薬理と治療

Objectives To examine the safety and efficacy of pazopanib hydrochloride tablets in patients with renal cell carcinoma in routine clinical practice. Methods A drug use-results survey in patients with renal cell carcinoma prescribed pazopanib hydrochloride for the first time was initiated in July 2014. The observation period for individual patients was 1 year from the start of treatment. In the safety evaluation, adverse events occurring over a 28-day period following the last dose of pazopanib hydrochloride were analyzed. Tumor response was assessed in accordance with RECIST guidelines. Results By October 18, 2017, 183 patients from 32 institutions were registered. Of 141 patients with complete case report forms, 140 patients were included in the safety and efficacy analysis sets. Regarding the composition of patients, males accounted for 65.00%, and the mean age was 69.1 years. The incidence rates of adverse drug reactions(ADRs) and serious ADRs were 82.14% and 11.43%, respectively. ADRs ≥Grade 3 (incidence rate: 38.57%) included liver dysfunction(13.57%), hypertension (12.86%), and proteinuria(3.57%), all occurring in at least five patients. In 2 of 27 patients who died, the cause of death was an ADR (liver dysfunction or interstitial pneumonia╱disseminated intravascular coagulation). In the efficacy evaluation, the response rate and disease control rate was 20.00% and 65.00%, respectively. The response rate according to the treatment line was 28.38% for first-line, 5.88% for second-line and 12.24% for third-line or later treatment. Overall survival did not reach the median survival. Conclusions The interim analysis of data from this post-marketing all-patient surveillance revealed that the safety and efficacy profiles of pazopanib hydrochloride were similar to those obtained at the time of approval, with no new issues identified.

A long-term(3-year)post-marketing prospective study of anagliptin(brand name: Suiny(R)), a dipeptidyl peptidase-4(DPP-4)inhibitor, in patients with type 2 diabetes mellitus is currently underway using the central registration method. This study aims to identify the safety and efficacy of anagliptin in clinical practice and also to promote the proper use of anagliptin. This time, we conducted an interim analysis in 4743 patients who were observed for 2 years. The incidence of adverse drug reactions(ADRs)in 4573 patients of the safety analysis set was 8.1%(369 patients, 457 episodes). The most frequent ADRs were hypoglycemia(43 patients, 0.9%), constipation(31 patients, 0.7%), abnormal hepatic function(15 patients, 0.3%), dizziness(14 patients, 0.3%), hypertension (13 patients, 0.3%)and increased urea nitrogen(12 patients, 0.3%). The incidence of serious ADRs was 1.4%(66 patients, 74 episodes). No new problems were identified with respect to the priority study items(status of occurrences of hypoglycemia, intestinal obstruction, acute pancreatitis, serious skin disorders, infections and malignant tumors, safety in patients with hepatic function disorder, patients with renal impairment and elderly patients as well as impact on cardiovascular risks). Changes in HbA1c, random blood glucose and fasting blood glucose levels from baseline at 2 years of treatment were－0.77%, －34.7 mg╱dL and－19.7 mg╱dL, respectively, showing significant decreases. The treatment effect of anagliptin for up to 1 year has already been demonstrated, and this time, a sustained blood glucose-lowering effect of anagliptin for up to 2 years has been demonstrated. Also, the proportions of patients achieving the glycemic control target HbA1c of<6.0%, <7.0% and<8.0% increased from baseline by 6.6 percentage points, 30.3 percentage points and 21.7 percentage points, respectively. The results of the interim analysis of this study suggest that anagliptin is a useful DPP-4 inhibitor in the treatment of type 2 diabetes mellitus.

