薬理と治療
Volume 46, Issue 10, 2018
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扉・目次
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TOPICS 第17回CRCと臨床試験のあり方を考える会議 2017 in 名古屋
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- 教育セッション2/現場視点の臨床研究支援について~チェックすべきポイント(プロトコル作成から実施まで)~
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ORIGINAL ARTICLES
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インクレチンは小腸においてApolipoprotein B48 の合成を抑制する
46巻10号(2018);View Description Hide DescriptionObjectives A feature of diabetic dyslipidemia is hypertriglyceridemia╱high remnant lipoproteinemia, which play an important role in occurrence of arteriosclerosis and diabetic nephropathy. We have reported that incretin reduced serum triglyceride(TG)and remnant cholesterol. This mechanism is considered to be the direct effect of incretin, that is, the decrease of chylomicron lipoprotein by suppression of apolipoprotein B48(Apo B48)synthesis via GLP-1 receptor in the small intestine. In this study we examined the effect of incretin on the expression of Apo B48 in cultured human small intestinal epithelial cells. Methods TG-rich lipoproteins were isolated from patientʼs plasma by ultracentrifugal method. Normal human small intestinal epithelial cells from Cell Systems Co. were cultured at 37℃, 5% CO2, 95% air. The cells were incubated for 24h with TG-rich lipoproteins at the concentration of 100μg╱mL. Exendin 4 (active form)and Exendin 9-39(inactive form)were added at the concentrations of 50 pmol╱L, 100 pmol╱L and 300 pmol╱L on the 2nd day of the culture. After 6 hours, total cellular RNA was obtained. Reverse transcriptase-polymerase chain reaction was performed to evaluate the expression of Apo B48, GLP-1 receptor, Apo B100 and Apobec1 mRNA as a ratio to endogenous GAPDH mRNA. Results Exendin 4 increased GLP-1 receptor mRNA expression in human small intestinal epithelial cells. In addition, Exendin 4 decreased Apo B48 mRNA expression, but did not affect Apo B100 mRNA expression. Exendin 9-39 did not affect GLP-1 receptor, Apo B 48 and Apo B 100 mRNA expression. Exendin 4 reduced Apobec 1 mRNA expression. Conclusions Incretin(GLP-1)suppresses the synthesis of Apo B48 in the small intestine. This is one mechanism by which incretin(GLP-1)reduces serum levels of triglyceride, chylomicron and remnant lipoprotein in type 2 diabetic patients. -
“αG ヘスペリジンPA—LE”がヒト臍帯静脈内皮細胞およびヒト近位尿細管上皮細胞に与える影響
46巻10号(2018);View Description Hide DescriptionObjective In this study, we investigated the impact of polyphenols on vascular endothelial and renal functions associated with the development of swelling. We studied the effects of the polyphenol αG hesperidin PA-LE on cellular function in human umbilical vein endothelial cells (HUVEC)and human renal proximal tubular epithelial cells(HRPTEpC). Methods αG hesperidin PA-LE was added to HUVEC and HRPTEpC cultures at final concentrations of 1.25%, 0.625%, 0.312%, and 0.156%. To assess vascular endothelial function, we measured the expression of nitric oxide(NO)synthase and NO production in HUVEC. To evaluate renal function, we measured Na+╱K+ATPase activity and expression level using HRPTEpC. Results Three and seven days treatment with αG hesperidin PA-LE increased endothelial NO synthase(eNOS)gene expression and NO production in HUVEC and suppressed gene expression of Na+╱K+ATPase and inhibited Na +╱K+ATPase protein accumulation in HRPTEpC. Conclusions These results suggest that αG hesperidin PA-LE increases NO production via the expression of the eNOS gene in HUVEC and suppresses Na+╱K+ATPase gene expression in HRPTEpC, thus inhibiting the accumulation of Na+╱K+ATPase proteins. -
Dipeptidyl Peptidase—4 阻害薬を投与している2 型糖尿病患者へのSodium—glucose Co—transporter2 阻害薬の追加とビグアナイド薬の追加に関する医療情報データベースを用いた比較検討
