薬理と治療

Objectives　It is extremely important to prevent the development and exacerbation of atherosclerotic cardiovascular disease and diabetic complications, especially nephropathy, in patients with diabetes mellitus（DM）. Recently, sodium-glucose cotransporter 2（SGLT2）inhibitors have been reported to reduce cardiovascular death in DM patients by 38％ and have protective effects for several organs, such as heart and kidney. In this study, we examined the effectiveness of tofogliflozin on the clinical parameters in type 2 DM patients with obesity. Methods　Subjects were recruited for the condition: body mass index 25 or higher, HbA1c over 8％, serum creatinine under 2 mg/dL, and have not previously taken SGLT2 inhibitors. For 18 type 2 DM patients with obesity, tofogliflozin was administered at 20 mg╱day for 1 year, and clinical parameters including body weight, blood pressures, postprandial plasma glucose（PPG）, HbA1c, blood cells, liver and renal functions, lipids, urinalysis, urinary microalbumin（urine Alb）, urinary NAG, urinary β2-MG, urinary L-FABP, and plasma BNP were measured every 2 months. During the period, adverse events were also investigated, and the usage and dose of antihypertensive and antilipid drugs and DM treatments were not changed. Results　Tofoglifrozin significantly decreased the levels of PPG and HbA1c after 2 months, systolic blood pressure after 12 month, GOT after 6 months, GPT after 10 months, urinary Alb after 8 month, and urinary β2-MG after 6 months. Although body weight, pulse rate, blood cells, lipids, renal function, and plasma BNP did not change, urinary NAG and L-FABP showed tendency to decrease after 2 months. During the period, there were no adverse events such as hypoglycemia, urinary tract infections, or increased urinary ketones. Conclusion　This study revealed that tofogliflozin is an effective and safe drug that has the effect of protecting liver and kidney dysfunctions in addition to improve glucose metabolism in type 2 DM patients with obesity.

Background　Pharmacotherapy is performed in accordance with the guidelines for each disease. The number of drugs to be taken increases when a patient has multiple diseases. Polypharmacy may be a problem owing to increased side effects and interactions. Methods　The subjects were at/home patients（patients who received home visits）during the year from April 2016 to March 2017. Age, sex, disease, number of drugs, and reason for drug changes were compared in patients who were hospitalized and patients who were not hospitalized within 1 year of intervention. Results　Many at-home patients had multiple disease（75.61％）. The number of drugs was reduced after 12 months compared with the time of intervention（P＜0.01）. Among prescription changes, pharmacists proposed most of the prescription changes（91.34％）. In addition, the number of drugs taken by at-home patients who were not hospitalized within 1 year of intervention was reduced （P＝0.037）. However, this reduction was not seen at-home patients who were hospitalized within 1 year of intervention. Conclusions　If pharmacists can actively intervene and reduce polypharmacy in at-home patients, this may reduce unnecessary hospitalization due to polypharmacy interactions and side effects. It is possible that this intervention may lead to an overall reduction in the number of inpatients.

Background　Department store employees are required to maintain a smiling face while serving customers. Since it is difficult to smile under stress, employees need techniques for stress reduction that can be easily incorporated into the daily routine. Objective　We investigated whether mastication of chewing gum could reduce stress among department store employees. Methods　A total of 346 department store employees were enrolled, with 169 being allocated to the chewing gum group（78 men and 91 women; mean age: 38.4±11.3 years）and 177 being allocated to the control group（80 men and 97 women; mean age: 40.1±11.5 years）. The chewing gum group masticated gum four times daily for six weeks and there was no intervention in the control group. To investigate the effect on stress, the Hospital Anxiety and Depression Scale and the 23-item short version of the new Brief Job Stress Questionnaire were completed by the participants. Results After six weeks of masticating gum on a regular basis, the chewing gum group had significantly lower scores for“depression”items in the Hospital Anxiety and Depression Scale compared with the control group. The chewing gum group had also lower scores for items related to“physical and mental stress reaction”in the Brief Job Stress Questionnaire. Conclusion　Habitual chewing of gum reduced stress among department store employees involved in customer service. These findings suggest that store employees could use routine mastication of gum to alleviate stress. （ID：UMIN000037338）

