薬理と治療

Background and Objectives　Persistence rate of treatment in dyslipidemia is lower than that of other non-communicable diseases. We aim to investigate the reasons for discontinuation by drug categories（statins, polyunsaturated fatty acid, fibrates and small intestine cholesterol transporter inhibitor）and clarify the consciousness gap in dyslipidemia, treatment and medication between doctors and patients. Methods　Web-based questionnaires toward doctors and patients. Results　Answers from 504 doctors and 1547 patients were analyzed. Among the reasons for discontinuation,“Adverse effect” is high in statins and fibrates but low in other drug categories. “Lack of efficacy” is higher in other drug categories than in statins. In all drug categories, “dropout of outpatients”is high among doctors; by contrast “unknown”and“unnecessary for medication”are high among the patients. In contrast to more than 90％ of the doctors said they are giving instructions on diet and exercise therapies, 55％ of the patients answered they are receiving instruction. There was a difference in the recognition between doctors and patients as to who in the medical staff takes care of patientsʼ diet and exercises as well as checking their daily life and compliance. Conclusions　Both surveys show the difference in the percentage of“Adverse effect”and “Efficacy”among reasons for discontinuation by each drug category. Unclear reasons are identified in all drug categories, which seems due to an insufficient communication between doctors and patients. There is a gap in consciousness about management of patientsʼ daily life and compliance. A follow-up including daily life management is important for a better adherence of treatment.

Objectives　Apolipoprotein（apo）E, one of the main protein constituents of lipoproteins, has the ability of binding to the receptors and plays a role in lipoprotein metabolism. Apo E has genetic polymorphism（E2, E3 and E4）. We previously reported that the effects of lipid modifying agents vary depending on the presence or absence of the apo E4 allele. Ezetimibe inhibits cholesterol absorption in the small intestine and reduces plasma LDL cholesterol. The purpose of this study is to clarify the effects of apo E4 allele on plasma LDL cholesterol response to ezetimibe monotherapy in hypercholesterolemic patients. Subjects and Methods　Subjects consisted of 16 hypercholesterolemic patients with the apo E3╱3 genotype（8 men, 8 women）, and 13 hypercholesterolemic patients with the apo E4 allele （apo E4╱3 genotype: 12 patients; apo E4╱4 genotype: 1 patient）（4 men, 9 women）. Subjects took 10 mg of ezetimibe once daily after breakfast. Treatment was continued for 3 months, with fasting blood samples being taken before breakfast in the morning. Results　Ezetimibe was administered over 3 months. In the apo E3╱3 group, total cholesterol levels decreased significantly from 236±6 mg╱dL before treatment to 197±7 mg╱dL（percent reduction: －16.2％, P＜0.001）, and LDL cholesterol levels also decreased significantly from 158±5 mg╱dL before treatment to 124±6 mg╱dL（－21.2％, P＜0.001）. In the apo E 4 group, total cholesterol levels decreased significantly from 256±7 mg╱dL before treatment to 185±8 mg╱dL（percent reduction: －28.0％, P＜0.001）; and LDL cholesterol levels also decreased significantly from 168±5 mg╱dL to 103±5 mg╱dL（－38.4％, P＜0.001）. The percent decrease in total cholesterol before and after ezetimibe treatment was significantly higher in the apo E4 group than in the apo E3╱3 group （－16.2％ vs. －28.0％, P＜0.001）. The percent decrease in LDL cholesterol before and after ezetimibe treatment was significantly higher in the apo E4 group than in the apo E3╱3 group（－21.2％ vs. －38.4％, P＜0.001）. Conclusion　This study indicate that the LDL cholesterol-lowering effects of ezetimibe are more effective in individuals who have the apo E4 allele. It is concluded that the apo E4 is one genetic factor regulating the cholesterol-lowering response to ezetimibe.

