薬理と治療
Volume 48, Issue 2, 2020
Volumes & issues:
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扉・目次
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TOPIC 第19 回CRC と臨床試験のあり方を考える会議 2019 in YOKOHAMA
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- 受賞演題
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ORIGINAL ARTICLES
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ドチヌラドの肝毒性発現リスクに関する非臨床安全性検討
48巻2号(2020);View Description Hide DescriptionSerious drug-induced liver injuries were reported in a uricosuric drug, benzbromarone. We investigated the risk of liver injury for dotinurad, a newly created uricosuric drug candidate, on hepatocellular injury, cholestasis, activation of apoptotic pathway, covalent binding, inhibition of mitochondrial function and stimulation of immune response in nonclinical studies. In 13-week, 26-week and 39-week oral dose toxicity studies of dotinurad in rats and monkeys, hepatocellular injury, cholestasis or apoptosis was not observed at the highest dose levels, and exposures at the highest dose levels were 264 to 781 times the clinical exposure. In an in vitro study, covalent binding of 14C-dotinurad to human hepatocytes was 13.8 pmol/mg protein and taking the maximum recommended human dose(4 mg)into consideration, dotinurad was classified in the Safe zone based on the zone classification system. In in vitro studies, dotinurad inhibited mitochondrial respiration using succinate and glutamate as substrates with the IC50 values of 30 and 23μmol/L, and these concentrations were 51 and 39 times the clinical exposure, respectively; however, dotinurad had little effect on mitochondrial enzyme complexesⅠ to Ⅳ at 100 μmol/L. In an in vitro study on stimulation of immune response, dotinurad increased IL-8 production from THP-1 cells at 30μmol/L, and this concentration was 51 times the clinical exposure. In conclusion, there was no finding suggestive of drug-induced liver injury by dotinurad through hepatocellular injury, cholestasis, activation of apoptotic pathway, covalent binding, inhibition of mitochondrial function and stimulation of immune response, taking into consideration the maximum recommended human dose and clinical exposure. -
処方変更エスフルルビプロフェン貼付剤(ロコア® テープ)のウサギ皮膚水分蒸散量および角質剝離量に対する作用
48巻2号(2020);View Description Hide DescriptionObjective LOQOA® tape is a tape-type patch formulation composed of esflurbiprofen(SFP), a nonsteroidal anti-inflammatory drug(NSAID). In order to improve the difficulty of removal after use(peel strength), a commercial formulation of the LOQOA® tape was modified. In this study, the effects of the modified formulation on the transepidermal water loss and the exfoliation of stratum corneum of the skin were evaluated in rabbits. Methods The modified formulation, commercial LOQOA® tape and some typical NSAIDs patches were applied on the back skin in rabbits. The transepidermal water loss was measured before application and after removal of the patches on the skin, and the increase rate of transepidermal water loss was calculated. Using the formulations after removal, the amounts of exfoliated stratum corneum of the skin were determined. These parameters were evaluated as indicators of skin damage. Results Compared with the commercial LOQOA® tape, the modified formulation showed the reduction of increase rate in transepidermal water loss in the rabbit skin. In addition, the increase rate of transepidermal water loss and the amount of exfoliated stratum corneum of the skin after application of the modified formulation were comparable to those of typical other NSAIDs patches. Conclusions Based on the results of this study, the modified formulation caused less skin damage at the removal of patches than the commercial LOQOA® tape in rabbits, and it is expected that the modified formulation could reduce the damage to the skin at removal of the patches in clinical use. -
高脂肪飼料摂取モデルマウスの血中脂質および肝細胞中脂肪小滴に与える防風通聖散・大柴胡湯の影響