46巻10号(2018);View Description Hide DescriptionObjective The influences of SGLT2 inhibitors(D+S group)versus biguanides(D+B group) as add-on medications on glycemic control, hepatic function, and kidney function were compared in diabetic patients receiving DPP-4 inhibitors in the real-world clinical setting. Method Data were obtained from the Japanese hospital-based medical database constructed by Medical Data Vision Co., Ltd. from January 2013 to September 2017. The propensity score method was used to match patients in the D+S and D+B groups based on their baseline characteristics. The changes in HbA1c, ALT, AST, and eGFR were compared between groups. Results There were no significant differences in HbA1c reduction between the D+S and D+B groups at 6 months and 1 year after treatment. ALT and AST were significantly lower or tended to be lower in the D+S group than in the D+B group at 6 months and 1 year. eGFR was lower in the D+S group than in the D+B group at 6 months of treatment, but there were no significant differences between the two groups at 1 year of treatment. Conclusion It was indicated that SGLT2 inhibitors or biguanides add︱on medications to DPP-4 inhibitors provide equivalent glycemic control in the clinical setting. In addition, SGLT2 inhibitors add-on medications to DPP-4 inhibitors may be more beneficial in patients with abnormal hepatic function tests and may also have renal protective effects. -
5—アミノレブリン酸が正常ヒト皮膚線維芽細胞の代謝へ及ぼす影響
46巻10号(2018);View Description Hide DescriptionObjective Supplementation with 5-aminolevulinic acid(ALA)has previously demonstrated an increase in dermal collagen density and skin hydration in middle-aged women. This study aimed to provide further insight into this observation by investigating the effects of ALA on collagen and hyaluronic acid production in cultured normal human dermal fibroblasts (NHDFs). Methods NHDFs were treated with various concentrations of ALA for 48-72 h to determine cell growth, collagen and hyaluronic acid production, and mitochondrial number and activity. Results ALA promoted collagen and hyaluronic acid production at 2-20μM, which did not affect NHDF growth. Although ALA increased the mitochondrial number and activity, the concentration of ALA required for these effects were relatively higher(>200μM). Therefore, the effects of ALA on collagen and hyaluronic acid production may be distinct from those on mitochondrial number and activity. Conclusion The previous observation that supplementation with ALA increases dermal collagen density and skin hydration may be partly explained by the stimulation of collagen and hyaluronic acid production in dermal fibroblasts. -
Evaluation of the Efficacy and Safety of Long—term Intake of a Dietary Supplement Containing Salmon Nasal Cartilage—derived Proteoglycan on Subjects with Subjective Knee Symptoms ―An Open Study―
46巻10号(2018);View Description Hide DescriptionProteoglycans, in addition to collagen and hyaluronic acid, are contained in large amounts in connective tissues, such as cartilage and skin, as important components of the extracellular matrix. Recently, a method using acetic acid solution for extracting proteoglycans from salmon nasal cartilage was developed, and it was shown that salmon nasal cartilage-derived proteoglycan(SPG)exerts anti-inflammatory as well as skin-beautifying effects. However, the effects of SPG on the articular cartilage have not yet been investigated. In this study, we evaluated the effects of long-term intake of SPG on arthralgia(both objective findings and subjective symptom)and the serum╱urinary levels of cartilage metabolism markers, as also its safety, in 12 subjects(3 male and 9 female, aged 40 to 74 years old; mainly Kellgren-Lawrence(K-L)grade 0-Ⅱ)suffering from mild knee pain. The study was designed as an open study, and the subjects took one test food capsule daily containing a SPG dose of 10 mg╱day for 12 weeks. For the efficacy endpoints, the parameters frequently used for efficacy evaluation in patients with arthritis were selected: the scores on the Japanese Knee Osteoarthritis Measure(JKOM), scores of arthralgia measured on a visual analogue scale(VAS)to evaluate the patientsʼ subjective