A long-term(3-year)post-marketing prospective study of anagliptin is underway to examine the safety and efficacy in clinical practice in patients with type 2 diabetes mellitus. In the“1-year Interim ReportⅡ of SWIM-JPN,"1)we reported the effects of anagliptin on blood glucose and serum lipids in 4719 patients receiving anagliptin in the approved dose range between 100 and 400 mg╱day (usual-dose group), who were observed for 1 year. In the present report, we examined the effects of anagliptin on blood glucose and serum lipids including combination therapy with anagliptin and metformin in 4743 patients who were observed for 2 years. Changes in HbA1c, random blood glucose and fasting blood glucose levels from baseline at 2 years of treatment with anagliptin were －0.77%, －34.7 mg╱dL and －19.8 mg╱dL, respectively. Thus, a sustained blood glucose-lowering effect of anagliptin for up to 2 years was demonstrated. In addition, the efficacy of anagliptin was confirmed regardless of patient background. The change in LDL-cholesterol(LDL-C)levels from baseline at 2 years of treatment was －7.7 mg╱dL, showing a significant decrease. In addition, a stratified analysis according to baseline LDL-C levels revealed changes of －22.4 mg╱dL and －36.1 mg╱dL in patients with baseline LDL-C levels of ≥120 mg╱dL and ≥140 mg╱dL, respectively. Thus, patients with higher baseline LDL-C levels showed a greater decrease in LDL-C, showing the same tendency as in the“1-year Interim ReportⅡ of SWIM-JPN."1) In addition to the blood glucose-lowering effect sustained for up to 2 years in the usual-dose group of anagliptin, lowered LDL-C levels were observed. These results suggest that anagliptin can contribute to the treatment of type 2 diabetes mellitus in diverse patients including patients with diabetes mellitus and comorbid dyslipidemia.

Objectives To determine the bioequivalence between the tablet and dry syrup of lacosamide (LCM), an open-label, randomized, single-oral dose, 2-way cross-over clinical trial (EP0059;ClinicalTrials. gov identifier: NCT02972125, EudraCT Number: 2016-002462-31)was conducted. Methods Healthy male Japanese volunteers aged from 20 to 55 years were eligible for the study. Participants were randomly assigned in a 1:1 ratio to the tablet-dry syrup or dry syrup-tablet treatment sequence. Each participant received the tablet and dry syrup of LCM 100 mg. The co-primary pharmacokinetic(PK)parameters were the maximum observed plasma concentration(Cmax)and the area under the concentration-time curve until the time of last quantifiable concentration(AUC(0-t)). Results Between October 2016 and March 2017, 24 participants(12 in each treatment sequence)received the study drugs and completed the study. All participants were included in the analysis. The geometric means of Cmax and AUC(0-t) were similar between the tablet and dry syrup(Cmax, 4.242 and 4.456μg╱mL; and AUC(0-t), 55.96 and 56.20 μg・h╱mL, respectively). Analysis of the primary PK parameters demonstrated bioequivalence between 2 formulations with the 90% confidence intervals for the dry syrup╱tablet ratio of Cmax(0.9294 to 1.1871)and AUC(0-t)(0.9869 to 1.0217)being within the accepted bioequivalence range(0.80 to 1.25). Eight participants(33.3%)experienced at least one treatment-emergent adverse event(TEAE) during the study. The common TEAEs were bradycardia (12.5%)and rhinorrhea(8.3%). All TEAEs were mild in intensity. Conclusions The tablet and dry syrup of LCM 100 mg were bioequivalent in healthy male Japanese volunteers. Both formulations were well tolerated.

Objective The aim of this systematic review was to synthesize data from randomized controlled trials(RCTs)investigating the effects of oolong tea on postprandial triglyceride(TG) levels. Methods A literature search was performed using the electronic databases of PubMed, Cochrane Library, EMBASE, Ichushi-Web(Japan), JDreamIII(Japan), and Thai-Journal Citation Index(TCI)search (Thailand). We detected 233 related literature articles in the databases. Of these, two studies fulfilled the eligibility criteria of our study. Results A total of 50 participants from the two studies fulfilled the selection criteria, and the interventions of both studies were oolong tea rich in oolong tea polymerized polyphenols (OTPP). OTPP dosage ranged from approximately 70 mg and resulted in a significantly more pronounced decrease in postprandial TG levels at the 4th hour after a high-fat meal intervention(mean difference(MD): －18.87 mg╱dL, (95% confidence interval(CI)－22.92 to－14.82), P<0.00001, I2=0%, n =2 trials)and also at the 5th hour after a high-fat intervention(MD: －12.24 mg╱dL, (95% CI－16.47 to－8.01), P<0.00001, I2=0%, n=2 trials) as compared with controls, respectively. Conclusion The current systematic review provides some evidence that oolong tea, especially OTTP-enriched oolong tea, may have a beneficial effect on postprandial serum TG levels. However, the data are limited and the included trials had methodological limitations. Results from large, rigorously designed RCTs are needed to assess the effect of oolong tea consumption on postprandial serum TG levels.

