薬理と治療

Background This study investigated the effect of food on relative bioavailability of a fixed-dose combination（FDC）tablet containing 25 mg empagliflozin and 5 mg linagliptin after a meal compared to that in the fasted state in healthy Japanese male subjects. Methods This was an open-label, randomized, two-sequence, crossover design, PhaseⅠstudy（ClinicalTrials.gov Identifier: NCT02815644）. A total of 22 subjects were assigned to group A or B（11 subjects each）, and first administered FDC tablet once following an overnight fast（≥10 hours）or once 30 minutes after a standard Japanese breakfast according to the assigned treatment sequence. Blood samples for pharmacokinetics measurements were taken between 2 hours before and 72 hours after FDC tablet administration. Results All subjects completed the study. Compared with the fasted state, administration of FDC tablet in the fed state reduced the AUC0-tz of empagliflozin and linagliptin by 14％ and 18％, respectively（adjusted geometric mean［90％ CI］fed╱fasted ratio: empagliflozin, 85.99％ ［83.38％, 88.68％］; linagliptin, 82.19％［78.38％, 86.18％］）and the Cmax by 25％ and 44％, respectively（adjusted geometric mean［90％ CI］ fed╱fasted ratio: empagliflozin, 74.89％ ［66.27％, 84.64％］; linagliptin, 55.69％ ［48.22％, 64.33％］）. No adverse events were reported during the treatment period. Conclusion This study shows that food did not have a clinically relevant impact on the pharmacokinetics of FDC tablets containing 25 mg empagliflozin and 5 mg linagliptin in healthy Japanese male subjects. Therefore, the FDC tablet may be administered with or without food.

Objectives The aim of this study was to elucidate the effects of Lactobacillus acidophilus L-92 on subjective symptoms of perennial allergic rhinitis in subjects with mild to moderate symptoms using a randomized double-blind, placebo-controlled, parallel-group comparison study. Methods Subjects were divided into 2 groups which consumed tablets containing L-92（2*1010 cells）or placebo once a day for 8 weeks. In the study period, Subjects assessed their nasal and ocular symptoms every day. These symptoms were scored from 0（no symptoms）to 4 （very severe）. Also, subjects recorded use of medicine. The symptom-medication score were calculated by the daily symptom score and the daily rescue medication score. Nasal cavity findings, that is, swelling and color of the nasal mucosa, and amount and property of mucus were scored by medical doctor. Additionally, to assess the safety of the study tablets, a physical and blood examination were performed. Results A significant difference in baseline changes in nasal symptom medication scores was also observed between the placebo and L-92 groups. Additionally, the score of mucus property decreased at 8wk from baseline in L-92 group, but not in placebo group. The adverse events due to the consumption of the study tablets were not observed. Conclusions These results suggest that oral administration of L-92 can alleviate the symptoms of perennial allergic rhinitis in the subjects with mild to moderate symptom. Furthermore, the tablets containing L-92 used as study foods were presumed to be safe.

Objective The impact of a beverage comprising the powder of Antrodia cinnamomea mycelium, fermented grain extracts, L-cystine, and chitosan oligosaccharide on alcohol metabolism. Methods We conducted a randomized, double-blind, placebo-controlled, crossover trial in 16 healthy Japanese adult participants with a low tolerance of alcohol. During each visit, participants consumed single dose of either the active beverage, placebo beverage, or two positive control beverages （commercial products）with a washout period of 1 week between each visit. Participants consumed one of the beverages 30 min before drinking alcohol followed by a glass of whiskey and water（1：1 ratio; approximately 0.5 g ethanol per kg body weight）. We obtained blood samples at 0, 30, 60, 120, and 180 min after drinking alcohol and assessed the blood concentration at each assessment point and total area under the curve（AUC）of ethanol and acetaldehyde. Furthermore, we evaluated subjective symptoms related to drunkenness. Results The blood ethanol concentration in the active beverage was significantly lower than that of the two positive control beverages（P＜0.05）and was prone to be lower than that of the placebo beverage（P＜0.10）. No significant differences were observed in the blood acetaldehyde concentration among four beverages. Furthermore, no significant improvement was observed in subjective symptoms related to drunkenness in drinking the active beverage compared with that of the other beverages. Conclusions The consumption of the active beverage before drinking alcohol could prevent the increment in the blood ethanol concentration because of the effect of four major ingredients.

Objectives The aim of this study was to evaluate the effect of continuous 4-week ingestion of tablets containing lactotripeptides（Val-Pro-Pro, VPP; Ile-Pro-Pro, IPP）on lassitude in young healthy people. Methods We conducted a randomized, double-blind, placebo-controlled trial in healthy male university students who exercise regularly. The subjects were randomly divided into test or placebo groups. They ingested tablets containing lactotripeptides（VPP, 2.5 mg; IPP, 3.7 mg）or placebo continuously for 4 weeks. Lassitude as assessed using a visual analog scale（VAS）was set as the primary endpoint, while muscle pain assessed using VAS as well as lassitude, muscle pain, and blood creatine kinase activity assessed using a multiple-choice questionnaire were set as secondary endpoint. Results Lassitude increased significantly in both groups 4 weeks after treatment as compared to that before treatment（test group, P＜0.05; placebo group, P＜0.01）; however, the test group exhibited a significantly lower lassitude after 4 weeks of treatment than that of the placebo group（P＜0.01）. Furthermore, while no significant change in muscle pain was observed in the test group, it increased significantly in the placebo group（P＜0.01）. Conclusions These results indicate that 4 weeks of continuous ingestion of tablets containing lactotripeptides is a beneficial for reduction of lassitude in healthy, young people who exercise regularly.