Background and Objectives　Several erythropoiesis stimulating agents, such as biopharmaceutical products, are used in the treatment of renal anemia. Biosimilars of these agents are being developed from a pharmacoeconomic perspective. This study aimed to confirm the equivalent efficacy and compare the safety of biosimilar SK-1401 with Darbepoetin Alfa in renal anemia patients on hemodialysis, and evaluate the longitudinal safety of SK-1401. Methods　In a randomized, single-blind, parallel comparative study, renal anemia patients on hemodialysis receiving Darbepoetin Alfa were recruited. The patients were randomized to Darbepoetin Alfa or SK-1401, intravenously administered once a week for 24 weeks. Next, all patients received SK-1401 for additional 28 weeks. The primary endpoint was the mean change in the hemoglobin（Hb）concentration. Secondary endpoints assessed included time course of Hb concentrations, target Hb concentration maintenance ratio, and endpoints regarding dosing schedule. Results　Mean change in Hb concentration was －0.23±0.82 g╱dL（mean±SD）in the SK-1401 group and － 0.29±1.00 g╱dL in the Darbepoetin Alfa group. The difference between the two treatments was 0.06 g╱dL（95％ CI：－0.22-0.34）. These results demonstrated an equivalent efficacy between the treatment groups. There were no differences regarding secondary endpoints between the two groups. Safety profiles of SK-1401 and Darbapoetin Alfa were similar, and no safety problems were reported during the 52 weeks. No antibodies to SK-1401 or Darbepoetin Alfa were detected. Conclusion　The results demonstrate equivalent efficacy and similar safety profile between SK-1401 and Darbepoetin Alfa and a well-tolerated profile of SK-1401 during the 52-week administration. （JapicCTI-173525）

Background and Objectives　Several erythropoiesis stimulating agents, including biopharmaceutical products, are used in the treatment of renal anemia. Biosimilars of these agents are being developed from a pharmacoeconomic perspective. This study was conducted to evaluate safety and efficacy of a biosimilar of Darbepoetin Alfa, SK-1401, in renal anemia patients associated with non-dialysis chronic kidney disease. Methods　Renal anemia patients associated with non-dialysis chronic kidney disease were recruited in a long-term open study. Patients treated with any erythropoiesis stimulating agent were recruited and SK-1401 was administered subcutaneously every 2 or 4 weeks for 52 weeks. Safety was evaluated by analyzing the adverse events and adverse reactions reported, laboratory tests, electrocardiogram, and anti-SK-1401 antibody. The efficacy endpoints were the time course of hemoglobin（Hb）concentration, target Hb concentration maintenance ratio, and time course of dose. Results　Incidences of adverse events and adverse reaction were 86.6％（58╱67）and 4.5％（3╱67）, respectively. Twenty-five serious adverse events in 15 patients were reported, of which one case of stroke was assessed as an adverse reaction. No antibodies to SK-1401 were detected. Mean Hb concentration assessed every 4 weeks was maintained between 10.0 g╱dL and 12.0 g╱dL. Target Hb maintenance ratio at the 52-week timepoint, was 60.4％. The mean dose of SK-1401 increased throughout the trial period. Conclusion　The results of this study revealed the well-tolerated profile of SK-1401 and its clinical availability during the 52-week administration in renal anemia patients associated with non-dialysis chronic kidney disease.（ JapicCTI-173526）

Objective　To investigate the anti-inflammatory effects of Liquid of Fermented Plant Extract SW, including low-molecular-weight collagen（LFPE-SW）, containing various fruits and vegetables. Methods　Differentiated macrophage precursor cells （THP-1 cell line）were stimulated using lipopolysaccharide（LPS）, which caused a pseudo-immune reaction to promote the secretion of proinflammatory cytokines and growth factors. LFPE-SW was added to RPMI-1640 medium at final concentrations of 1％ and 5％ in the presence of 1μg╱mL LPS. After 2, 5, and 24 h of treatment, the anti-inflammatory effects were determined by measuring the expression levels of genes encoding proinflammatory cytokines（TNF-α, IL-1, and IL-6）and growth factors（FGF-1, FGF-2, and EGF）using real-time RT-PCR. Results　TNF-α expression levels were significantly decreased after short-term and long-term LPS stimulations for 2 and 5 h, respectively. Additionally, IL-1 expression levels were significantly decreased after short-（2 h）, medium-（5 h）, and long-term（24 h） stimulations. Furthermore, IL-6 expression levels were significantly suppressed by long-term stimulation. No remarkable changes were identified in FGF-1 and EGF expression levels, whereas FGF-2 expression levels were significantly increased after medium-and long-term stimulations. Conclusions　LFPE-SW suppresses the expression of various proinflammatory cytokines under long-term stimulation. Moreover, it increases the expression of FGF-2 and fibroblast growth factor, and therefore, it may promote tissue repair.

