薬理と治療

目的　各種ラット病態モデルを用いて，hydromorphoneの鎮痛作用について比較検討した。方法　実験にはSD 系雄性ラットを使用し，completeFreundʼs adjuvant（CFA）誘発炎症モデル，脊髄神経結紮損傷モデル，足底切開モデル，抗がん剤誘発神経障害モデルを作製した。疼痛行動評価はすべてvon Frey フィラメントを用い，足底への機械刺激に対する逃避反応を指標に実施し，up︱down 法により50％反応閾値を求めた。各モデルにおいて，50％反応閾値を正常レベルまで改善した場合を100％として，hydromorphone 皮下投与後30 分および60 分時点での改善率ならびにED50を求めた。結果　Hydromorphone（0.03，0.1，0.3 mg╱kg，s. c.）は，すべてのモデルにおいて50％反応閾値低下を用量依存的に改善させた。CFA 誘発炎症モデルのED50（投与30 分後0.07 mg╱kg，投与60 分後0.11mg╱kg）を1.0 として他のモデルのED50の相対値を算出すると，脊髄神経結紮損傷モデルで2.3～2.4，足底切開モデルで1.3，抗がん剤誘発神経障害モデルで1.1～1.4 であった。結論　以上の結果より，hydromorphone は各種ラット病態モデルにおいて鎮痛作用を有することが示された。ED50の比較から，CFA 誘発炎症モデル＞抗がん剤誘発神経障害モデル＝足底切開モデル＞脊髄神経結紮損傷モデルの順に作用が強かった。

Objective Iguratimod is an antirheumatic drug, launched in September 2012 in Japan. During post-marketing surveillance, severe side effects, such as bleeding and coagulopathies, were reported upon concomitant use with the anticoagulant agent, warfarin. To investigate whether this drug-drug interaction（DDI）occurred through inhibition of metabolism, the effects of iguratimod and its metabolite M2 （N-acetylated metabolite）, a major metabolite of iguratimod in human plasma on the metabolism of S-warfarin were examined. Furthermore, the in vivo DDIs between iguratimod and cytochrome P450 2C9（CYP2C9）substrates were predicted from the in vitro data. Methods The in vitro inhibitory effects of iguratimod and M2 on the metabolism of S-warfarin were examined using human liver microsomes. In addition, CYP2C9 substrates diclofenac and celecoxib were also used as references in the study. Based on the data from this study and other literatures, the increases in area under the concentration-time curve（AUC）of S-warfarin, diclofenac, and celecoxib when used concomitantly with iguratimod were estimated using static or dynamic model approaches. Results Iguratimod and M2 inhibited the metabolism of S-warfarin, with IC50 values of 14.7 and 21.0μmol╱L, respectively. Iguratimod and M2 also inhibited CYP2C9 substrate metabolism, with IC50 values of 11.7 and 22.1μmol╱L for diclofenac, and 8.22 and 17.7μmol╱L for celecoxib, respectively. The AUC increase of celecoxib when used concomitantly with iguratimod was estimated to be 1.16 using a dynamic model, although those of S-warfarin, diclofenac, and celecoxib were estimated to be 1.22-, 1.16- and 1.34-fold, respectively, using static model approach. Conclusion The results in this study suggest that iguratimod would not affect the exposure of these concomitant drugs, although iguratimod and M2 do inhibit CYP2C9-catalyzed metabolism.

背景・目的　シルニジピン10 mg とバルサルタン80mg の配合剤であるアテディオ® 配合錠は，L╱N 型Ca チャネル阻害作用とアンジオテンシンⅡタイプ1受容体阻害作用をあわせもつトリプルブロッカーとして降圧治療に用いられている。しかしながら，日常診療における本剤の大規模製造販売後調査は報告されていない。方法　2200 例の症例回収を目標とした特定使用成績調査を2014 年10 月から開始した。12 ヵ月間の使用実態下での安全性および有効性を検討した中間報告を行う。結果　合計2672 例が登録され，2017 年3 月までに2095 例が回収された。そのうち解析対象症例2045例の男性割合は53.6％，女性割合は46.4％，平均年齢は67.5±12.6 歳であった。72 例（3.52％）に副作用が発現した。外来と家庭における収縮期血圧，拡張期血圧および脈拍数は，投与開始前とくらべ3 ヵ月後以降で有意に低下し，12 ヵ月後まで低値を維持した。結論　2000 例以上を対象とした日常診療下における12 ヵ月間の調査において，アテディオ® 配合錠は高血圧患者に長期間安全に投与することが可能であり，脈拍数を上昇させることなく，安定した降圧効果を示すことが確認された。