Background　The collagen octapeptide Gly-Ala-Hyp-Gly-Leu-Hyp-Gly-Pro inhibits angiotensin converting enzyme and its positive effects on blood pressure and vascular function are suggested. Objective　To verify safety and the effect of the collagen octapeptide Gly-Ala-Hyp-Gly-Leu-Hyp-Gly-Pro on vascular endothelial function（flow-mediated dilation; FMD）in a randomized, double-blind, placebo-controlled, parallel-group study. Methods/study design　Volunteers（n＝50）, aged 20-64 years, whose FMD level was relatively low were randomly assigned to an investigational food that contained 3.9 mg of the collagen octapeptide Gly-Ala-Hyp-Gly-Leu-Hyp-Gly-Pro（group A）or a placebo food（group P）（1：1）. FMD was assessed in pre-trial period and during the investigational food intake period of 8 weeks, and changes in values between the pre-trial and the last of the observationperiod（ΔFMD）were compared between groups. Results　Although the endpoint measures were not significantly different between the two groups in per protocol set （n＝22 and 23 in groups A and P, respectively）, stratified analyses revealed significant differences in ΔFMD at week 8. In subjects with their habitual alcohol intake frequency at ≤0.5　times/week（group A, n＝11; group P, n＝12）or habitual alcohol consumption at ≤13.5 g/week（group A, n＝10; group P, n＝13）, ΔFMD values in group A were significantly higher than those in group P（＋1.68±1.16％ vs. －1.28±0.49％, P＝0.024；and＋2.09±1.11％ vs. －1.23±0.45％, P＝0.006）. No serious adverse event related to the active food intake was observed. Conclusion　Benefit of the collagen octapeptide Gly-Ala-Hyp-Gly-Leu-Hyp-Gly-Pro intake on vascular endothelial function is suggested. （UMIN study ID：UMIN000031071）

Objectives　To evaluate the effect of enzymatically modified isoquercitrin（EMIQ）on amino acids absorption, we investigated plasma amino acid concentrations after whey protein ingestion with or without EMIQ. Methods　We conducted a randomized double-blind cross-over trial in 10 healthy men. These subjects ingested whey protein with or without EMIQ. Plasma amino acid levels were measured before ingestion, and 30, 45, 60, 120, 240, 420 minutes after ingestion. Results　At 60 minutes after ingestion of whey protein with EMIQ, the concentration of total proteinogenic amino acids（TAA）in plasma was significantly higher than without EMIQ, while essential amino acids（EAA）and branched-chain amino acids（BCAA）tended to be higher than without EMIQ. Moreover, areas under the curve（AUC）for TAA and EAA after whey protein ingestion with EMIQ tended to be higher than without EMIQ. In addition, the concentration of certain amino acids like cysteine（cystine）, tyrosine, histidine, and methionine were significantly higher at 45 or 60 minutes after ingestion of whey protein with EMIQ than without EMIQ. Conclusions　These results suggested that EMIQ helped amino acids absorption when ingested with whey protein.

Objectives　The major soybean protein β-conglycinin confers several human health benefits, one of them being improved lipid metabolism. In the present study, we evaluated the effects of processed foods containing β-conglycinin-rich soybean （Nanahomare）on postprandial serum triglyceride（TG）levels in healthy subjects in a clinical trial（UMIN000012031）. Methods　Twenty-four healthy adults participated in this randomized, double-blinded, placebo-controlled, crossover trial. The subjects ingested either test food（containing β-conglycinin-rich soybean）or placebo food after overnight fasting. Blood samples were collected from subjects before ingestion and at 2, 3, 4, 5, and 6 h after ingestion to determine TG levels and other parameters. Results　After ingesting active test food, the area under the curve（AUC0-6h）for triglycerides was significantly decreased. Furthermore, the AUC0-6h for remnant-like particle cholesterol was decreased by the ingestion of active test food. No adverse events were observed during the trial. Conclusions　These results indicated that processed foods containing β-conglycinin-rich soybean can control postprandial serum triglyceride levels.