Objective　The aim of the present study was to investigate the effect of soy-derived peptide containing chewable tablet on a physiological and psychological response in human, a randomized, double-blind, placebo-controlled crossover study were conducted. Methods　In this crossover trial, healthy volunteers were allocated into two groups, Group A and Group B. Eight（8）subjects in the Group A, the test article（chewable tablet containing 200 mg of soy-derived peptide）were administered once in the 1st phase and placebo tablet were administered once in 2nd phase after ＞one week washout period. Similarly, seven（7） volunteers in the Group B were administered in reverse order with the same washout period. In the administration phase, amylase activity of saliva, blood pressure and pulse rate were determined, and two questionnaires（POMS and STAI）were filled out before administration. Fifteen minutes for a resting period after administration, subjects carried out Kraepelinʼs arithmetic test for another fifteen minutes. During thirty minutes of the resting and calculating periods, the electrocardiogram monitoring were conducted for each subject. After the electrocardiogram examination, another set of test （amylase activity, blood pressure, pulse rate and questionnaires） were carried out. Results and Conclusions　As the result, the POMS score of“Depression-Dejection”item in the test article group was significantly reduced as compared with the placebo group, suggesting that the soy-derived peptide containing chewable tablet may ameliorate a feeling of depression and anxiety as psychological effect.

Background　While acetic acid bacteria has not been associated with toxicities in short-term animal studies, consumption of acetic acid bacteria themselves as a supplement has not been evaluated in humans. Here, we have conducted a study to confirm the safety of acetic acid bacteria when taken in a large amount. Methods　We tested soft capsules that contained an extract of an acetic acid bacteria （Gluconoacetobacter hansenii GK-1）. Each capsule contained 45 mg of dry acetic acid bacterium powder, and each subject took 450 mg acetic acid bacteria per day. The subjects were men and women aged between 20 and 69 years who drank alcohol twice or more per week. Subjects took acetic acid bacteria in quantities 5 times the reference amount recommended in the Japanese Ministry of Health, Labour and Welfareʼs Guideline of Food for Specified Health Uses Subjects for 4 weeks. Subjects completed physical examinations, complete blood counts, blood biochemistry, and urinalysis, in addition to completing a diary of intake and subjective symptoms every day during the study. Results　Consumption of a food supplement containing dry acetic acid bacterium powder for 4 weeks was not associated with any significant adverse effects on weight, blood pressure, hematology, or clinical chemistry related to liver and kidney function. Although there were significant differences seen in some variables over the study period, these changes were all within the range of the reference values. Conclusions　We observed no harms related to the daily consumption of a food supplement containing 450 mg of dry acetic acid bacterium powder over 4 weeks.

Background　While acetic acid bacteria has not been associated with toxicities in short-term animal studies, our previous study evaluating the short-term consumption of large quantities of acetic acid bacteria themselves as a supplement was the first to evaluate such supplemental use in humans. Here, we conducted a study to confirm the safety of consuming moderate amounts of dry acetic acid bacterium powder when taken over 12 weeks. Methods　We tested soft capsules that contained an extract of an acetic acid bacteria（Gluconacetobacter hansenii GK-1）. Each capsule contained 45 mg of dry acetic acid bacterium powder, and each subject took 90 mg acetic acid bacteria per day. The subjects were men and women aged between 20 and 69 years who drank alcohol twice or more per week. The subjects took the predefined amount of acetic acid bacteria with a beverage before and during drinking alcohol during the 12-week study period. Subjects completed physical examinations, complete blood counts, blood biochemistry, and urinalysis, in addition to completing a diary of intake and subjective symptoms every day during the study. Results　Consumption of small quantities（90 mg╱day）of dry acetic acid bacterium powder food supplement was not associated with any significant adverse effects on weight, blood pressure, hematology, or clinical chemistry related to liver and kidney function over 12 weeks of intake. Although there were significant differences seen in some of the items, these were all changes within the range of the reference values. Conclusions　We observed no harms related to the daily consumption of a food supplement containing 90 mg of dry acetic acid bacterium powder over 12 weeks.

