薬理と治療

糖尿病治療薬であるsodium︱glucose co︱transporter2（SGLT2）阻害薬，tofogliflozin（Tofo）の1型糖尿病に対する有効性と低血糖リスクについて評価するため，1 型糖尿病モデル動物として広く用いられているストレプトゾトシン投与ラットモデル（STZ ラット）を用いて検討した。Tofogliflozin はSTZ ラットにおいて単剤で血糖降下作用を示し，インスリンとの併用による相加効果も認められた。その血糖降下作用はインスリン投与とくらべて個体差が少なく，またインスリン投与群において散見される過度な血糖降下作用はみられなかった。さらに本薬のきわめて高いSGLT2 選択性が低血糖リスクの低減に有用かを検討するため，SGLT1 およびSGLT2 非選択的阻害作用を有するフロリジンとの比較を行った。インスリン投与により血糖値が低下した状態では，フロリジン投与では血糖値をさらに低下させる傾向がみられたのに対し，tofogliflozin では血糖値を過度に低下させる傾向は認められなかった。これらのことは，SGLT に対する選択性の違いが一因と考えられる。以上より，tofogliflozin は2 型糖尿病だけでなく，1 型糖尿病においても有効かつ低血糖リスクの少ない血糖降下薬として有望である可能性が示唆された。【利益相反】著者らは興和㈱の社員である。

目的マガキ軟体部抽出液から同定した新規抗酸化物質3,5︱dihydroxy︱4︱methoxybenzyl alcohol （以後，DHMBA）の酸化ストレスマウスに及ぼす抗酸化作用とストレス軽減作用を検討した。方法マガキ軟体部からDHMBA を含有する抽出液（DHMBA 含有量24.3μg╱mL）とDHMBA を含まない抽出液の2 種類を調整した。Slc: ICR 雄性マウス30 匹を42 日間の長期個別飼育を行い，酸化ストレスマウスを作製した。それらのマウスを3 群に分け， それぞれ， 水，DHMBA 非含有抽出液，DHMBA 含有抽出液を8 日間経口投与した。その後，採血，肝臓，副腎を含む腎臓，膵臓，脾臓を摘出し，各臓器中のmalondialdehyde（MDA）値，腎臓中の8︱hydroxy︱2′︱deoxyguanosine（8︱OHdG）値と血漿中コルチコステロン値を測定した。結果DHMBA含有抽出液の摂取群のみで各臓器中MDA 値，腎臓中8︱OHdG 値が有意に減少し，血漿中コルチコステロン値が有意に低下した。結論マガキ軟体部に含まれるDHMBAは，各臓器中での脂質抗酸化作用，腎臓中のDNA 抗酸化作用による疲労軽減作用，および，血漿コルチコステロン値低下によるストレス軽減作用を示した。

Objective The present study was designed to examine the influence of hyaluronic acid（HA） on the ability of synoviocytes to produce periostin, which is one of important effector molecule in the development of osteoarthritis, in response to IL︱13 stimulation in vitro. Methods Synoviocytes（1×105cells╱mL）derived from an osteoarthritis patient were stimulated with 10.0 ng╱mL IL-13 in the presence of various concentrations of HA for 48 hours. The levels of periostin in culture supernatants was examined by ELISA. To examine the influence of HA on transcription factor, STAT6, activation and periostin mRNA expression, synoviocytes （1×105cells╱mL）were also cultured in a similar manner for 12 and　 24 hours, respectively.　STAT6 activation was examined by ELISA and the levels of mRNA expression was real-time　RT-PCR. Results Addition of HA into cell cultures caused the suppression of IL-13-induced periostin production from synoviocytes. The minimum concentration that caused significant suppression of periostin production was 5.0 mg╱mL. HA at more than 5.0 mg╱mL also inhibited STAT6 activation and periostin mRNA expression, which were increased by periostin stimulation in synoviocytes. Conclusion These results strongly suggest that HA favorably modify the clinical condition of osteoarthritis patients through the suppression of periostin production from synoviocytes after IL-13 stimulation.