symptom of knee pain, and scores on the Japanese Orthopaedic Associationʼs Knee Osteoarthritis Therapeutic Response Rating Scale (JOA), a rating scale based on objective findings. In addition, the serum╱urinary levels of C2C and CTX︱Ⅱ, both markers of cartilage type Ⅱ collagen degradation, and of CPⅡ, a marker of cartilage type Ⅱ collagen synthesis, were measured to evaluate the effect of SPG on cartilage metabolism. Furthermore, the serum type Ⅱ collagen degradation╱synthesis ratios(C2C╱CPⅡ ratio and CTX︱Ⅱ╱CPⅡ ratio)were used as indicators to evaluate the effect of SPG on type Ⅱ collagen metabolism.(UMIN000033138) The results revealed significant improvement of the scores on all subscales of the JKOM, the VAS scores for arthralgia under all three conditions examined (pain at rest, pain on walking, and pain on ascending╱descending stairs), and the scores on 3 of the 5 subscales of JOA(“pain╱walking function,”“pain╱step up and down function”and“aggregate total symptoms”)at 12 weeks as compared with the values at the baseline. Of these subscales, the score for“Ⅰ. severity of knee pain,”an subscale of the JKOM and the VAS scores for pain severity during“walking”and“stair negotiation”began to decrease significantly by 2 weeks after the start of SPG intake, while the scores for the remaining subscales showed significant improvement by 8 weeks of intake. SPG was confirmed to have a persistent rather than a transient effect in improving the pain. Furthermore, of the cartilage metabolism markers, the serum level of C2C, a marker of cartilage type Ⅱ collagen degradation, as well as that of CP Ⅱ, a marker of cartilage type Ⅱ collagen synthesis, were significantly increased at 12 weeks as compared with the values the baseline(P<0.01 for both). Furthermore, the C2C╱CPⅡ ratio, which is considered to represent the balance between type Ⅱ collagen degradation and synthesis, tended to be lower at 12 weeks as compared with that at the baseline(P=0.085), suggesting that the intake of the test food may lead to the relative suppression of cartilage degradation(or relative enhancement of cartilage synthesis). The above results confirm that SPG provides relief from mild knee pain in individuals with mainly K-L grade 0 to Ⅱ, and can be taken safely. The intake of SPG was not associated with any adverse reactions or abnormal changes of the laboratory test results during the study period. -
難消化性デキストリンおよびガラクトオリゴ糖配合食品がヒトの腸内環境に与える影響―ランダム化プラセボ対照二重盲検並行群間比較試験―
46巻10号(2018);View Description Hide DescriptionObjective This study investigated the effects of foods containing resistant dextrin and galactooligosaccharide on the intestinal environment in healthy Japanese adults who defecated 2-5 times per week. Method This was a randomized, double-blind, placebo-controlled, parallel-group trial. Forty-four healthy Japanese adult subjects with a lower Bifidobacterium ratio in their intestinal flora and lower defecation frequency were selected by a physician. Subjects were assigned to either an active or placebo group using a computerized random number generator and consumed the appropriate test foods for two weeks. As the primary outcome, intestinal flora was analyzed using terminal restriction fragment length polymorphism(T-RFLP). Subjective symptoms, stool form, and defecation frequency were evaluated using the Constipation Assessment Scale-middle term(CAS-MT), stool form scale, and a diary, respectively. All outcomes were evaluated each week. A safety evaluation was also performed. Results The outcomes in the active(n=22)and placebo(n=21)groups were analyzed. In the active group, the Bifidobacterium ratio increased significantly compared with that in the placebo group at 1 and 2 weeks. In addition, the total CAS-MT scores decreased significantly and defecations per day increased significantly in the active group compared with the placebo group at 2 weeks. There were no adverse effects. Conclusions Consumption of foods containing resistant dextrin and galactooligosaccharide significantly improved the intestinal environment and promoted defecation by increasing the occupation ratio of Bifidobacterium in healthy Japanese adults who defecated 2-5 times per week. Trial registration UMIN-CTR: UMIN000022760 Funding Aishitoto Co., Ltd -