Objective　To investigate the effects of consumption of konjac processed food （KPF） on defecation in subjects who defecate three to five times per week. Methods　Thirty-three Japanese subjects who defecate three to five times per week participated in a randomized, double-blind, placebo-controlled study between March and October 2017. The subjects were randomly allocated to group A（one pack of KPF daily, n＝11）, group B（two packs of KPF daily, n＝11）, or a placebo group（one pack of placebo daily, n＝11） using a computerized random-number generator. All subjects consumed their assigned food every day for four weeks. The effects on defecation were assessed based on defecation frequency, shape of stool, smell of stool, subjective symptoms of constipation（CAS-MT）, bacterial flora analysis（T-RFLP）, and Bristol stool chart. A safety evaluation was also performed. Results　The outcomes of the subjects in groups A（n＝7）, B（n＝8）, and placebo（n＝7） were analyzed using per-protocol set. With respect to the bowel movement diary, group A showed significant increase in defecation days（P＝0.027, P＝0.025, respectively）and defecation frequency（P＝0.032, P＝0.029, respectively）at 4 weeks and Δ4 weeks compared with those of group B. No adverse effects were reported regarding the test food. Conclusions　Consumption of KPF for 4 weeks increased the frequency of defecation in subjects who defecate three to five times per week, suggesting that KPF improves defecation in people with constipation. Trial registration　UMIN-CTR UMIN000027836 Foundation　ORIHIRO PLANTDEW Co., Ltd.

The objective of this study was to evaluate the effects of collagen peptide（CP）supplementation on the maintenance of knee joint condition in healthy university students belonging to a running club. Fifty-one male healthy university students were recruited from the running club of Josai University and were given a placebo or CP for 8 weeks. Subjective knee condition was evaluated by the Japanese Knee Osteoarthritis Measure（JKOM）score as the primary outcome. Secondary outcome was defined as changes in serum parameters. The total JKOM score and the JKOM Ⅱ score for “pain and stiffness in the knees”were significantly lower in the CP group than in the placebo group at 4 weeks. Moreover, the JKOM Ⅲ score for “knee condition in daily life” in the CP group was lower than that in the placebo group at 4 and 8 weeks of intervention. At 4 weeks, interleukin-6 and 3-methylhistidine in serum were significantly elevated in the placebo group, whereas in the CP group, they were unchanged. No adverse events were observed. In summary, CP supplementation improved knee joint condition in male healthy subjects belonging to a running club and also demonstrated the potential to suppress inflammation and reduce muscle tissue damage.

Objective　Our aim was to determine the effects of a single-dose of nattokinase administration on activity of natural killer（NK）cells, blood pressure, and body temperature in healthy male Japanese. Methods　A randomized, double-blind, placebo-controlled crossover nattokinase intervention study was carried out in 10 healthy males（30.2±7.6 yr）. Following the baseline blood draw and measurements, each subject was randomized to receive either a single-dose of 4000 FU nattokinase（NSK-SD, Japan Bio Science Laboratory Co., Ltd）or placebo with subsequent crossover of the groups. Subjects donated blood samples at 6 hours following administration for analysis of activity of NK cells. Blood pressure and body temperature measurements were also performed. Results　There was a significant interaction of activity of NK cells between administration and time（P＝0.013）. The percent change in the activity of NK cells before and after 6 hours of administration was also different between nattokinase and placebo groups（P＝0.013）. The change in tympanic temperature tended to increase after 6 hours of nattokinase administration compared with placebo（P＝0.09）. Alternatively, no change was found in blood pressure before and after nattokinase administration in healthy individuals. Conclusion　A single-dose of nattokinase administration appears enhancing activity of NK cells.

Objectives　We investigated the effects of feeding hesperidin derived from fermented tea leaves made by mixing thinned satsuma mandarin fruit and tea leaves at the level of 1：3, on cold intolerance, shoulder stiffness, fatigue, and quality of sleep. Methods　Cold intolerance was estimated by measuring the finger skin surface temperature of the hand exposed to cooling stress at 15℃ for a minute. Shoulder stiffness and fatigue were measured by using subjective scale, visual analog scale （VAS）. Quality of sleep was evaluated by using questionnaire methods, Athens Insomnia Scale（AIS）and modified OSA sleep inventory MA version（OSA-MA）. Results　Single administration of fermented tea leaf powder which contains 36.7 mg hesperidin immediately raised the skin surface temperature of the hand. The VAS scale for shoulder stiffness after the road of writing work was decreased by single feeding tea leaf powder. Continuous feeding of the powder reduced the VAS scale for chronic fatigue. For quality of sleep, the AIS score was reduced and the OSA-MA score was increased by the tea leaf powder intake for two weeks. Conclusions　These results showed that feeding hesperidin derived from fermented tea leaves ameliorates cold intolerance（UMIN-CTR000034813）, shoulder stiffness（UMIN-CTR000034814）, fatigue（UMIN-CTR000030244）, and quality of sleep（UMIN-CTR000034812）.

