薬理と治療

As a part of the safety evaluation of A-mix, a mixture of three amino acids, L-alanine, L-phenylalanine and L-arginine, bacterial reverse mutation test was conducted using five strains of bacteria including Salmonella typhimurium TA100, TA1535, TA98 and TA1537 and Escherichia coli WP2 uvrA. The highest concentration of A︱mix was 5000μg╱plate, the recommended maximum concentration in the reverse mutation test, and a total of five concentrations including 2500, 1250, 625 and 313μg╱plate were tested. The results revealed that there was no increase in revertant colonies in any strain of bacteria at any concentration with or without metabolic activation; therefore, it was concluded that A-mix had no potential for inducing bacterial reverse mutation.

As a part of the safety evaluation of A-mix, a mixture of three amino acids, L-alanine, L-phenylalanine and L-arginine, chromosomal aberration test was conducted using cultured Chinese hamster lung fibroblast（CHL╱IU）cells. The highest concentration of A-mix was 5000μg╱mL, and a total of three or four concentrations including 2500, 1250 and 625μg╱mL were tested （625μg╱mL was used only for long-term exposure test）. The results revealed that the TA values（total number of cells with aberration excluding gap）and number of polyploid cells were less than 5％; therefore, it was concluded that A-mix had no potential for inducing chromosomal aberration.

As a part of the safety evaluation of A-mix, a mixture of three amino acids, L-alanine, L-phenylalanine and L-arginine, micronucleus test was conducted using bone marrow cells of rats. The rats were treated with A-mix by oral gavage for consecutive two days, at dose levels of 4000, 2000 and 1000 mg╱kg body weight. The results revealed that there was no increase in micronucleated polychromatic erythrocytes compared with the concurrent negative control; therefore, it was concluded that A-mix had no potential for inducing micronucleus.

As a part of the safety evaluation of A-mix, a mixture of three amino acids, L-alanine, L-phenylalanine and L-arginine, the acute oral toxicity was assessed in male and female SD rats. A-mix suspended in 0.5％ methylcellulose solution was administered to rats once by oral gavage at dose levels of 0, 400, 1200 and 4000 mg╱kg body weight and the animals were observed for 14 days after administration. No deaths occurred and there were no test article-related changes in the clinical observations, body weight changes or necropsy. Therefore, it was concluded that the approximate lethal dose of A-mix was greater than 4000 mg╱kg body weight when A-mix was administered orally to rats once and the acute toxicity was very low.

As a part of the safety evaluation of A-mix, a mixture of three amino acids, L-alanine, L-phenylalanine and L-arginine, repeated-dose toxicity was assessed in male and female SD rats. A-mix suspended in 0.5％ methylcellulose solution was administered by gavage to rats once a day for 13 weeks, at dose levels of 0, 200, 600 and 2000 mg╱kg body weight╱day. There were no toxic changes induced by A-mix in the clinical observations including mortality, body weight changes, ophthalmology, urinalysis, hematology, blood chemistry, necropsy, organ weights or histopathology. Therefore, it was concluded that the no observed adverse effect leve（lNOAEL） of A-mix was 2000 mg╱kg body weight╱day for both males and females in the present study.

The antimetastatic effect of peptidoheteroglycan（FA-1a）and╱or 5-FU was examined in an experimental model of lung metastases induced by Lewis lung carcinoma in mice. Injection of FA-1a i. p. after removal of the implanted primary tumor inhibited the development of lung metastases. Combination treatment with FA-1a and 5-FU inhibited significantly the lung metastases. Lung metastases were inhibited by i. v. injection of FA-1a︱activated adherent peritoneal exudate cells（PEC）, and these cells showed the direct cytocidal action on tumor cells. FA-1a depressed aniline hydroxylase and aminopyrine demethylase activities of the hepatic microsomal drug-metabolizing system in tumor-bearing mice. Moreover, the concentration of 5-FU in the tissues（lung, liver, kidney, spleen, and blood）was increased significantly by coadministration of FA-1a. These findings raise the possibility that FA-1a may have clinical value in the prevention of cancer metastasis.