Objective　The objective of this study was to know how the consecutive ingestion of new self-emulsifying formulation containing astaxanthin and lutein would change blood astaxanthin and lutein concentration of the healthy subjects. Methods　87 healthy participants（20-49 years old, BMI≳18.5 and＜25）were enrolled in randomized, double-blind, parallel-group comparison study. They ingested self-emulsifying formulation containing astaxanthin and lutein（test food）or non-emulsifying formulation containing astaxanthin and lutein（control food）after breakfast daily for 3 weeks. Fasting blood astaxanthin and lutein concentration were measured at baseline and after 7 and 21 days of continuous ingestion. Results　The change in blood astaxanthin concentration after 3 weeks of ingestion was significantly higher in test food group（30.6±3.0 ng/mL）than in control group（18.7±2.4 ng╱mL） （P＝0.0062, 163％（test food╱control food ratio））. On the other hand, the change in blood lutein concentration was higher in test food group, but the difference was not significant. Furthermore, the change of Area Under the Curve（AUC）values of blood astaxanthin was also significantly higher in test food group than in control group. The change in AUC of blood lutein tended to be higher in the test food group than in the control food group. Conclusions　These results suggest that self︱emulsifying formulation containing three glycerin esters improves the absorbability of carotenoids. In the future, it is expected to be applied to various developed products.（UMIN ID: UMIN000035493）

Objectives　The aim of this study was to evaluate the effect of protease-digested Royal Jelly （pRJ）supplementation on skin conditions and assess its safety. Methods 　A randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted in healthy Japanese men and women. They were administered either pRJ or placebo orally for 12 weeks. The level of skin stratum corneum hydration, trans-epidermal water loss, elasticity, pore conditions, pigmentation and wrinkle were measured. A safety assessment was also performed by blood test, urinary test and interview with a medical doctor. Results　The data obtained from 79 volunteers were analyzed. The skin stratum corneum hydration of arm, pore conditions of face and pigmentation level of face in pRJ group was significantly improved compared with placebo group. Any serious adverse events were not observed during the study period. Conclusions　These results suggested that pRJ supplementation positively and safely improved skin conditions（stratum corneum hydration, pore conditions and pigmentation）in healthy Japanese adults. （UMIN-CTR000034539）

Background　Decreased physical activity with aging is a significant risk factor for age-related diseases and requires nursing care. Objective　Sesame lignans（SE, sesamin and episesamin）exert anti-oxidative and anti-inflammatory effects. Here, we evaluated the effect of SE on decline in spontaneous activity in aging rats. Methods　Fourteen-month-old Sprague-Dawley rats were fed a diet with or without 0.1％ SE for 8 months. Spontaneous activity was measured by using an accelerometer at 14, 17, and 22 months of age before or after SE administration. Five-month-old rats were included as a young control group. Results　Spontaneous activity decreased with aging; SE significantly prevented the decrease. SE reduced the decrease in fast-twitch muscle mass, but not slow-twitch muscle, with aging and also suppressed increased muscle RING finger 1（Murf1）gene expression in muscle and interleukin（IL）-6 in plasma. Conclusion　Consecutive intake of SE modulated muscle mass through inhibition of Murf1 expression due to anti-inflammatory effects, resulting in preventing decreased spontaneous activity with aging.

With the advancement in supportive care, cancer chemotherapy is administered as a combination therapy, thereby improving treatment outcomes. Nivolumab is a novel anticancer drug with a mechanism of action different from those of cytotoxic antitumor drugs or molecular target agents and is used for the treatment of gastric cancer. We administered nivolumab to a patient with advanced gastric cancer and right ventricular metastasis undergoing chemotherapy. Our team of doctors, pharmacists, and other staff were able to respond to immune-related adverse events appropriately, enabling continuation of treatment, which controlled lesion growth and improved the symptoms.