48巻2号(2020);View Description Hide DescriptionWe have investigated the effects of hypolipidemic agents on obesity, dyslipidemia and fatty liver in mice fed a high-fat diet. Intakes of fibrous supplement and hypolipidemic drugs, eicosapentaenoic acid, fluvastatin, probucol and colestimide decreased plasma lipids and fatty drops in liver of mice fed a high︱fat diet. Japanese herbal medicines, Bofutsushosan and Daisaikoto have been used as an anti/obesity agent, a hypocholesterolemic agent and a therapeutic and/or preventive agent for cholesterol gallstone disease with hypertriglyceridemia. Hence, we investigated the effects of two medicines on plasma lipids and hepatic fatty drops in mice fed a high-fat diet. These medicines lowered the body growth, the plasma levels of lipids and the numbers of hepatic fatty drops in mice. Besides, Daisaikoto seemed to be more effective than Bofutsushosan in the body growth. Improvement of lifestyle and timely using of Kampo-remedies might be beneficial for prevention of obesity, dyslipidemia and fatty liver. -
高尿酸血症患者を対象としたトピロキソスタットの効果検討―SANADA Study―
48巻2号(2020);View Description Hide DescriptionBackground Recently, hyperuricemia is associated to be a risk factor for not only gouty arthritis but also renal dysfunction and cardiovascular events. Therefore, targeting to uric acid is very important therapeutic approaches to prevent for renal dysfunction and cardiovascular events. Topiroxostat, a selective xanthine oxidereductase inhibitor, showed an albuminuria-lowering effect in a double-blind study. In this retrospective study, we evaluated the efficacy and safety of topiroxostat administration in real-world. Methods Eighty three patients with hyperuricemia were given topiroxostat in past. Of these, sixty two were newly administration, seventeen were switched from allopurinol to topiroxostat, and three were switched from febuxostat to topiroxostat. We examined the primary endpoint;L-FABP(L-FABP concentration and L-FABP/Cre), secondary endpoints; serum uric acid (SUA)and renal function markers(urinary albumin and urinary albumin-to-creatinine ratio (ACR), urinary β2-microglobulin(β2-MG), N-acetyl-β-D-glucosaminidase(NAG)), lipid markers(TC, LDL-C), intima-media thickness (IMT). Results After 24 weeks, topiroxostat administration resulted in significant reduction in SUA and urinary albumin, ACR, β2-MG, TC, LDL-C, tendency to reduce in NAG compared with baseline values. On the other hand, L-FABP did not change significantly. Conclusion These results suggest that topiroxostat has not only the hypouricemic effect but also the renoprotective and lipid-lowering effects in patients with hyperuricemia. UMIN-CTR number:UMIN000023584 -
Chondroitin Sulfate Improves Knee—extensor Strength―A Randomized, Double—blind,Placebo—controlled Study―
48巻2号(2020);View Description Hide DescriptionBackground Chondroitin sulfate(CS)is used to treat arthralgia and lumbalgia in Japan. Results from our previous study indicated that CS is a useful pharmacotherapy for pain relief in patients with knee osteoarthritis(OA). Weakness of the knee extensor is related to an increased risk of knee OA. Therefore, we investigated the effect of CS on locomotor function with knee-extensor strength in humans, because the efficacy of CS for the improvement of knee-extensor strength remains unclear. Methods A randomized, double-blind, placebo-controlled study was designed to investigate the effect of CS in Japanese women and men aged 35 -79 years. Participants included 34 Japanese subjects with knee-extensor strength recruited from among peoples who visited Chubu University. Participants were randomly assigned to receive either 0 mg/d CS(Placebo group) or 1560 mg/d CS (CS group). The CS tablets contained 260 mg of CS. Participants in both groups took two tablets three times per day. The strength of both knee extensors was measured using a strain gauge after 4 weeks. Results After 4 weeks of intervention, knee-extensor strength increased significantly in the CS group. In addition, the amount of change in knee-extensor strength was significantly greater in the CS group than in the Placebo group. Conclusion After 4 weeks, CS administration improved knee-extensor strength. Our findings indicate that CS may be beneficial for force transmission on knee extensors. (UMIN000031899) -
健康な成人を対象に口腔プロバイオティクスの効果を検討したランダム化二重盲検プラセボ対照比較並行群間試験