目的 日本人RA 患者におけるトファシチニブの有効性，安全性を実臨床で評価する。対象・方法2014 年2 月から2016 年5 月に静岡リウマチ整形外科リハビリ病院でトファシチニブを投与したRA 患者55 例を対象に，短期および長期の有効性と安全性を検討した。結果平均年齢70.0 歳，女性51 例，平均罹病期間11.2 年，MTX 併用43 例，生物学的製剤の前治療歴あり35 例。初回評価時（トファシチニブ投与2～6週後），DAS28︱CRP は投与開始時にくらべて低下し，疾患活動性の有意な改善が認められた。40 週以上投与を継続した37 例において，寛解達成例は初回評価時に13 例（35.1％），最終評価時（中央値＝51 週，範囲40～63 週）には31 例（83.8％）であった。その効果は生物学的製剤の前治療歴の有無にかかわらず一貫して認められた。安全性については，55 例中8 例が副作用により投与を中止した。おもな副作用は帯状疱疹（3 例）であった。結論 RA に対してトファシチニブは，臨床症状を短期から改善し，長期使用することで効果は維持・増強されることが示された。生物学的製剤不応例における有用性も示唆された。【COI】本論文について開示すべきCOIは，講演料を武田薬品工業㈱から受領している。

Background Garlic has been widely shown in animal and human studies to be hypolipidemic, although the impact of garlic on human lipid parameters has become more and more controversial. In Japan there is a unique type of traditional health food known as“kurozu-garlic（KG）”that has been made from kurozu（unrefined black rice vinegar）and garlic combination through an acetic acid fermentation process. Using a representative commercial product of KG diet as the study diet, the present clinical trial was undertaken to investigate the effect of KG on serum lipid profiles, particularly serum total cholesterol（TC）and low-density lipoprotein cholesterol（LDL-C）, in volunteer subjects with prehypercholesterolemia and mild-to-moderate hypercholesterolemia. Methods A randomized, double-blind, placebo-controlled intervention study was conducted in 64 subjects with serum LDL-C ranging from 120 to 180 mg╱dL at baseline. Each subject was given KG diet capsules containing 200 mg of KG（KG group）or matching placebo capsules（placebo group）daily for 12 weeks. Blood samples were taken from all subjects to measure serum lipid parameters at weeks 0 （baseline）, 4, 8, and 12. Results Intervention with the KG diet resulted in a moderate but statistically significant decrease in TC and LDL-C levels that was observed at 4, 8, and 12 weeks of active intervention. By the end of the study, TC and LDL-C levels in KG group had fallen by 6.4 and 6.2％ （both: P＜0.01）, respectively, from baseline, and between-group differences in changes from baseline of TC and LDL︱C levels were significant at week 4（P＝0.031 and P＜0.01, respectively）. A similar hypocholesterolemic effect of the KG diet consumption was also observed when substudy analyses were performed on the subjects with relatively low LDL-C levels at baseline（120︱159 mg╱dL）referred as the subpopulation L. In KG group of this subpopulation, there were significant reductions in TC and LDL-C levels from baseline at weeks 4, 8, and 12（P＜0.01 or＜0.05）with a significant difference from placebo group in changes from baseline of LDL-C values at week 4（P＝0.038）. Conclusion Although the results are not definitive, the present study showed that the KG diet intake may have the potential for improving serum levels of TC and LDL-C in the subject population comprising prehypercholesterolemic and mild-to-moderate hypercholesterolemic subjects（LDL-C levels, 120-180 mg╱dL）, as well as in the subpopulation whose LDL-C levels are between 120 and 159 mg╱dL.

Objective To evaluate the effects of astaxanthin on the sense of fatigue occurring in daily life and to investigate the relationship of the fatigue-reducing effect with the antioxidative potential. Method A 12-week, randomized, placebo-controlled, parallel-group study was conducted. After screening for eligibility, 39 subjects with fatigue were assigned to 2 groups. The astaxanthin group received 12 mg of astaxanthin and 20 mg of tocotrienol, while the control group received 20 mg of tocotrienol alone. All subjects took Uchida-Kraepelin performance tests as mental loading and cycled using a bicycle ergometer as physical loading in Weeks 0, 4 and 8. A visual analog scale（VAS）of perceived fatigue was performed before and after loading. In Weeks 0 and 8, a Profile of Mood States（POMS）questionnaire was performed. The biological antioxidant potential（BAP）was measured with blood samples taken at the screening and in Week 12. Results Thirty-eight subjects completed the study. Intent-to-treat（ITT）analysis revealed that the sense of fatigue after both physical and mental loading was significantly lower in the astaxanthin group than in the control group in Week 8. The change in Friendliness in POMS was significantly higher in the astaxanthin group than in the control group in Week 8. No significant differences were observed in the change rate in the BAP value in Week 12 between the astaxanthin group and control group. Conclusion Astaxanthin reduced the daily sense of fatigue caused by both mental and physical loads. No increase in BAP was, however, observed in subjects receiving astaxanthin.