Background This study was carried out to elucidate effects of ninjinyoeito, Japanese herbal medicine, on the mitochondria amount as one of clarifying the mechanism of action on the anti-fatigue effect. Methods Effects of ninjinyoeito on cell counts and mitochondria contents by using MTS assay or Mitotracker green in cultured HUVEC were determined in the in vitro assay. Results Ninjinyoeito enhanced formazan synthesis under the conditions with both growth phase and confluent cultured HUVEC with no influence on cell proliferation. In addition, ninjinyoeito increaed mitochondria content. Conclusion It is likely appeared that effecancy of ninjinyoeito may be mediated by the increased mitochondria contents in HUVEC.

Objective Recovery effect of a peptidoheteroglycan prepared from Chlorella pyrenoidosa on the number of blood cells and hematopoietic progenitor cells in the irradiated mice were investigated. Methods (1)Serum biochemical investigation in non︱irradiated group, 5.0 Gy irradiated group or 5.0 Gy irradiation plus peptidoheteroglycan(10 mg╱kg⊠2╱day)treated group were examined. (2)The number of spleen and╱or bone marrow cells in the dependent of the level of erythroid burst-forming cell(BFU-E), colony-forming unit-erythropoetin(CFU-E)dependent, and granulocytes- macrophage colony-forming cell(CFU-GM). (3)An examination on hematological test and hemopoietic progenitor calls were perfomed in 10 cases of each group. (4)For the histopathological examination, the organs of spleen and thymus were fixed 10% formalin, embedded in paraffin and cut in slices(6μm thick), then stained with hematoxylin-eosin. Microscopic examinations were performed on 3 samples each of the groups at 11 days after administration. Results 5.0 Gy x-irradiated mice induced the decrease of platelet, white blood cell, granulocytes, lymphocytes and monocytes. Intraperitoneally administration of peptidoheteroglycan (PHG)tended to decrease these damage on hematopoiesis and PHG was increased significantly on the number of spleen and bone marrow cells in the dependent of BFU-E and CFU-E. A markedly elevation in DFU-GM level was observed. Histological examinations revealed that PHG accerelated the hematopoietic recovery and decrease on damage of spleen and thymus. Conclusions These results at least that PHG might be one of the valuable material in preventive effect on the numbers of blood cells and hematopoietic progenitor cells suppression by radiation injury.

This study was conducted for the purpose of examining the salivary promoting action of Mouth mate(R). This study was divided into preliminary test and main test. The purpose of the preliminary test is to examine the ratio of those who realize that the salivary secretion at ingestion of Mouth mate(R) is greater than when taking placebo. The preliminary test was conducted as a single-blind, randomized, two-drug two-stage crossover study, and the subjects were 50 healthy Japanese adults. The preliminary test results showed that the proportion of subjects who consciously perceived that the saliva was more secreted at ingestion of Mouth mate(R) was significantly higher than at the time of ingestion of placebo. The purpose of main test is to verify that the salivary content is increasing when using Mouth mate(R). The main test was conducted as a two-drug, two-stage, double-blind, randomized crossover study, and the subjects were 60 Japanese adults aware of dry mouth. In the main test, the salivary increment was calculated by using linear mixed effect model, from the measured data of the saliva volume and the saliva weight at ingestion of Mouth mate(R). The main test results showed the saliva volume and the saliva weight increased significantly when ingesting Mouth mate(R) compared to placebo ingestion. As a result of preliminary test and main test, it was concluded that the Mouth mate(R) has the salivary secretion promoting action to the extent that it can be recognized and quantified.

