリモートSDV・モニタリング実施に向けての課題や対策についても提示したい。

がんのランダム化比較試験（RCT）では，治療のリスク，ベネフィット，および忍容性についての情報を提供するために，症状，機能，およびその他の健康関連QOL の側面等の患者報告アウトカム（PRO）を評価することが多くなっている。しかし，専門家の見解および批判的な文献レビューからは，がんのRCT では最適なPRO の解析についてのコンセンサスが存在しないため，結果の解釈が困難であることが示された。PRO の解析のための推奨を確立するために，PRO およびQOL 評価項目データの解析における国際標準策定（Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data）コンソーシアムが設立された。以下の4 つが優先課題とされた：適切な統計手法に合致した研究目的の分類法の開発，PRO の解析のための適切な統計手法の特定，欠測データに関連する統計用語の標準化，欠測データの適切な取扱い方法の決定。このポリシーレビューでは，推奨の基礎となる批判的な文献レビューおよび多様な国際的ステークホルダーとの構造化された共同プロセスを通して開発されたPRO の解析のための推奨を提示し，これらの推奨に関する進行中の議論についても考察する。

Objectives　Hypertriglyceridemia was shown to be a risk factor for bone fractures by SWAN study. We previously reported that hypertriglyceridemia contributes to a lower bone density in type 2 diabetic patients and confirmed that hypertriglyceridemia is a risk factor for osteopenia and bone fractures. Fibrate agents, peroxisome proliferator-activated receptor alpha（PPARα）-agonists, have a strong effect to reduce plasma TG levels. Although the previous reports have shown the causal relation of hypertriglyceridemia on osteopenia, there are few data concerning the effect of fibrate agents on bone disease. In the present study we examined the effects of fenofibrate on TG-rich lipoproteins-loaded osteoblastic cells. Methods　TG-rich lipoproteins was collected from plasma by density gradient ultracentrifugation. Normal human osteoblastic cells were cultured, and were loaded with TG-rich lipoproteins. Fenofibrate was added to TG-rich lipoproteins-loaded human osteoblastic cells at a concentration of 50, 100, or 300μmol╱L, and after 6 hours of incubation, total RNA was isolated for analysis. The mRNA expression of PPARα, RANKL, Type 1 collagen, Runx2 and Twist was quantified by RT-PCR. Results　The addition of fenofibrate in TG-rich lipoproteins-loaded osteoblastic cells significantly decreased RANKL mRNA expression and significantly increased Type 1 collagen mRNA expression in a concentration-dependent manner. The addition of fenofibrate significantly increased Runx2 mRNA expression and significantly decreased Twist mRNA expression in a concentration-dependent manner. Conclusion　Fenofibrate has beneficial and protective effects on bone loss through a plasma TG-lowering action and a direct action on osteoblastis in patients with hypertriglyceridemia and diabetes. （Jpn Pharmacol Ther 2022；50：2151‒6）

Objectives　Equol, a metabolite of a soybean isoflavone daidzein, is produced by intestinal bacteria and has various effects on the health of menopausal women. Approximately half of the Japanese population can produce equol in the intestine, but the other half cannot. If equol is not produced in the body people does not have the benefits of it even soy foods are ingested. This study investigated a potential of future health prediction by which a cross-sectional observation between women who can and cannot produce equol in members of a health insurance society. Methods　Those who had a health checkup result for the last 2-3 years were subjected to a questionnaire survey and determination of equol productivity. A urine sample with an equol concentration of 1.0μM or more was detected as an equol producer（EQL-P）, and an equol concentration of less than 1.0μM was regarded as a non-producer（EQL-N）investigated. Results　In postmenopausal womenʼs analysis, EQL-P had less severe menopausal symptoms than EQL-N（P＝0.020）. Number of participants who has“facial hot”（P＝0.030）“, easy to get tired”（P＝0.015）, was significantly lower in EQL-P than EQL-N. Based on the analysis of all subjects（n＝455）, allergic rhinitis（including hay fever）existing person（P＝0.012）, and frequency of headache（P＝0.046）was lower in EQL-P than EQL-N. Conclusions　Those data suggested that the presence or absence of equol-producing ability was considered to provide useful information for predicting the future health of women. （Jpn Pharmacol Ther 2022；50：2157‒65）