Lactobacillus brevis SBC8803(SBL88TM乳酸菌)摂取による睡眠の質改善効果―ランダム化プラセボ対照二重盲検並行群間比較試験―
46巻10号(2018);View Description Hide DescriptionObjectives Lactobacillus brevis SBC8803(SBL88TM)is speculated to enhance the quality of sleep(QOS). Hence, this study aims to investigate QOS following the 4-week SBL88TM intake. Methods In this randomized, double-blind, parallel-group, placebo-controlled study, we enrolled healthy Japanese subjects(n=220)who reported QOS dissatisfaction. Subjects were randomly assigned into either the intervention or placebo group(n=110 each)using a computerized random-number generator. Each group ingested either one SBL88TM tablet or placebo tablet per day at the optional timing for 4 weeks. Outcomes were evaluated using the OSA sleep inventory MA version(OSA-MA)and sleep scanning mat device. Furthermore, the safety was evaluated. Results The per protocol set comprised 103 subjects(103 subjects for sleep test data)in the intervention group and 101 subjects(99 subjects for sleep test data)in the placebo group. In the intervention group, factor I(sleepiness on rising)and factor IV(refreshing)scores in the OSA-MA, the primary outcomes, significantly improved(P<0.05). Sleep efficiency and occurrence of the rapid eye movement(REM)significantly increased, and the appearance of awaking significantly decreased(P<0.05). Moreover, rate of deep sleep significantly suppressed the decrease in the first half of sleep but increased in the second half(P<0.05). Furthermore, no adverse effects were observed. Conclusions Our results suggest that SBL88TM intake improves QOS. Furthermore, SBL88TM intake was safe under the conditions of this study. Trial registration UMIN︱CTR: UMIN000029210 Foundation SAPPORO HOLDINGS LTD. -
健常成人に対するナチュラルスーパーキナーゼⅡ(ナットウキナーゼ含有食品)の末梢血流改善効果―プラセボ対照ランダム化二重盲検クロスオーバー比較試験―
46巻10号(2018);View Description Hide DescriptionObjective Nattokinase is a thrombolytic enzyme contained in natto, which is reported that it acts on endothelial cells and enhances the production of t-PA that is used for treatment such as myocardial infarction. The purpose of this study is to evaluate the blood flow improving effect of nattokinase on peripheral blood vessels. Methods We conducted a randomized, placebo-controlled, double-blind, crossover study for fifteen healthy volunteers(7 males and 8 females, aged from 30 to 48 years). Subjects consumed either soft capsules that contain 2000 FU of nattokinase(NSK-SD:110 mg)as test food, or the soft capsules that contain dextrin instead of nattokinase as placebo, together with 100 mL of water. The peripheral blood flow of middle fingers of both hands, the back of the left hand, the back of the right hand and insteps of both feet were measured before and 40, 80, 120, 180 minutes after consumption of the test food. Result The consumption of nattokinase significantly improved the change in peripheral blood flow in the middle fingers of both hands compared to the placebo. The change in peripheral blood flow in the middle fingers 180 minutes after ingestion of the test food group was significantly higher than in the placebo group(P=0.026), and the rate of change from 0 minute in the test food group was significantly higher than that of the placebo group at 120,180 minutes after ingestion(P=0.036, P=0.016). No adverse events were observed in all subjects during the test period. Conclusion These results indicate that soft capsules containing nattokinase improve the peripheral blood flow of healthy adults.
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INFORMATION
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CONSORT 2010声明―ランダム化並行群間比較試験報告のための最新版ガイドライン―(薬理と治療2010;38:939-49. より再掲載)
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