Objectives Although vaccination is effective method to prevent influenza infection, current influenza vaccines have inadequate efficacy in general populations. For these reasons a supplement that prevent influenza infection is keenly anticipated. In basic research, it is demonstrated that kuromoji(Lindera umbellate Thunb.)extract has an effectiveness preventing influenza infection. The aim of this study was to assess whether kuromoji extract has a protective effect on influenza infection in clinical settings. Methods In a randomized, double-blind, placebo-controlled, parallel-group study, 135 adult volunteers, they are healthy nursing staff and are met inclusion and exclusion criteria, participated in this study. Sixty-seven participants received test candy(containing 67 mg╱day of kuromoji extract), and another 68 participants received placebo candy. Results Test candy significantly reduced influenza infection after 12 weeks compared with placebo candy. Conclusions This is the first clinical study to assess the effectiveness of kuromoji extract in the prevention of influenza infection. Our results suggest that kuromoji extract is a safe supplement for the prevention of influenza infection(. UMIN000030339)

Objectives The placenta extract includes many active ingredients necessary to maintain homeostasis in the body and provides excellent materials for health and beauty. In this study, we examined the effects of porcine placental extract on human skin functions were investigated. Methods Twenty-three Japanese female subjects from 45 years old to 60 years old ingested the placenta extract powder-formulated food for 12 weeks, and the following results were obtained. The skin parameters at the same site on the left cheek were measured before a start, four weeks and 12 weeks later. Results Water content in the stratum corneum significantly increased at both 4 and 12 weeks compared to before ingestion of the test food(P<0.01). Changes in the index of skin viscoelasticity(R7)were significantly increased at both 4 and 12 weeks(P<0.01)compared to before ingestion of the test food. Brightness L* values were significantly higher at both 4 and 12 weeks compared to before ingestion of the test food(P<0.01). Red-coloured a* values were significantly lower at both 4 and 12 weeks compared to those before ingestion of the test food(P<0.01). Yellow-coloured b* values were significantly increased at both 4 and 12 weeks compared to before ingestion of the test food(P<0.01). There was a trend toward a decrease in the total number of wrinkles after 4 weeks compared to before ingestion of the test food and a significant decrease after 12 weeks(P<0.05). The visual judgment score of wrinkles was significantly reduced at both 4 and 12 weeks compared to before ingestion of the test food(P<0.01). Conclusion These results suggested that the skin parameters such as skin moisture content in the stratum corneum, skin elasticity, tone of the skin color, were improved by the intake of the placenta extract food and moreover the placenta extract food possessed the effects to make the fine wrinkle less noticeable.

Objective We conducted a randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of a green tea catechin-rich beverage on abdominal fat area and body weight in obese individuals. Methods After a 4-week pre-observation period, 150 overweight individuals(mean body mass index[BMI]±standard error of the mean[SEM], 27.21±1.28; mean age, 47.1±9.1 years)were divided into the catechin group, in which subjects consumed a tea catechin-rich beverage(540 mg tea catechins, 14 mg caffeine, 500 mL╱day), and the placebo group, in which subjects consumed a placebo beverage(0 mg tea catechins, 14 mg caffeine, 500 mL╱day), for 12 weeks, followed by another 4-week post-observation period. Results At week 12, the amount of change from baseline(week 0)in abdominal visceral fat area(ΔVFA), the primary endpoint, was significantly greater in the catechin group (ΔVFA=－5.99±16.31 cm2)than in the placebo group(ΔVFA=0.30±17.56 cm2). Secondary endpoints, including total visceral fat area, subcutaneous fat area, and body weight, were also significantly lower in the catechin group than in the placebo group. The incidence of adverse events and safety parameters did not differ significantly between the two groups. Conclusion Continuous consumption of the tea catechin-rich beverage for 12 weeks effectively decreased abdominal fat area and body weight with no side effects. Trial registration The study protocol was pre-registered with the University Hospital Medical Information Network Clinical Trial Registry. The registration number: UMIN000023491.