Objective The study aimed to verify that ingestion of a dietary supplement containing gymnemic acid, mulberry leaf extract, green tea extract, chitosan, kidney bean extract, and Kaempferia parviflora extract would reduce the postprandial blood glucose level of subjects. Methods A randomized, double-blind, placebo-controlled, cross-over study was conducted for 37 participants aged 22 to 63 years whose postprandial blood glucose levels increased more than 140 mg╱dL, ingested the dietary supplement containing 9.4 mg of gymnemic acid, 200 mg of mulberry leaf extract, 200 mg of green tea extract, 100 mg of chitosan, 4.8 mg of kidney bean extract, and 150 mg of Kaempferia parviflora extract or placebo with 200 g of rice as a test diet. The blood glucose and insulin levels were measured before and 30, 60, 90, and 120 minutes after the intake of a test diet, and compared with the changes between placebo and the dietary supplement. Results Intake of the dietary supplement was significantly suppressed the delta AUC（area under the curve）values of postprandial blood glucose and insulin levels after ingestion of a test diet（P＜0.05）. We also observed significant suppression of the elevation of postprandial blood glucose levels after ingestion of a test diet by intake of the dietary supplement（P＜0.05）.Conclusions These results suggest the dietary supplement containing 9.4 mg of gymnemic acid, 200 mg of mulberry leaf extract, 200 mg of green tea extract, 100 mg of chitosan, 4.8 mg of kidney bean extract, and 150 mg of Kaempferia parviflora extract suppresses the elevation of postprandial glucose level.

Objective The study aimed to verify that ingestion of a dietary supplement containing gymnemic acid, chitosan, green tea extract, mulberry leaf extract, kidney bean extract, and Kaempferia parviflora extract would reduce the postprandial serum triglyceride level of subjects. Methods A randomized, double-blind, placebo-controlled, cross-over study was conducted for 60 participants whose fasting serum triglyceride levels were 34 mg╱dL to 193 mg╱dL, ingested the dietary supplement containing 9.4 mg of gymnemic acid, 100 mg of chitosan, 200mg of green tea extract, 200 mg of mulberry leaf extract, 4.8 mg of kidney bean extract, and 150 mg of Kaempferia parviflora extract or placebo with a high fat mea（l 40.0 g fat）. The serum triglyceride level and remnant-like lipoprotein particle cholesterol（RLP-C）level were determined before and 2, 3, 4, 6 hours（hr）after a high fat meal ingestion. Results Intake of the dietary supplement was significantly suppressed the postprandial increase in the serum triglyceride level compared to that in the placebo group. The difference was significant at 2, 3, 4, and 6 hr following ingestion（P＜0.05）. This change was accompanied by the difference in the delta area under the curve（AUC）for serum triglyceride levels （mean±SE: 552.3±33.8 mg・h╱dL for the dietary supplement intake vs. 658.4 ±47.9 mg・h╱dL for the placebo intake; P＜0.01）. We also observed significant suppression of the elevation of postprandial RLP-C level（AUC for delta RLP-C: 22.17±1.70 mg╱dL for the dietary supplement intake vs. 27.39±2.31 mg╱dL for the placebo intake; P＜0.01）. Conclusions These results suggest the dietary supplement containing 9.4 mg of gymnemic acid, 100 mg of chitosan, 200mg of green tea extract, 200 mg of mulberry leaf extract, 4.8 mg of kidney been extract, and 150 mg of Kaempferia parviflora extract suppresses the elevation of postprandial serum triglyceride level and RLP-C level in healthy subjects or subject with moderately high fasting triglyceride levels.

Objectives To evaluate effects of a food containing Eucommia leaf extract on reducing body fat reduction for 12 weeks after ingestion. Methods This study was a randomized, double-blind, placebo-controlled, parallel-group study. Healthy males and females with obese tendencies（BMI: 25-30）were divided into the test food group and the placebo group and given the test products containing Eucommia leaf extract（6 tablets per a day; 12 weeks）or the control products not containing Eucommia leaf extract（6 tablets per a day; 12 weeks）, respectively. Weight, body fat percentage, BMI, blood pressure, pulsation, hematologic and blood biochemical screening tests were examined at Week 8 and Week 12, after ingestion, respectively. CT scanning test analyzed with FatScan（visceral fat）was conducted at Week 12. Results By CT scanning test analyzed with FatScan, it was demonstrated that visceral fat was significantly decreased in the test food group compared with that of the placebo group at Week 12. Body fat percentage also was significantly decreased in the test food group compared with that of the placebo group at Week 12. Conclusion It was shown that a food containing Eucommia leaf extract was effective for body fat reducing.

