薬理と治療

本稿は，2 型糖尿病患者を対象に経口治療薬の服薬状況の実態把握と残薬が生じることへの影響要因を明らかにすることを目的とした。経口糖尿病治療薬服用の全国患者を対象にインターネット，郵送および訪問留置による調査を実施し2942 例の回答を得た。結果，3 割以上の患者で残薬が生じている，という回答がみられ，あらためて残薬の存在が確認された。残薬が生じている患者の服薬状況として，服薬頻度が多く，服薬のタイミングを守ることがむずかしいと考えており，残薬の申告をしていない傾向がみられた。また，HbA1c が高い患者であることが確認された。そのため，服薬薬剤の一包化の推奨，服薬回数╱種類を減らす，服薬管理は自身に加えて周囲にも留意してもらうなどの改善が必要である。また，病識・治療態度と生活スタイル・性格に関する回答の因子分析の結果，残薬が生じている患者には，「楽観志向」と「治療あきらめ志向」の二つの傾向がみられた。このように「残薬が生じている患者」は属性，服薬状況，生活スタイル・性格などに特徴がみられた。今後は，糖尿病治療にかかわる医療従事者のみならず，介護関係者ならびに患者家族が，患者の服薬コンプライアンス向上を念頭においた支援を推進していく必要がある。

Background Fibrates have been shown to effectively reduce hypertriglyceridemia and increase HDL cholesterol（HDL-C）levels. This indicates that fibrates therapy complements residual cardiovascular risk beyond the HMG-CoA reductase inhibitors（statins）treatment. Therefore, statins and fibrates combination therapy is a potentially useful strategy to prevent cardiovascular events. However, adverse drug reactions（ADRs）such as transaminase and creatinine elevation have been reported to fibrates treatments. In addition, statins and fibrates combination therapy have potential untoward effects on skeletal muscle, such as elevation of creatine kinase（CK）and myopathy. Here we evaluate and predict potential ADRs of pemafibrate（Parmodia(R) tablet, also known as K-877）, which was approved in July 2017. Methods Approval application data for pemafibrate were obtained from PMDA Web site （http:╱╱www.pmda.go. jp╱PmdaSearch╱iyakuSearch╱）. To evaluate efficacy and safety of pemafibrate, we compared several parameters between pemafibrate and fenofibrate from meta -analysis data of eight clinical trials. These include three comparative trials investigating the efficacy of pemafibrate and fenofibrate. Results Pemafibrate has greater PPARα activation potency than other fibrates with a lower EC50 value and high degree of subtype selectivity. Although, most of fibrates primarily excreted via the kidneys and display some increase in t1╱2 in patients with renal impairment, pemafibrate primarily eliminate via the liver and had a greater safety window compared with other fibrates. Fenofibrate-treated patients demonstrated a statistically significant increase in serum AST, ALT, γ-GTP, and creatinine level, and reduction in eGFR compared with pemafibrate-treated patients at Weeks 12. Conclusions In this meta-analysis and approval application data, pemafibrate was found to be superior to other fibrates for the treatment of patients with renal impairment. In addition, low drug-drug interaction and wide safety window of pemafibrate would allow to lower risk in myopathy by pemafibrate and statins combination therapy.

目的　爪に悩みがある健常成人に，豚皮由来コラーゲンペプチド5 g の経口摂取による爪への効果を検討した。方法試験食品と豚皮由来コラーゲンペプチド5 g，対照食品をデキストリンとした二重盲検試験。12 週間の経口摂取前後の爪水分量，経爪水分蒸散量，爪中のスフィンゴシンおよびセラミド量を測定し，試験食品摂取群と対照食品摂取群との群間比較を行った。結果　1 ）水分量　摂取12 週間後において試験食摂取群は，対照食品群と比較して有意に水分量が高く，摂取前後においても有意に増加していた。2 ）水分蒸散量　摂取12 週間後の群間差は認められなかったが，対照食品摂取群で認められた摂取前後の有意な上昇は，試験食品摂取群では認められなかった。3 ）硬度　摂取12 週間後の対照食品摂取群と試験食摂取群との群間比較において，試験食品群は有意に低値であった。4 ） スフィンゴシンおよびセラミド　摂取前後の比較において，対照食品摂取群では有意な変化を認めなかったが，試験食摂取群では有意にスフィンゴシンおよびセラミドの増加が認められ，対照食品群との群間比較においても有意な増加が認められた。結論　豚皮由来コラーゲンペプチドの経口摂取は，爪の水分量を増加させ，硬度を低下させる機能があることが確認された。また，経爪水分蒸散量の増加を抑制することや爪のスフィンゴシンおよびセラミドの増加を促すことも，対照食品摂取群との比較で認められた。以上の結果から，豚皮由来コラーゲンペプチドの経口摂取は，爪中の細胞間脂質を増加させることにより爪の保水性を保って乾燥を防ぎ，爪のしなやかさを向上させると考えられた。