A long-term（3-year）post-marketing prospective study of anagliptin（brand name: Suiny(R)）, a dipeptidyl peptidase-4（DPP-4）inhibitor, in patients with type 2 diabetes mellitus is currently underway using the central registration method. This study aims to identify the safety and efficacy of anagliptin in clinical practice and also to promote the proper use of anagliptin. This time, we conducted an interim analysis in 4719 patients who were observed for 1 year. The incidence of adverse drug reactions（ADRs）in 4626 patients of the safety analysis set was 5.5％（256 patients, 311 episodes）. The most frequent ADRs were hypoglycemia（31 patients, 0.7％）, constipation（23 patients, 0.5％）, abnormal hepatic function（13 patients, 0.3％）and dizziness（10 patients, 0.2％）. The incidence of serious ADRs was 0.8％（37 patients, 41 episodes）. No notable problems were identified with respect to the priority study items（status of occurrences of hypoglycemia, intestinal obstruction, acute pancreatitis, serious skin disorders, infections and malignant tumors, safety in patients with hepatic function disorder, patients with renal impairment and elderly patients as well as impact on cardiovascular risks）. Changes in HbA1c, fasting blood glucose and random blood glucose levels from baseline at 1 year of treatment were －0.75％, －19.4 mg╱dL and －31.4 mg╱dL, respectively, showing significant decreases. Thus, a sustained blood glucose-lowering effect of anagliptin during the first 1 year of treatment was demonstrated. In addition, the proportions of patients achieving the glycemic control target HbA1c of ＜6.0％, ＜7.0％ and ＜8.0％ increased from baseline by 6.2 percentage points, 26.7 percentage points and 19.1 percentage points, respectively. The results of the interim analysis of this study suggest that anagliptin is a useful DPP-4 inhibitor in the treatment of type 2 diabetes mellitus.

A long-term（3-year）post-marketing prospective study of anagliptin is currently underway to examine the safety and efficacy in clinical practice in patients with type 2 diabetes mellitus. Data on the usefulness of anagliptin in 4719 patients who were observed for 1 year were reported in the“1-year Interim ReportⅠ of SWIM-JPN.”1） In the present report, we closely examined the effects of anagliptin on blood glucose and serum lipids in patients receiving anagliptin in the approved dose range between 100 and 400 mg╱day（usual-dose group）.Changes in HbA1c, fasting blood glucose and random blood glucose levels from baseline at 1 year of treatment with anagliptin were －0.75％, －19.5 mg╱dL and －31.3 mg╱dL, respectively. Thus, a sustained blood glucose-lowering effect of anagliptin during the first 1 year of treatment was demonstrated. In the examination of efficacy by patient demographic characteristic, the efficacy of anagliptin was confirmed regardless of sex, age, BMI, duration of diabetes mellitus, with or without concomitant antidiabetic drugs, with or without prior diabetes treatment, and with or without hepatic function disorder or renal impairment. The change in LDL-cholesterol（LDL-C）levels from baseline at 1 year of treatment was －7.8 mg╱dL, showing a significant decrease. In addition, a stratified analysis according to baseline LDL︱C levels revealed changes of －20.7 mg╱dL and －34.0 mg╱dL in patients with baseline LDL︱C levels of ≥120 mg╱dL and ≥140 mg╱dL, respectively. Thus, patients with higher baseline LDL-C levels showed a greater decrease in LDL-C. A similar statistical significant decrease was also observed in triglyceride（TG）levels. In addition to the blood glucose-lowering effect sustained throughout the 1-year treatment period in the usual-dose group of anagliptin, lowered LDL-C and TG levels were observed. These findings indicate that anagliptin is a potential treatment option for type 2 diabetes mellitus complicated by dyslipidemia.

Objectives To examine the effects of plasmalogen on brain function, a randomized double-blind placebo-controlled parallel group comparison study was conducted with 50 to 70 years old healty male and female who were aware of forgetfulness. Methods Plasmalogens used in this study were prepared from chicken breast meat, and were administered of low dose（1 mg plasmalogens╱day）to high dose（100 mg plasmalogens╱day） for 12 weeks to subjects. Results In Urbans neuropsychological test, significant scores were observed at the high dose and low dose groups compared with 12 weeks after intake to before intake in the overall evaluation item, respectively. Even in Cognitrax test, the score in some items increased significantly compared with before to after intake. The safety of plasmalogens was confirmed, because no adverse events were obserbed during this study. Conclutions It can be said that plasmalogens derived from chicken beast meat can be safely consumed in everyday diet and be expected to improve cognitive functions and prevent alzheimer disease.

Objective In recent years, it has been reported that the ingestion of bilberry extract improves visual function. However, few clinical studies have investigated the efficacy of bilberry extract for the improvement of eye fatigue-related symptoms that are induced by visual display terminals（VDT）. Therefore, we examined the safety and efficacy of bilberry extract （BILBERON(R)）in the treatment of VDT-induced eye fatigue-related symptoms. Methods In this human trial, healthy adult subjects with subjective eye fatigue who were exposed to VDT work for over 4 h╱day were recruited. The subjects were randomly divided into two groups（n＝10 for the test product group and n＝11 for the placebo group）and orally ingested either 160 mg╱day of BILBERON® or the placebo capsule for 6 weeks. The VDT was loaded on the examination days before and after the 6-week ingestion period. A Schirmerʼs test was performed before the VDT load to assess eye dryness, and the following investigations were performed before and after the VDT load: miosis frequency（MF）, near point pupil diameter （NPD）, and far point pupil diameter（FPD）examination to determine the accommodative function, critical flicker frequency（CFF）to assess eye fatigue, and a Likert scale questionnaire to assess subjective symptoms. Results Significant improvements were observed in the MF, variation between NPD and FPD, ratio of Schirmer value and subjective symptoms, including an eye fatigue sensation and a neck and shoulder stiffness sensation, of the test product group after the 6-week ingestion period compared to those of the placebo group. Moreover, the CFF（red light）, as a measure of eye fatigue, was less in the placebo group compared to that of the test product group, which suggests that the accumulative eye fatigue was suppressed in the test product group. Discussion Healthy subjects with subjective eye fatigue showed improvements in their VDT-induced eye fatigue-related symptoms, including accommodative function, eye fatigue, eye dryness, subjective symptoms of eye fatigue sensation, and neck and shoulder stiffness sensation, following an ingestion of 160 mg╱day bilberry extract（BILBERON(R)）for 6 weeks. In addition, the test product appeared to be safe under the conditions employed in the present study.