Objective　The Department of Pharmacy at Fukuoka University Chikushi Hospital introduced a hospital version of the picking support system（PORIMS®）in August 2019 to prevent drug type and specification errors. Here, we comparatively investigated the number of dispensing errors, time required for dispensing, and mental state of the dispensing personnel before and after the introduction of PORIMS®. Methods　The number of dispensing errors and mean dispensing time per drug during 3 months before and after the introduction of PORIMS® were investigated. Furthermore, we conducted a survey using a 5-point scale to ascertain the mental state of personnel in terms of anxiety they felt regarding dispensing and auditing before and after the introduction of PORIMS® and to gage their impressions regarding the GS1 DataBar®. Result　The number of times the wrong quantity, drugs with the wrong specifications, or wrong the type of drug was dispensed decreased from 14 to 11, 1 to 0, and 4 to 0, respectively, with the introduction of PORIMS®. The mean time required to dispense one drug increased after the introduction of PORIMS®（median of 21.2 seconds vs. 31.4 seconds, P＝0.035）. Anxiety associated with dispensing and auditing considerably reduced following the introduction of PORIMS®. All dispensing personnel felt that having the GS1 DataBar® barcode on each tablet on a blister pack was“Good”. Conclusion　The study suggests that the introduction of PORIMS® is effective in preventing human dispensing errors and reducing the mental stress of pharmacists. （Jpn Pharmacol Ther 2022；50：2167‒74）

Objectives　Excessive physical activity induces mental fatigue in addition to physical fatigue. Mental fatigue is thought to be a state of reduced brain activity. To maintain normal brain activity, neurons require large amounts of adenosine triphosphate（ATP）for neurotransmission. Therefore, a decrease in energy production in neurons leads to decline in brain function, which may be one of the causes of mental fatigue. In this study, we investigated the effects of taurine and a combination of five essential amino acids on energy production in human neuroblastoma SH-SY5Y cells with the aim of creating a useful countermeasure for mental fatigue. Methods　Human neuroblastoma SH-SY5Y cells were incubated with taurine and╱or five essential amino acids（L-threonine, L-leucine, L-isoleucine, L-valine, and L-phenylalanine）for 24 h in the Dulbeccoʼs modified Eagleʼs medium without amino acids supplemented with 10％ fetal bovine serum. After incubation, we evaluated the intracellular ATP content, localization of intracellular ATP, mRNA expression levels of electron transport chain components（NDUFS1, COX4I1 and ATP5F1A）, and rate-limiting enzyme of TCA cycle（CS）. Results　The combination of taurine and five essential amino acids increased the intracellular ATP content compared with control group. Furthermore, the intracellular ATP colocalized with mitochondria mRNA expressions of NDUFS1, COX4I1, ATP5F1A and CS were increased by treatment with the combination. Conclusions　The combination boosted the intracellular ATP content with increased the mRNA expressions of mitochondrial electron transport chain components in human neuroblastoma SH-SY5Y cells. （Jpn Pharmacol Ther 2022；50：2175‒81）

Background　In January 2016, Bexarotene（Targretin® capsule 75 mg）was approved for the treatment of cutaneous T-cell lymphoma（CTCL）. A find analysis of the drug use-results survery（ all-case surveillance）was conducted as a codition, and we describe the result here. Methods　This survey is a non-interventional prospective observational study based on new accumulated data under routine medical examination by a post-marketing surveillance. Patients with CTCL enrolled in the central registry system were included in the study based on the data compiled from June 23, 2016, to Jun 31, 2019, and we examined the safety and efficacy of cases with institutional consent. Results　There were 291 cases subject to safety analysis and 282 cases subject to efficacy analysis. There were 205 cases（70.5％）who received this drug for 3 months or longer. Adverse effects were observed in 284（97.6％）, with the most frequent endocrine disorders in 242 （83.2％）, followed by metabolic and nutritional disorders in 226（77.7％）. Serious side effects were observed in 35 patients（12.0％）. The efficacy cases evaluated by mSWAT were 173 cases, and the response rate was 104 cases（60.1％）. On the other hand, 114 cases were evaluated by PGA, and the response rate was 46 cases（40.4％）. Conclusion　The present survey confirmed the safety and efficacy of bexarotene in routine clinical practice. （Jpn Pharmacol Ther 2022；50：2183‒98）