目的Sodium glucose co︱transporter 2（SGLT2）阻害薬ルセオグリフロジンの高齢2 型糖尿病患者における使用実態下での安全性と有効性を，特定使用成績調査として検討する。方法ルセオグリフロジン市販開始から約3 ヵ月間（2014 年5 月23 日～8 月31 日）に本薬の投与が開始された65 歳以上の2 型糖尿病患者を対象に，可能な限り全例を収集する特定使用成績調査を実施した。観察期間は投与開始日から1 年間とした。結果本調査の安全性解析対象は1262 例，有効性解析対象は1249 例であった。安全性解析対象（1262例）の平均年齢は73.0 歳，糖尿病の平均罹病期間は10.2 年，ルセオグリフロジン投与前の平均HbA1cは7.63％，平均BMI は26.2 kg╱m2，平均推算糸球体濾過量（eGFR）は67.6 mL╱min╱1.73 m2であった。ルセオグリフロジン投与開始時の他の血糖降下薬の併用状況は，ルセオグリフロジンと2 薬剤以下（併用なしも含む）の血糖降下薬を併用する高齢患者が81.9％を占めていた。副作用は安全性解析対象症例1262 例中169 例に201 件発現し，発現率は13.39％であった。なお，若年層を含む本薬承認時までの臨床試験成績では1262 例中236 例に副作用が発現し，発現率は18.7％と報告されている。また，ルセオグリフロジン投与開始時のeGFR で層別して本薬投与後のeGFR 推移を評価したが，有意な変化は認められなかった。有効性解析対象（1249 例）におけるHbA1c，空腹時血糖および体重の推移や変化量は，有意に低下していた。結論高齢2 型糖尿病患者を対象としたルセオグリフロジン使用実態下での特定使用成績調査からは，新たに注意喚起が必要な安全性情報は得られなかった。有効性については，本薬承認時までに得られた臨床試験データと類似したものであった。【COI】本調査は大正製薬㈱が実施した特定使用成績調査である。さらに，本論文の投稿費用は大正製薬㈱が負担し，本稿の作成には大正製薬㈱の資金提供により㈱インターサイエンス社が関与した。【謝辞】本調査にご協力を賜り，貴重なデータをご提供いただきました医師の方々ならびに関係者の皆さまに厚く御礼申し上げます。

Background Guiding principles in the use of antihistamines for patients with long QT syndrome have not been fully discussed, although there are some case reports showing longer QT interval after administration of antihistamines. Methods We exhaustively investigated non-clinical electropharmacological profiles of antihistamines according to the ICH-S7B guideline using the drug interview form and research papers, and assessed their risk of QT interval prolongation. Results Both in vitro IKr assay and in vivo QT assay have been carried out in 13 out of 27 antihistamines, and most of the drugs are second-generation antihistamine. The remaining 14 antihistamines, including most of the first-generation drugs, do not have enough in vivo or in vitro data for accurately assessing the risk of drug-induced QT interval prolongation. Conclusions About half of antihistamines have electropharmacological data, which can be utilized for risk assessment of drug-induced QT interval prolongation.Electropharmacological profiles of the first-generation antihistamines should be checked for safety use for patients with long QT syndrome.

Objectives The aim of the present study was to investigate an effect of rare sugar syrup（RSS） on sucrose absorption in humans. Method Firstly, effect of RSS on α-glucosidase was assessed by measuring sucrase and maltase activities in the small intestine of rat. Secondly, effect of RSS with sucrose on blood glucose and insulin was evaluated by a series of two single blind, randomized, placebo-controlled crossover trials in humans. In 50 g tolerance test, 10 normal humans ingested one of 4 treatments with different ratios of RSS and sucrose, 0：10（control）, 3：7, 5：5 and 7：3, containing 50 g carbohydrate of each（dry solid base; dsb）in the fasting state. In 10 g tolerance test, 12 normal humans ingested 10 g（dsb）of mixtures at the ratio of 5：5 or 10 g sucrose as control in the fasting state. Blood was collected over 120 min after ingestion to check the blood glucose and insulin levels. Result Both sucrase and maltase activities were inhibited by RSS, and the inhibitory effect was stronger on sucrase. In 50 g tolerance test in humans, the ratio of 7：3 showed significant reductions in incremental areas under the curve（ΔAUC）of blood glucose and insulin, and the ratio of 3：7 showed significant reduction in insulin ΔAUC. Both 10 g and 50 g trials showed significant reductions in ΔAUC of blood glucose and insulin at the ratio of 5：5. Conclusion These results suggest that RSS has attenuating effect on blood glucose and insulin responses by inhibiting sucrase activity when ingested with sucrose.