Objectives　Investigate the effects of Maca（Lepidium meyenii）extract-containing diet（ME diet）intake on male sexual dysfunction, particularly erectile dysfunction （ED）and other related health conditions（e.g. hormonal and mood status）. For this purpose, ME diet was administered to middle-aged and older men affected by medium to moderate ED and its results were measured. Methods　A randomized, double-blind, placebo-controlled clinical trial was conducted on 32 subjects, who received either tablet-form ME diet（n＝16）containing 1200 mg of prepared Maca extract powder or placebo（n＝16）for 8 weeks. ME diet effects on free-testosterone and dehydroepiandrosterone sulfate（DHEA︱S）levels on blood were measured. For measuring erectile and other sexual functions, International Index of Erectile Function（IIEF）and Global Assessment Question（GAQ）tests were applied. Mood status was measured applying the Japanese version of the POMS Short Form（POMS-S）. Measurements above were performed at baseline, week 4 and 8 or only at baseline and week 8. Results　The analysis was performed on 14 subjects on ME group and 15 subjects on placebo group who finished the test. The mean IIEF EF domain score for the ME group increased during the 8-week intervention period and showed a significant difference in Δ-value at week 4（P＝0.029）in comparison with placebo group values. There was a significant 9.1％ improvement in the overall IIEF score for the ME group compared with 0.6％ for the placebo group at week 4（P＜0.05）. The ME diet significantly increased serum concentration of DHEA-S（P＜0.01） without substantial effects on free testosterone concentration. An improvement on mood status was also confirmed by POMS-S test results. No ME diet-related adverse events were reported. Conclusion　The supplementation with ME diet may be beneficial for improving ED and other sexual dysfunctions, increasing serum concentration, as well as for improving male hormone function and mood status.

Objectives　This study aimed to evaluate the effect of colon-targeted capsules containing Bifidobacterium longum BB536 on defecation frequency, stool consistency and Quality of Life using the randomized, double-blind, placebo-controlled, parallel-group comparative method. Methods　Sixty healthy volunteers （age 20-65 y）with a tendency for constipation or loose stool were randomly divided into test（n＝30）and placebo groups（n＝30）. Groups received a colon-targeted capsule containing Bifidobacterium longum BB536（more than 5.0⊠109 cfu） or a placebo daily for 4 weeks. The bowel habits were recorded each day for 2 weeks before the intake period and 4 weeks during the intake period. Gastrointestinal Symptom Rating Scale （GSRS）and 36-item Short Form Survey（SF-36）were measured at day before the intake period and 14th day and 28th day of the intake period. Results　All 60 participants completed the study, with no adverse events related to colon-targeted capsules. Seven participants were excluded before efficacy analysis because of conflict with exclude criteria; the 53 participants were analyzed. Defecation frequency, stool consistency and GSRS did not differ significantly between test and placebo groups. In the SF-36, mental health score and change in social function score of the test group were significantly higher than that of the placebo group after intake period. In participants with a tendency for loose stool, stool consistency andʻloose stoolʼscore of the test group significantly improved compared to that of the placebo group after intake period. Conclusions　Colon-targeted capsules containing Bifidobacterium longum BB536 were shown to have effects of improving the loose stool and health︱related Quality of Life. （UMIN000034463）