Background　Salivary IgA has a major role in mucosal immunity by protecting the body from pathogens, and it is a promising biomarker for immunity. Salivary IgA analysis has never before been used in mail-in tests nor for a large-scale survey using mailed samples. In this study, we examined the temperature stability of the salivary IgA and conducted a large-scale survey using questionnaires and mailed samples to investigate the relationship between salivary IgA levels and lifestyle. Methods　To evaluate the temperature stability of salivary IgA, samples were exposed to 25℃ and 37℃ for 7 days, and the percentage remaining from the initial value was calculated. In a large-scale survey using mailed samples, 930 Japanese（345 males, 583 females, and 2 unresponsive） mailed saliva samples twice（one week apart）. Using the mail-in tests, salivary IgA levels were collected and at the same time a lifestyle survey was conducted. Results　Salivary IgA was stable for one week at room temperature and high temperature. The relationship between lifestyle and salivary IgA from previous studies was reproduced in the large-scale survey. Analysis showed a significant increase in salivary IgA levels for those that reported a decrease in fatigue between the first and second session（P＝0.02）. Furthermore, a relationship between salivary IgA levels and BMI was shown. Conclusions　This study confirmed the temperature stability of salivary IgA to be used for mail-in tests. In addition, a large-scale survey using mailed specimens resulted in the similar trends as previous studies regarding the relationship between salivary IgA levels and lifestyle habits, suggesting the validity of the mail-in test. （Jpn Pharmacol Ther 2022；50：2199‒205）

Objectives　We developed fermented tea leaves by mixing thinned fruits of satsuma mandarin and fresh green tea leaves at the level of 1：3. We investigated the effects of feeding fermented tea leave powder for 12 weeks on cognitive function. Methods　We conducted a randomized, double-blind, placebo-controlled, parallel-group comparative study. Subjects were divided into the two groups, and were either given fermented tea leave powder containing 36.7 mg hesperidin or placebo powder not containing hesperidin. Mini-Mental State Examination（MMSE）and Trail Making Test-Japan（TMT-J）Part A and Part B which are generally used for the cognitive functions were conducted. Results　The time to complete TMT-J Part A were significantly shortened by feeding fermented tea leave powder containing hesperidin compared to feeding powder not containing hesperidin after 12 weeks. Conclusions　This result suggested that the fermented tea leaves made from thinned fruits of satsuma mandarin and fresh green tea leaves is effective for improving cognitive function. （UMIN ID: UMIN000045217）（Jpn Pharmacol Ther 2022；50：2207‒14）

Background and purpose　Aged people are more likely to become the undernutrition and╱or sarcopenia because of some diseases, aging, living environment, change of hormone and lack of dietary intake. Therefore, there are many reports about dietary intake including protein for preventing undernutrition and sarcopenia. In this study, a single group pre-post trial was carried out to investigate the effect of fish paste products, satsuma-age, intake in aged healthy humans. Methods　A group of 15 aged healthy subjects（6 males; 9 females; age, 65.67±3.46）was invited to have the fish paste products, satsuma-age（90 g）daily for 28 days. Physical characters and blood biochemical parameters were measured before（0 day）and after（28 days）consumption of the satsuma-age. Qualitative analysis of compounds in the satsuma-age were investigated by HPLC system. Results　No abnormalities and side effects were observed in the satsuma-age intake for 28 days. Muscle levels of after 28 days satsuma-age administration tended to be higher than those of before satsuma-age administration. The levels of left and right grip strength, back strength were significantly higher after 28 days of satsuma-age consumption. Moreover, blood total proteins, albumin and urea nitrogen levels were significantly higher after 28 days of satsuma-age consumption. Essential amino acids and some kinds of vitamins were contained in the satsuma-age. Conclusions　To the authorsʼ knowledge, this is the first report on the effectiveness of satsuma -age on body management for 28 days administration in aged healthy humans. This report suggest that satsuma-age intake might be beneficial for preventing undernutrition and sarcopenia. （Jpn Pharmacol Ther 2022；50：2215‒23）

Objectives　This study aims to verify the effects of supplements containing 4′-demethyl nobiletin and 4′-demethyltangeretin on logical thinking ability. Methods　A randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted on subjects who felt their memory decline with aging. Seventy-two Japanese volunteers were randomly assigned to 2 groups and ingested either placebo or the test foods containing 10 mg 4′-demethylnobiletin and 5.2 mg 4′-demethyltangeretin daily for 12 weeks. Subjects were given a logical thinking test to measure their ability to think logically, and their attention, concentration, judgment were examined using cognitive function tests（Cognitrax）. Results　The population from the full analysis set（FAS）revealed significant improvements in the logical thinking test score change amounts at 12 weeks in the test food groups compared to the placebo food groups（P＜0.05）. Additionally, Cognitrax score change amounts at 12 weeks in the test food groups also, significantly showing improvements compared to the placebo food groups（P＜0.05）. Conclusions　The results suggested that the intake of supplements containing 4′-demethyl nobiletin and 4′-demethyltangeretin improved logical thinking ability. （UMIN ID: UMIN000046689）（Jpn Pharmacol Ther 2022；50：2225‒36）