背景　高分子多糖類のプロテオグリカンは，近年，注目度が高まっている日本独自の機能性素材である。そして，その膝関節炎への機能性には，免疫寛容を介した抗炎症作用によってもたらされるとされている。方法　本試験では，鮭鼻軟骨由来プロテオグリカン含有の食品を健常人に12 週間摂取させ，膝関節への有効性を評価した。被験食品群は，鮭鼻軟骨抽出物を配合したゼラチンハードカプセル1 粒から1 日1 回プロテオグリカン（900～1400 kDa）を5 mg 摂取した。試験では，独自のvisual analogue scale（視覚アナログ尺度，VAS）アンケートと高感度C 反応性タンパク（CRP）を主要評価項目として，主観的な評価に加えて炎症のバイオマーカーでも評価した。なお，被験者選定は，境界域の被験者が含まれないよう厳密に行った。結果　試験の結果，VAS アンケート設問Q1（総合評価）にて，4 週間後における変化率の群間比較で有意差（P＝0.049）が示され，被験食品の膝関節への有効性が示された。また，長時間の負荷や高負荷に対する違和感を評価した設問でも，4 週間後における変化量の群間比較で統計学的な有意傾向（正坐時Q10 P＝0.053，長時間の歩行時Q11 P＝0.097）も示された。同時に，高感度CRP でもVAS スコアQ1の変化と一致した減少傾向が示され，VAS で示された膝関節への有効性は，プロテオグリカンを含有する鮭鼻軟骨抽出物による免疫寛容を介した抗炎症作用によるものと示唆された。結論　本試験より，プロテオグリカンを含有したサプリメントを摂取することで膝関節の違和感を改善・予防することが示された。

Objective The aim of this study was to investigate the effect of intake of sweet beverage made from rice koji（amazake）on skin barrier functions in adult women. Methods We conducted a randomized, double-blind, placebo-controlled, parallel-group study with women subjects with moderately dry skin condition. Women subjects（64 persons aged from 20 to 64 years）were randomly allocated to 2 groups: placebo group（group P, n＝32）or amazake group（group A, n＝32）. They consumed 125 mL of amazake or placebo beverage daily for 8 weeks. After 4 and 8 weeks of the start of intake, measurements of stratum corneum hydration and trans-epidermal water loss（TEWL）on the left cheek and left upper arm as well as a self-assessed skin condition survey were conducted. The change from pretrial value were compared between the two groups（skin condition survey）. Results All of the subjects completed the study, whereas, 2 subjects in group A met the exclusion criteria for efficacy analysis. Thus, data for 62 subjects（n＝30 in group A and n＝32 in group P）were analyzed for efficacy. Since the results suggested an efficacy in elderly subjects with higher TEWL levels, a confirmatory analysis was performed on subjects（over 40 years old with their median cheek TEWL value≥14.7 g╱hm2（n＝12 in group P and n＝7 in group A）. The results revealed that TEWL in group A at week 4 was significantly lower（improved）compared to that in group P. No serious adverse event was observed during this study. Conclusions Intake of amazake is suggested to improve skin condition in women, especially in who aged over 40 and with moderate dry skin conditions.

Objectives The aim of this study was to investigate the effect of molecular hydrogen-infused water intake on the status of obesity in adult subjects whose body mass index（BMI） is less than 30. Methods A double-blind, placebo-controlled, parallel-group study was conducted with 62 healthy subjects（aged from 20 to 64）, who were allocated to placebo drink group（group P, n＝31）or active drink group（group A, n＝31）. Subjects consumed either placebo drink or active drink（molecular hydrogen-infused water; containing 0.64 mg of molecular hydrogen per daily dose, 500 mL）for 12 weeks. Changes in body mass index （ΔBMI）, abdominal visceral and subcutaneous fat area（ΔvFA and ΔscFA, respectively）, and serum lipids and oxidative stress markers were compared between the two groups by unpaired t-test. Results All of the subjects completed the study, and data for these subjects were analyzed for efficacy and safety. ΔBMI in group A was significantly lower than that in group P at week 4（－0.13 ±0.10 vs. ＋0.21±0.11, P＜0.05）and week 8（－0.14±0.11 vs. ＋0.18±0.11, P＜0.05）. Further, ΔscFA in females in group A was significantly smaller（－13.14 ±5.32 cm2 vs. ＋5.37±6.71 cm2, P＜0.05）compared to that in group P. Significantly reduced values for ΔBMI, ΔscFA, and ΔvFA（at week 12）were observed in group A in comparison to group P in a stratified analysis performed with subjects whose serum diacron-reactive oxygen metabolites （one of the oxidative stress markers）were higher than the average. No adverse events associated with the intake of hydrogen-infused water were observed during this study. Conclusions Our investigation suggests that intake of hydrogen-infused water improves the status of obesity.