Objectives　The aim of this study was to investigate whether the intake of dietary fiber derived from psyllium husk reduces the amount of sodium absorbed into the body in healthy Japanese men. Methods　We conducted a randomized, double-blind, placebo-controlled, crossover trial in healthy Japanese adult males（mean age 43.3±9.2, n＝21）. Subjects consumed the provided meals for the first two days of each study period and the test capsules at breakfast on Day 2. The test capsules contained psyllium husk（4 or 10 g）or placebo（dextrin）. Stools were collected the day after the intake of provided meals, and fecal excretion of sodium and other minerals were determined. Urine was collected using a 24-hour urine collecting system to determine urinary excretion of sodium and other minerals. Results　Fecal sodium excretion was significantly increased by intake of psyllium husk compared to placebo. Fecal excretion of other minerals（K, Ca, Mg, P, Cu, Zn, Mn, and Fe）had no significant differences. Conclusions　The results suggest that ingestion of capsules containing psyllium husk increases fecal sodium excretion and suppresses intestinal sodium absorption. （UMIN000030586）

Objectives　This study aimed to investigate the effects of psyllium husk intake on blood pressure in high-normal blood pressure subjects. Methods　A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 72 high-normal blood pressure subjects. The subjects were randomly assigned to either the psyllium group（n＝36）or the placebo-controlled group（n＝36）. The subjects consumed the study product before each of the three daily meals for 12 weeks. The psyllium group consumed test food containing 3.6 g of dietary fiber derived from psyllium husk at a time, and the placebo group consumed control food without dietary fiber derived from psyllium husk. The changes in the blood pressure levels of the two groups were compared. Results　Seventy subjects completed the study. Systolic blood pressure（SBP）and diastolic blood pressure（DBP）of the two groups were not significantly different. However, subgroup analysis of subjects whose estimated daily salt intake during the study were above the mean of subjects revealed that the change from baseline to Week 12 in SBP was significantly greater in psyllium group（P＜0.05）. Conclusion　These results suggest that continuous intake of dietary fiber derived from psyllium husk decreases SBP in high-normal blood pressure subjects with a high salt intake. （UMIN000035223）

Objectives　This study aimed to investigate the effects of psyllium husk ingestion on the suppression of postprandial blood glucose elevation in healthy adults. Methods A randomized, double-blinded, placebo-controlled, crossover study was conducted. A total of 50 subjects ingested psyllium husk or placebo（without psyllium husk）and consumed 300 g of salted rice balls as a high-carbohydrate meal（106.5 g of carbohydrate）15 min after ingestion of psyllium husk or placebo. Blood samples were collected before and 30, 60, 90, and 120 min after meal to measure blood glucose and insulin levels. Results　Psyllium husk ingestion significantly suppressed the change in blood glucose levels at 30 min postprandially（P＜0.001）; it significantly suppressed the area under the curve （AUC0-120 min）and incremental area under the curve（iAUC0-120 min）from 0 to 120 min postprandial（P＜0.05）. In addition, psyllium husk ingestion significantly suppressed the change in insulin levels at 30 and 60 min postprandial（30 min, P＜0.001; 60 min, P＜0.05）, the AUC0-120 min and iAUC0-120 min were also significantly low（P＜0.01）. Conclusions　These results confirm that psyllium husk ingestion suppresses the postprandial elevation in blood glucose and insulin levels（. UMIN000035336）

Objectives　This study aimed to investigate the effects of psyllium husk ingestion on the suppression of postprandial serum triglyceride elevation in healthy adults. Methods　A randomized, double-blinded, placebo-controlled, crossover study was conducted. A total of 80 subjects ingested psyllium husk or placebo（without psyllium husk）and consumed 180 g of hamburger, two butter rolls, and 30 g of shoestring potatoes as a high-fat meals load （total fat: 43.2 g）15 min after ingestion. Blood samples were collected before meals and 2, 3, 4, and 6 h after meals to measure serum triglyceride and remnant-like particle cholesterol （RLP-cholesterol）levels. Results　Psyllium husk ingestion significantly suppressed the change in serum triglyceride levels at 2 and 3 h postprandially than after placebo ingestion（2 h, P＜0.001; 3 h, P＜0.05）and the incremental area under the curve from 0 to 6 h postprandially（iAUC0-6h）than after placebo ingestion（iAUC0-6h, P ＜0.05）. In addition, psyllium husk ingestion significantly suppressed the change in RLP-cholesterol levels at 3 and 4 h postprandially（P＜0.05）, and the iAUC0-6h was also significantly lower than after placebo ingestion（P＜0.01）. Conclusions These results confirm that psyllium husk ingestion suppresses the postprandial elevation of serum triglyceride and RLP-cholesterol levels（. UMIN000035337）