目的　本試験は，システインスルホキシド類を高含有化したタマネギエキスを用いて，システインスルホキシド類の男性更年期症状の改善効果およびテストステロン濃度への影響を，プラセボ対照ランダム化二重盲検並行群間比較試験で検討することを目的とした。方法　男性更年期症状の自覚がある50 歳以上80 歳未満の健康な日本人男性60 名を30 名ずつ2 群に分け（試験食品群30 名，対照食品群30 名），試験食品群には，1 日摂取量3 粒あたりシステインスルホキシド類を30 mg 含有する錠剤を4 週間摂取させ，対照食品群にはプラセボ錠を同様に摂取させた。摂取前，摂取2 週間後，摂取4 週間後に有効性に関する指標として，AMS スコア（Aging males’ symptomsスコア），SF‒36v2 日本語版：アキュート版（36‒ItemShort‒Form Health Survey），IIEF（International Index of Erectile Function），血清中総テストステロン，唾液中テストステロンを測定した。結果　被験者60 名が試験を完遂し，試験食品が起因と考えられる有害事象はなかった。被験者管理事項に抵触した者12 名を除外し，48 名を有効性評価の解析対象とした。試験食品の摂取により，対照食品群と比較して，試験食品摂取後のAMS スコア（総スコア，心理的因子）およびSF‒36 の「心の健康」の改善が確認された。また，摂取2 週間後の唾液中テストステロンの有意な上昇が確認された。結論　システインスルホキシド類高含有タマネギエキスの摂取は，男性更年期症状を改善することが示された。また，機能成分はシステインスルホキシド類であることが示唆された。本研究は，タマネギエキスの摂取により男性更年期症状が改善することを明らかにしたはじめての報告である。【利益相反】本研究の研究費および試験食品は日清ファルマ㈱より提供され，試験は第三者機関により適切に実施された。

Objectives To evaluate the effect of a beverage containing isomaltodextrin（IMD） on bowel movements in healthy subjects with a tendency toward constipation. Methods A randomized, placebo︱controlled, double︱blind, crossover study was conducted. Twenty subjects ingested a beverage once per day with（test beverage）or without（placebo beverage）5 g IMD for 2 weeks. The defecation frequency, defecation days, and stool volume were investigated as the main evaluation items. Seventeen subjects were included in the analysis because 3 subjects were withdrawn from the study. Results Defecation days and stool volume during the period of test beverage intake were significantly higher than that during placebo beverage intake. Conclusions The intake of IMD improves bowel movement of healthy people with a tendency toward constipation.

Objective Chronic loss of appetite caused by gastric discomfort can impair the quality of life. We examined the effect of oral L-arginine L-glutamate hydrate（ArgGlu）, which was reported to improve gastric disorders in animals, on appetite and gastric symptoms in volunteers with postprandial fullness and early satiety. Methods A randomized, double-blind, placebo-controlled parallel-group, comparative trial was conducted in 60 healthy volunteers who complained of postprandial fullness, early satiety and less of food consumption than before. They were randomized to receive ArgGlu or placebo for 4 weeks, and postprandial fullness, early satiety, appetite, and food intake were evaluated in both groups. Results The postprandial fullness score on Day 2 and Day 4 and loss of appetite score on Day 5, Day 6 and Week 3 were both significantly lower in the ArgGlu group compared to the placebo group. During the study period, significantly more subjects reported an increase in food consumption in the ArgGlu group than in the placebo group. There were no adverse effects of ArgGlu treatment. Conclusion Oral ArgGlu reduced symptoms of postprandial fullness and early satiety in healthy volunteers with postprandial fullness and early satiety. ArgGlu also improved appetite and increased daily food consumption. These findings indicate that ArgGlu could be beneficial for improving the appetite and quality of life in persons with postprandial fullness and╱or early satiety.