Objective The study aimed to verify that ingestion of a dietary supplement containing gymnemic acid, mulberry leaf extract, green tea extract, chitosan, and kidney bean extract would reduce the postprandial blood glucose level after intake of sucrose. Methods A randomized, double-blind, placebo-controlled, cross-over study was conducted for 40 healthy volunteers aged 20 to 65 years. Subjects 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, and 4.8 mg of kidney bean extract or placebo with 75 g of sucrose as a test meal. The blood glucose and insulin levels were measured before and 15, 30, 45, 60, 90, 120 minutes after intake of a test meal, and compared with the changes between placebo and the dietary supplement. Results Ingestion of the dietary supplement was significantly suppressed AUC(area under the curve)values of postprandial blood glucose and insulin levels after intake of a test meal. We also observed significant suppression of the elevation of postprandial blood glucose and insulin levels after intake of a test meal by ingestion of the dietary supplement. 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, and 4.8mg of kidney bean extract suppresses the elevation of postprandial glucose level after intake of sucrose.( UMIN ID UMIN000032122)

Background A clinical trial was conducted using 21 healthy adults randomly assigned to a saffron extract group or placebo group in order to confirm the increase of sleep quality by taking saffron extract. Objective To determine the effect of saffron extract on the sleep quality of 21 healthy adults. Trial design A clinical parallel, double-blind, randomized control trial (RCT)was conducted. Subgroups were defined by good sleeper or poor sleeper using a PSQI test for analysis. Method The participants, who gave self-report information, were under a randomized controlled trial(RCT)study designed for all participants receiving the saffron extract(crocin:0.6 mg╱day)or placebo. Result There was a significant reduction in score for the Pittsburgh sleep quality index (PSQI)only in the group treated with the saffron extract. In addition, a significant saffron extract effect on daytime dysfunction over 4 weeks was apparent between the extract group and the placebo group in the subjects with poor sleeper at baseline. Conclusion Overall, the effect of saffron extract on sleep quality in healthy adults was observed(. UMIN000026112)

Background The aim of this study was to evaluate the effects of intake of royal jelly peptide on skin conditions of healthy woman. Methods A randomized double-blind placebo-controlled, parallel-group study was conducted on healthy women. Healthy volunteers were administered test food containing 1000 mg of the royal jelly peptide or placebo food for 8 weeks. The level of skin stratum corneum hydration and transepidermal water loss(TEWL)and elasticity were measured. Results The data of 33 subjects were obtained and analyzed. TEWL of the royal jelly peptide uptake group was significantly reduced compared with the placebo group after the eight-week period. The levels of skin hydration and elasticity were not improved in the royal jelly group compared to the placebo group. In addition any clinical adverse events were not found throughout the study period. Conclusions These results of the present study suggested that daily consumption of royal jelly peptide could improve barrier function of human skin. ( UMIN-CTR ID:000026573)

Objectives The aim of the study was to investigate the ameliorative effects of a oligomerized-polyphenol from Litchi chinensis fruit extract (OPLFE)on temporary physical fatigue in healthy track and field athletes. Previously, the benefits had been elucidated by objective assessments in the clinical study and reported, however, the subjective ones were not discussed in it. Thus, we analyzed the subjective indices and summarized as the second report. Methods A randomized, double-blind, placebo-controlled trial with 20 healthy track-and-field athletes was conducted. The subjects ingested 100 mg╱day of OPLFE during two months of regular training. Anti-fatigue effects were evaluated by Profile of Mood States (POMS)and Visual Analog Scale(VAS)relating a feeling of fatigue. Results In POMS, the OPLFE group showed significant improvement in“Tension-Anxiety", “Depression-Dejection"“, Fatigue"“, Confusion"and“Total"in comparison with the placebo group. OPLFE markedly improved the VAS score of fatigue feeling in comparison with pre-intake while placebo did not improve. but also the placebo intake. Additionally, the variation of VAS score from initial to final was significantly improved in the OPLFE group in comparison with the placebo group. Conclusions These results suggest that OPLFE attenuates the fatigue feeling after track-and-field training in healthy subject. Furthermore, it contributes to restore the mood states which may bring chronic fatigues and depression. The function may bring the anti-oxidative effect of OPLFE including characteristic A-type procyanidins such as procyanidin A2 and pavetannin A2.