Objectives　To investigate the effects of acetic acid bacteria（Gluconacetobacter hansenii GK-1; GK-1）ingestion on plasmacytoid dendritic cell（pDC）activity and body condition. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted on 98 healthy Japanese adults who were susceptible to cold-like illness. They were categorized into two groups: acetic acid bacteria group and placebo group. Participants ingested daily GK-1 compounded capsules（9×109 cells╱day）or placebo diet over a 12-week period. A diary-administered physical condition questionnaire survey was administered daily during the intervention period. Blood sampling was performed pre- and 12 weeks postintervention, and peripheral blood mononuclear cells were used to measure pDC activity. Results　The results of the physical condition questionnaire revealed that the GK-1 group had significantly fewer cumulative days of symptom onset than the placebo group across eight items of the questionnaire, including feeling sick, runny nose, stuffy nose, sneezing, cough, head discomfort, chest discomfort, and feeling tired. Moreover, when the overall subjective symptom assessments pooled across all 11 items of the physical condition questionnaire were compared every 3 weeks, the GK-1 group had significantly fewer cumulative onset days than the placebo group at weeks 1-3, 7-9, and 10-12. At 12 weeks, the GK-1 group had significantly higher levels of pDC activity markers, CD80 and CD40, than the placebo group. Conclusions　The findings of this study indicate that long-term ingestion of GK-1 may activate pDC and act to maintain immune function. （UMIN ID: UMIN000045838）（Jpn Pharmacol Ther 2022；50：2237‒48）

Objectives　We aimed to examine whether the ingestion of Gluconacetobacter hansenii GK-1 （GK-1）could affect IFN-α production and physical condition maintenance. Methods　We conducted a randomized, double-blind, placebo-controlled study. Sixty healthy Japanese adults were randomly assigned to the GK-1 or placebo group. The participants ingested GK-1（9×109 cells╱day）or placebo（dextrin）for 8 weeks. Immune response was determined by the evaluation of IFN-α, and the diary-administered physical condition survey was conducted during the study period. Results　The GK-1 group had a significantly higher ⊿IFN-α at 8 weeks after ingestion（P＜ 0.05）and maintained better physical condition than the placebo group with no adverse effects. Conclusion　Our findings suggest that the continuous ingestion of GK-1 regulates IFN-α to maintain physical condition. （UMIN ID：UMIN000045840）（Jpn Pharmacol Ther 2022；50：2249‒56）

Objectives　This randomized, double-blind, placebo-controlled, parallel-group study aimed to investigate the effects of supplementing foods with pine bark extract on skin health parameters. Methods　This study included 70 healthy adult women with dry skin who were randomly assigned to either a test food group or a placebo group. For eight weeks, participants consumed either test foods containing pine bark extract（adjusted to provide 2.4 mg╱day of procyanidin B1 and procyanidin B3）or placebo foods（similar foods without pine bark extract）. The primary outcomes（skin viscoelasticity and stratum corneum water content）and secondary outcomes（visual analogue scale［VAS］questionnaire survey on skin condition and skin color difference）were evaluated before and four and eight weeks after initiation of experimental diets. Results　The test food group demonstrated significant improvements in skin viscoelasticity, VAS scores“Wrinkles”and“Sagginess,”and skin brightness（P＜0.05）compared to the placebo food group. In contrast, no significant change was observed in stratum corneum water content. No adverse events attributable to the test foods were observed throughout the study period. Conclusions　Foods containing pine bark extract may improve skin parameters such as elasticity, subjective symptoms such as“Wrinkles”and“Sagginess,”and skin brightness in healthy adult women with dry skin. （UMIN-CTR ID: UMIN000046264）（Jpn Pharmacol Ther 2022；50：2257‒65）

In clinical trials of pharmaceuticals, it has been recognized that, when the effect is small or the placebo effect is large, it is difficult to obtain a statistical difference from placebo control, and a different control group is to be used in such cases. Although functional foods are such an example, almost all products are tested using a placebo control resulting in a difficulty in obtaining a statistical difference. Scientifically acceptable control groups other than placebo should be considered in the clinical trials for food function. （Jpn Pharmacol Ther 2022；50：2267‒70）

新型コロナウイルス感染症（COVID-19）に伴う超過死亡率について，本誌において5 月号と7 月号の2 回に分けて書きました1, 2）。ところが読み返してみると，超過死亡率の定義が異なって誤解を招いたかもしれないことに気づきました。本号で詳しく説明したいと思います。