48巻2号(2020);View Description Hide DescriptionObjectives The effect of oral probiotic Lactobacillus salivarius TI2711 strain(LS1) on gingiva was examined in healthy adults. Methods Randomized for humans with stable periodontal tissue(probing depth(PD)of 4 mm or more is 10% or less, bleeding on probing(BOP)is 10% or less)In one group, one group received 840 million tablet confections per LS1 and the other group took placebo tablet confections once a day before going to bed. The clinical symptom(BOP, PCR: plaque control record, PD)were measured before the start of administration, 4 weeks, 8 weeks, 12 weeks after the start of administration, and 4 weeks after administration. Results BOP was significantly different between the LS1 group(n=15)and the placebo group(n=14)at 12 weeks of administration. In addition, PCR decreased in the LS1 group, but increased in the placebo group, showing a significant difference at 12 weeks. Conclusions LS1 tablet confection maintained healthy gingiva for adults with healthy periodontal tissue compared to placebo tablet confection. (UMIN000032609) -
Safety Evaluation of Excessive Rose Hip Extract Intake in Healthy Subjects―A Randomized, Placebo‒controlled, Double‒blind, Parallel‒group Study―
48巻2号(2020);View Description Hide DescriptionObjective The aim of this study was to evaluate the safety of five times more than regular daily intake of rose hip extract for four weeks. Method This randomized, placebo-controlled, double-blind, parallel-group study included a total of 81 individuals who provided informed consent; 44 subjects who met the inclusion criteria were allocated equally but randomly into either the intervention or the placebo group(n=22/group), using a computerized random-number generator. The subjects were asked to chew five tablets of either 100-mg rose hip extract(five times more than the regular daily intake)or placebo after breakfast every day for four weeks. The studies were conducted from September 2018 to December 2018, and the safety evaluation included physical examination, urinalysis, blood analysis, and subjective symptoms. Results The final analysis included data from 22 subjects each in the intervention and placebo groups. Medical-related problems were not observed in the safety evaluation. In addition, no adverse effects from the test food were reported. Conclusion Under the conditions of this study on healthy Japanese subjects, excessive intake of rose hip extract for four weeks was found to be safe. UMIN-CTR:UMIN000034151 Funder:Morishita Jintan Co., Ltd. -
血糖値が高めの成人における塩糀の空腹時血糖低減効果―ランダム化二重盲検プラセボ対照並行群間比較試験―
48巻2号(2020);View Description Hide DescriptionObjective Rice koji is a solid state-culture of a koji mold, Aspergillus oryzae, on steamed rice which has long been used for producing various Japanese traditional fermented foods. The present clinical study was aimed to examine the hypoglycemic effects of commercial product of salted rice koji(shiokoji), a popular seasoning in Japan, in mildly hyperglycemic adults. Methods This randomized, double-blind, placebo-controlled parallel-group study included 48 healthy adult subjects with normal-high or marginally high fasting blood glucose(FBG)levels(100-125 mg/dL). The subjects were randomly assigned to receive either shiokoji(15 g╱day)or placebo for 12 weeks and the groups were compared(the primary analysis). We assessed the effects of shiokoji supplementation on the FBG level, as well as on the two other glucose metabolism parameters, HbA1c and HOMA-IR, after 4, 8, and 12 weeks of treatment. However, this population included 18 subjects who were judged ineligible for efficacy evaluation because of impaired lifestyle and╱or high insulin resistance. Thus, efficacy evaluation was also conducted in the residual 30 subjects (the secondary analysis). Results Data from the secondary analysis but not the first analysis showed that shiokoji supplementation lowered the FBG levels over the treatment period. Additionally, between-group differences in the magnitude of changes in the FBG levels at week-4 and week-12 significantly and near-significantly, respectively, favored shiokoji supplementation. Shiokoji was well-tolerated, and no untoward side effects nor laboratory abnormalities were observed during the treatment. Conclusion Our findings suggest that shiokoji supplementation is effective for lowering FBG levels in mildly hyperglycemic adults. This study is registered with UMIN Clinical Trials Registry(ID: UMIN000028238). -
未熟ミカンと緑茶葉を混合揉捻して製造した発酵茶葉由来ヘスペリジン摂取が血圧に及ぼす影響―ランダム化二重盲検プラセボ対照並行群間比較試験―