Objective Sunrouge tea is a special green tea with high content of epigallocatechin gallate （EGCG）which is reported having an inhibition effect of alfa-glucosidase activity and alfa-amylase activity. The aim of this study is to evaluate the suppressive effect of Sunrouge tea powder on postprandial blood glucose level. Methods We conducted a randomized, placebo-controlled, double-blind, crossover study for twenty healthy volunteers（8 males and 12 females, aged from 20 to 60 years）. Subjects consumed either Sunrouge tea powder beverage containing 140.2 mg of EGCG as test food, or the beverage containing corn flour instead of EGCG as placebo, together with loading meal（130 g of cooked rice）. Blood glucose and insulin level of subjects were measured prior to and, 15, 30, 45, 60, 90 and 120 min after consumption of the loading meal. Result Consumption of the test food showed significant suppress in the elevation of postprandial blood glucose level, but not in the insulin level, compared to that in the placebo group. The concentration of blood glucose at 15, 30 and 45 min after consumption of the test food were significantly lower than that of placebo（P＝0.049, P＝0.001 and P＝0.003）. Also, the changing values of blood glucose from 0 min of test food group were significantly lower than that of placebo group at 15, 30, 45 min after loading（P＝0.004, P＝0.0001 and P＝0.003）. The area under the curve of the changing values of blood glucose from 0 min of test food group was smaller than that of placebo group（P＝0.085）. Conclusion These results indicate that Sunrouge tea powder which contains EGCG suppress the elevation of postprandial blood glucose level in human.

Objectives We have revealed the efficacy and safety of Aquilaria subintegra （agarwood）leave extract on constipation-related symptoms. To evaluate the effect of low dosage of agarwood leaves extract, two clinical trials were performed in this study. Methods Clinical trial-1. We conducted a double-blinded, placebo-controlled, crossover trial in seventeen healthy volunteers-（ages 20 to 65 years old）with mild constipation. For the trial, we prepared a tablet containing a mixed powder of 75 mg agarwood leaves- extract and 75 mg dextrin. The subjects ingested placebo or 150 mg of the agarwood leave extrac（t 2 tablets daily） for 4 weeks. Clinical trial-2. We conducted the trial, which methods were the same as clinical trial-1, with twofold dosage of the agarwood leave extract. Fifteen healthy volunteers with mild constipation were participated in this trial. In each trial, the primary endpoints were changes in self-reported stool smell and the frequency of defecation. Results Clinical trial-1. No significant differences were indicated in any endpoints. And any clinically critical adverse events were not observed in this trial. Clinical trial-2. Significant improvements were indicated in the primary endpoints, the stool volume and the total frequency of defecation. Especially, the stool smell was improved at first week in the intake period of agarwood leaves extract tablets. In addition, any clinically critical adverse events were not observed during the trial. Conclusions Present results suggested that the intake of 300 mg of the agarwood leave extract serves to relieve constipation without adverse effects.

80 歳代女性，2014 年1 月に左右小脳梗塞を発症した。その後，徐々に経口摂取不可となり，同年6月に中心静脈栄養法が開始された。同年9 月より血圧上昇が認められ，ビソプロロールテープ剤（ビソノ(R) テープ4 mg）が開始されたが，貼付後より経表皮水分喪失量（transepidermal water- loss: TEWL）の上昇がみられ，皮膚バリア機能の低下が考えられた。また，大腿前外側部の角層水分量も低下し，乾燥皮膚が原因と考えられる瘙爬行動が日々顕著になった。医師と協働しヘパリン類似物質製剤（ヒルドイド(R) ソフト軟膏）を使用したところ，皮膚のツヤが肉眼的に観察され，瘙爬行動もなくなり，乾燥皮膚はもとより角層の剝離もほぼ消失した。高齢者は，皮膚が乾燥しやすく，貼付剤使用時には皮膚障害が起こりやすいと考えられる。しかし，貼付剤は，嚥下困難や要介護にある高齢者への使用が期待されることから，皮膚障害に対する積極的な対処法が求められる。本症例では，皮膚測定器によって薬剤師が皮膚の状態を客観的指標により評価し，適正な保湿剤の処方提案を行ったことで，ビソノ(R) テープによる皮膚障害の発現を防止した。本症例は在宅要介護高齢者における貼付剤の適正使用において，保湿ケアは示唆に富む有益な方法であると考えられる。【利益相反】本論文に関して，開示すべき利益相反状態は存在しない。