Objective The objective of this study was to investigate the effect of intake of jelly compounded with 3,5-dihydroxy-4-methoxybenzy- alcohol（DHMBA）-containing supernatant extracted from soft tissue of Crassostrea gigas on fatigue in healthy adult working men and women. Methods Healthy adult working men and women（84 study subjects）were enrolled in a randomized, double-blind, placebo-controlled, comparative study. The study subjects took 4 packets of jelly compounded with DHMBA-containing supernatant extracted from soft tissue of C. gigas or placebo jelly every day for 4 weeks. The fatigue state was evaluated using the Profile of Mood States Short form（POMS-S）and OSA sleep inventory MA version（OSA-MA）. Results In a stratified analysis in subjects aged 41 years or older, changes in the scores of POMS-S before intake of the study food for“depression”at weeks 2 and 4 were －17.3 ± 2.6 and －21.6 ± 2.0, respectively and for “fatigue”－13.5 ± 1.6 and －18.2 ± 2.2, respectively in the group receiving the jelly compounded with DHMBA-containing supernatant extracted from soft tissue of C. gigas, whereas the changes were －9.9 ± 2.0 and －15.3 ± 1.9 for “depression” and －8.5 ± 1.8 and －10.6 ± 1.8 for “fatigue” in the placebo group, showing a significant improvement in the Watanabe Oyster DHMBA Jelly group than in the placebo group. The change in the score of OSA-MA for the first factor（sleepiness on waking）at week 4 in the group receiving jelly compounded with DHMBA-containing supernatant extracted from soft tissue of C. gigas was 8.79 ± 1.75, showing a significant improvement in the Watanabe Oyster DHMBA Jelly group compared to the placebo group（4.44 ± 0.99）. There were no adverse events associated with the intake of the jelly compounded with DHMBA-containing supernatant extracted from soft tissue of C. gigas. Conclusion The intake of jelly compounded with DHMBA-containing supernatant extracted from soft tissue of C. gigas is effective in reducing the fatigue experienced in the daily lives of healthy middle-aged men and women.

Objective Crocetin, a kind of carotenoid, is a yellow pigment composition found in Gardenia fruits. The purpose of this study was to evaluate the safety of excessive intake of crocetin in healthy adult volunteers. Methods This study was a randomized, double-blind, placebo-controlled, parallel-group comparison trial. In total, 32 volunteers were randomly divided into two groups to consume either five crocetin（37.5 mg╱day）or five placebo capsules per day for four consecutive weeks. The safety of crocetin intake was evaluated by analyzing physical measurements, blood biochemistry, hematology, and urine. Results Safety evaluations of excessive intake of crocetin for four consecutive weeks revealed several significant differences; however, the changes were sporadic. Moreover, blood biochemistry analyses and hematological tests showed small changes that were within the normal range, and these were considered clinically insignificant and unrelated to treatments. Hence, no adverse changes related to crocetin intake in any volunteers were observed. Conclusion Excessive intake of crocetin （37.5 mg╱day）for four weeks was safe under the conditions of this study.

Objectives The aim of the present study was to investigate an effect of food containing rare sugar syrup（RSS）and sugar as sweetener compared to sugar alone on blood glucose response in healthy adult humans with various type of foods such as drink, solid food and liquid food. Method Three randomized, single blind, placebo-controlled and crossover trials were conducted. Subjects participated in 2 treatments using a placebo food containing sucrose alone as sweetener and a test food replacing half amount of sucrose by RSS in drink（n＝6）and solid food（n＝14）trials. There were 3 treatments for liquid food trial（n＝10）replacing sucrose by RSS at different ratios, i. e. 0％ for placebo, 30％ and 50％ of RSS for test foods. Blood collections were conducted 5 time-points before and after ingestion of foods to check the blood glucose and insulin levels. Result The results of both drink and solid food trials showed significant reductions in incremental area under the curve（iAUC）by each test food compared to the sucrose control. Significant reductions in iAUC were also found in liquid food trial in both test food groups. All test foods partially replaced sucrose by RSS, including drink, solid food and liquid food, showed significant reductions in iAUC of postprandial blood glucose compared to the sucrose control. There was no significant change found in insulin levels. Conclusion These results suggest that a partial replacement of sucrose by RSS in food and beverage would elicit a significant lower glycemic response than sucrose alone in humans.

Objectives This studyʼs objective was to examine the effects of a purple sweet potato（PSP） beverage rich in acylated anthocyanins on serum hepatic biomarkers in healthy Japanese men. Methods We previously published the results of a clinical study on this PSP beverage. In this secondary analysis, we re -examined the previous results of subjects with serum hepatic biomarker levels below the“reference value for which examination is recommended”, which is described in the“Standard Medical Checkup╱Insurance Guidance Program ［Revised Version］” published by the Ministry of Health, Labour and Welfare. Results The PSP group had significantly lower GOT values than the placebo group at 2 and 4 weeks after ingestion（P＝0.014 and 0.013, respectively）. In addition, the PSP group had significantly lower GPT values than the placebo group at 4 weeks after ingestion（P＝0.019）, and significantly lower γ-GTP values than the placebo group at 2, 6, and 8 weeks after ingestion（P＝0.039, 0.025, and 0.002, respectively）. Conclusions These results are consistent with those in the previous report, and showed that the PSP beverage improved liver function in healthy men with serum hepatic biomarker levels below the“reference value for which examination is recommended”.