Objectives Peucedanum japonicum is a vegetable in the family Apiaceae. Previous studies have suggested some effects on health. We evaluated effects of this material on postprandial blood glucose levels. Methods A randomized, placebo controlled, double︱blind, crossover study was conducted for 23 healthy adult volunteers（14 males and 9 females aged from 21 to 64 years）with fasting glucose levels less than 126 mg╱dL and 30 min postprandial blood glucose level ranging 140-200 mg╱dL. Subjects consumed either placebo or test food, followed by a carbohydrate loading diet, and the levels of blood glucose and insulin were determined after 30-120 min. Results Intake of the test food significantly suppressed the elevation of postprandial blood glucose levels compared to that in the placebo group. The value at 30 min after the intake of test food（121.5±3.8 mg╱dL）was significantly lower than that of placebo（130.3±3.6 mg╱dL, P＜0.05）. Total area under the curve of blood glucose level was 12,685±2329 mg・min╱dL in the test group and 13,283±482 mg・min╱dL in the placebo group（P＜0.05）. Total AUC of blood glucose was significantly attenuated in test group. Conclusions These results suggested that Peucedanum japonicum would be a viable prevention tool for type 2 diabetes.

Objective We have previously cleared that apple polyphenols beverage consumption reduces weight and body fat in obese subjects1）. In this study we performed a subanalysis for subject whose BMI is over 23 and less than 30 to evaluate effect to reduce body fat. We also performed a subanalysis for BMI or body fat. Methods This study was a randomized, double-blind, placebo-controlled, parallel-group study. Japanese males and females were divided into three groups; group drinking beverage with apple polyphenols（600 mg╱340 g）or group drinking beverage with apple polyphenols （300 mg╱340 g）or group drinking beverage without apple polyphenols. Subjects were given regular amount of beverage （340g）a day for 12weeks. Subjects of the previous report whose BMI was over 23 and less than 30 were selected and a subanalysis was performed for weight, body fat percentage, and body fat area with CT scanning. Further a subanalysis for BMI（high normal subjects：23≲BMI＜25 or classⅠ obese subjects：25≲BMI＜30）or visceral fat area （VFA）（VFA＜100 cm2 or 100 cm2≲VFA）was performed. Results In high normal subjects, VFA was significantly reduced in the group drinking beverage with apple polyphenols（600 mg╱day）comparing with that of the baseline at Week 12 and wasnʼt significantly changed in the placebo group. In classⅠ obese subjects, VFA was significantly reduced in the group drinking beverage with apple polyphenols（600 mg╱day）comparing with that of the placebo group at Week 12. Conclusion It was shown that drinking beverage with apple polyphenols（600 mg╱day）was effective on the reduction of visceral fat for high normal and classⅠ obese subjects.

背景　厚生労働省の調査によれば，食物繊維の摂取量は年々低下傾向を示し，それに関連して便秘傾向者は増加している。目的　食物繊維が豊富なココア摂取による，便通改善および便臭改善について検証した。方法　ココア10 g（リグニン含量1.5 g）の被験食品とココア風味対照食品を作製した。20 歳から60 歳の健康な男女で便秘傾向の22 人の被験者を無作為に2 群に分け，それぞれ2 週間ずつ被験食品または対照食品を摂取するクロスオーバー試験を行った。評価項目は，アンケートによる評価（排便回数，排便量，排便性状，便臭）および機器分析による評価（糞便中のアンモニア，インドール，スカトール濃度の定量）を行った。結果　被験食品摂取により排便回数は有意に増加し，排便量については増加の傾向が認められた。便臭に関しては，糞便中のアンモニア濃度が被験食品摂取により有意に減少した。結論20 歳から60 歳の健康な男女で便秘傾向の試験対象者が，ココア10 g を1 日1 回2 週間摂取することにより，便通および便臭が改善した。またこれら双方の改善効果に関与する主たる成分としては，ココアに含まれる不溶性食物繊維のなかでもカカオリグニンが寄与していると考えた。