Objective The purpose of the study was to evaluate the dose response effect of soy peptide supplementation on cognitive function in healthy middle-aged and elderly participants. Methods A randomized, double-blind, placebo-controlled study was conducted. A total of 60 healthy middle-aged and elderly participants （between the ages of 60-70 years）were randomly divided into the following groups: soy peptide group receiving a medium dose（4 g（seryltyrosine content: 9.89 mg）; n＝20）, soy peptide group receiving a low dose（2 g（seryltyrosine content: 4.95 mg）; n＝20）, or placebo group（n＝20）. Psychological tests were performed at baseline and 2 weeks after supplementation with the test foods. Results The performance of the soy peptide groups in the Uchida-Kraepelin test significantly improved. Soy peptide supplementation also had a dose-dependent effect on the performance of participants in the n-back task and recognition memory test. Soy peptide supplementation did not, however, influence the subjective evaluation of the visual analogue scale. Conclusions The current study suggests that daily supplementation with soy peptide improves cognitive abilities, including sustained concentration and attention, short-term memory, and long-term memory, of healthy middle-aged and elderly participants, in a dose -dependent manner（UMIN-CTR ID: UMIN000026779）.

Objective This study was conducted to confirm the efficacy of a puffed fermented Korean ginseng extract-containing drink for stress, fatigue, and sleep after intake for 8 consecutive weeks in male and female adult workers aged 30 to 60 years. Methods Forty subjects were selected for this randomized, double-blind, placebo-controlled, parallel-group study. Subjects ingested the puffed fermented Korean ginseng extract-containing drink（functional ingredient: 10 mg of ginsenosides）or the placebo drink for 8 weeks. Stress, fatigue, and sleep were assessed using questionnaires（the Japanese version of the Profile of Mood States 2nd Edition-Adult Short［POMS2-AS］, the Athens Insomnia Scale［AIS］, and the Japanese version of the Pittsburgh Sleep Quality Index［PSQI︱j］）and biomarkers（serum DHEA-S and serum cortisol）. This study was registered at UMIN-CTR （UMIN000022943）. Results For 38 subjects in the efficacy analysis set, no significant between-group difference was found in efficacy. In an additional analysis of POMS2-AS scores in 11 middle-aged and older subjects aged 50 years or more, however, fatigue-inertia from baseline to Week 4 improved significantly in the puffed fermented Korean ginseng extract-containing drink group compared with the placebo drink group（P＜0.05）. Conclusions It was confirmed that the puffed fermented Korean ginseng extract-containing drink improves mental fatigue especially in middle-aged and older subjects. The drink had no safety problem to consume under the conditions of this study.

Background In recent years, the prevalence rates of allergic diseases have been increasing. The predominant symptoms of allergic rhinitis are sneezing, nasal discharge, and nasal obstruction. Objective The effect of daily intake of kale containing food for 12 weeks was evaluated in men and women with nasal and ocular symptoms due to mite or house dust allergy. Methods/study design A randomized double-blind placebo-controlled parallel group comparison study was conducted in 120 Japanese adults. Subjects ingested one of the following powdered foods: high-dose kale containing food（H group）, low-dose kale containing food （L group）, and placebo food without kale（P group）. The primary endpoint was change in QOL questionnaire scores from baseline（before study treatment）. As secondary endpoints, scores for nasal and ocular symptoms were determined from symptom diaries, and some immune functions were measured. Results There were no significant improvements in QOL score between the H group and P group or between the L group and P group. According to the analysis of subjects with a low baseline salivary sIgA secretion rates, salivary sIgA secretion rates were increased in the H group and L group compared with those in the P group. In addition, the salivary sIgA secretion rate increased from baseline in all three groups. Among the QOL questionnaire scores, “the daily living score”showed greater improvement in the H group than the P group （significant at Week 4）, and decreased in the L group. Symptom diary“nasal discharge”score showed greater improvement in the H group than the P group （significant at Week 8）, and decreased in the L group. During this study, no safety problems related to intake of kale containing food were observed. Conclusion These findings suggest that daily intake of kale containing food for 12 weeks may activate immune function and may improve nasal and ocular symptoms in subjects with low salivary sIgA secretion rates.