Objectives The aim of this study was to evaluate the efficacy of ripe kumquats on various effects such as natural killer（NK）cell activity, fatigue, and stress in healthy adults with fatigue. Methods In an open-label, uncontrolled exploratory study, 9 healthy subjects with fatigue consumed one kumquat per day for 4 weeks. The subjects were advised to restrict intake of foods containing rich β-cryptoxanthin（CRX）such as Satuma mandarin orange during the clinical study. The primary endpoint was NK cell activity. The secondary endpoints were efficacy:e. g., bone metabolism, fatigue-related scales, and health-related quality of life（QOL）, adverse events, and serum β-CRX levels. All tests were performed at weeks 0（baseline）, 1, and 4 after kumquat ingestion and at 4 weeks follow-up, except in the case of adverse events. Results NK cell activity and serum β-CRX levels significantly decreased after the 4-week ingestion period onwards. For efficacy assessment, the total scores on the Chalder fatigue scale were measured and the fatigue-related scales significantly improved after 1 and 4 weeks ingestion. Moreover, mental health component summary scores in the SF-36 as health-related QOL also significantly improved, starting from 1 week after ingestion. No adverse events were related to the kumquat ingestion. Conclusions Ingestion of one ripe kumquat per day decreased both NK cell activity and serum β-CRX levels because of low ingestion of kumquat. Meanwhile, kumquats may have anti-fatigue and anti-stress effects. Further clinical studies of ripe kumquat are needed to determine the optimal dosing and efficacy in placebo-controlled trials.

Objectives The objective of this study was to investigate the effect of D-glucosamine hydrochloride（GlcN）administration on cartilage metabolism in bicycle players, based on stratified analysis utilizing biomarkers for cartilage and bone metabolism. Methods A randomized double-blind placebo-controlled clinical trial was conducted in 27 bicycle players. They were randomly assigned to 2 groups and administrated with a placebo（n＝13）or GlcN 1.5 g╱day（n＝14）for 3 months, and the effect of test supplements on cartilage metabolism was evaluated by analyzing a cartilage typeⅡ collagen degradation marker（CTX-Ⅱ, corrected by urinary creatinine Cr）using urine samples collected before（0 month）and after the administration of test supplements（3 months）. Results CTX-Ⅱ levels were not significantly different between the two groups（placebo group and GlcN 1.5 g╱day group）after the administration of test supplements（P＞0.2）. Next, the subject（n＝18）with small joint loading were evaluated based on the CTX︱Ⅱ level（＜500 ng╱mmol Cr）; CTX︱Ⅱ levels were substantially decreased in GlcN 1.5 g╱day group（n＝9, P＝0.05）compared with a placebo group（n＝9）after the administration of test supplement. Furthermore, among these subjects, the subject（n＝13）with small variation of joint loading （＜20％）were evaluated based on the level of NTx（a bone typeⅠ collagen degradation marker）; CTX︱Ⅱ levels were significantly decreased in GlcN 1.5 g╱day group（n＝7, P＜0.01）compared with a placebo group（n＝6）after the administration of test supplement. Conclusions These observations suggest that the daily administration of GlcN（1.5 g╱day） exhibits the chondroprotective action on the subjects with small joint loading by improving cartilage metabolism via the suppression of typeⅡ collagen degradation.

Objectives The objective of this study was to assess the safety of administration of mucuna sheets which contains L-dopa, by conducting the pharmacokinetics（PK）and the open-label trial in healthy elderly subjects. Methods Twenty-one Japanese healthy subjects, who were older than 60 years old, were enrolled in the study. The pharmacokinetics parameter of L-dopa which is the content of mucuna sheets were examined in two groups following the administration of two or four sheets of mucuna. Mucuna sheets were made of roasting and powdering the mucuna by Kisyu Hosokawa coroporation. After performing the PK trial, all participants ingested 6 sheets of mucuna per day for 12 weeks. The safety of ingestion of mucuna was evaluated through physical examination, interview, blood chemistry analysis, electrocardiogram（ECG）, and questionnaires on sleep and fatigue at baseline and every 4 weeks of treatment. Results The maximum plasma concentration（Cmax）of L-dopa of the groups which received two sheets and four sheets of mucuna were 137.4±96.8 nM and 483.0±409.7 nM, respectively. The individual variability of plasma concentration is around eight fold. Subjects showed no adverse reactions except slight sleepiness. Although there were significant differences in renal function and blood glucose level during 12 weeks of mucuna treatment, they do not impose any clinically important meaning and they are also considered not to be related with ingestion of mucuna sheet. Conclusion According to our findings, we conclude that continuous long-term administration of mucuna sheets at evaluated dose in elderly people is safe.