48巻2号(2020);View Description Hide DescriptionObjectives We developed a fermented tea made by mixing thinned satsuma mandarin fruit and green tea leaves at the level of 1:3. This fermented tea contained hesperidin which has the high water-soluble property. We investigated the effects of feeding hesperidin derived from fermented tea leaves for 12 weeks on blood pressure in volunteers. Methods Thirty nine Subjects with high-normal blood pressure and stageⅠ hypertension participated in a randomized, double-blind, placebo-controlled, parallel-group comparative test. Subjects consumed test beverage containing 1.20 g fermented tea leaves or placebo beverage without tea leaves for 12 weeks. Systolic and diastolic blood pressures were measured every 4 weeks. Results Beverage containing fermented tea leaves reduced systolic blood pressures after the start of feeding. Also, systolic blood pressures were significantly lower in the test beverage group than in the placebo beverage group during feeding period. Conclusions The results suggested that feeding hesperidin derived from fermented tea leaves made by mixing thinned satsuma mandarin fruit and tea leaves has an effect decreasing systolic blood pressures in subjects with high-normal blood pressure and stageⅠ hypertension. (UMIN ID:UMIN000032462, UMIN000032682) -
Effects of Oral Use of Phytosphingosine on Skin Moisturizing in Healthy Adults―A 12—week Double—blind, Randomized, Placebo—controlled Trial―
48巻2号(2020);View Description Hide DescriptionBackground The effects of ceramides on skin hydration have been well known, but an improvements in quality is still required. We successfully developed a system that produces phytosphingosine from soy sauce lees, which is a main structure of ceramide AP. Objectives The aim of the present study was to assess the efficacy of tablets containing 2 mg of the phytosphingosine compared with the placebo over 12 week period on skin-moisturizing, using trans epidermal water loss(TEWL)scores as the primary endpoint. Methods We conducted a clinical parallel, double-blind, placebo-controlled trial study to assess the efficacy of the phytosphingosine on skin-moisturizing. 41 healthy adults were divided by age, gender and body mass index(BMI)at baseline, into the ceramides extract group, in which the subjects consumed the tablets containing 2 mg of the phytosphingosine, and the placebo group, in which the subjects consumed a placebo tablets. Results At week 12, the improvement of score from baseline(week 0)in TEWL score was observed only in the ceramides extract group(P=0.005). A significant interaction(group× week)in TEWL score was also observed(P=0.012). Conclusions The study indicated that the oral use of tablets containing 2 mg phytosphingosine improve the skin-moisturizing in healthy adults. (UMIN000029690) -
健常な成人日本男女におけるギョウジャニンニク含有サプリメントの体温上昇効果の検証―ランダム化プラセボ対照二重盲検並行群間比較試験―
48巻2号(2020);View Description Hide DescriptionObjectives To verify the effects of the consumption of capsules containing Allium victorialis subsp. platyphyllum extract on the body temperature of healthy Japanese subjects. Methods Fifty-eight Japanese adults whose basal body temperature (BBT)on awakening was 35.6℃-36.5℃ participated in the present study. Subjects were randomized into groups receiving Allium victorialis subsp. platyphyllum(AVP group)or placebo(n=29 per group)using a computerized random number generator and accordingly took two capsules containing AVP or placebo per day for four weeks. BBT on awakening was evaluated as the primary outcome. Palmar skin surface temperature and subjective symptoms were evaluated as secondary outcomes. The palmar skin temperature was evaluated using a 1-minute cold water load. Results There were 27 subjects in each group. The AVP group had a significantly higher BBT on awakening than the placebo group after 4 weeks of treatment, and it also had a higher change in BBT on awakening after 4 weeks compared with the values at the baseline. The AVP group also showed marginally significant improvement in subjective symptoms of the heat experienced by the cold in the body before the cold water load compared with the placebo group after 4 weeks of treatment, and it also showed an improved change in the symptoms after 4 weeks of treatment compared with before treatment. No adverse effects were reported. Conclusions The ingestion of AVP extract for 4 weeks increased BBT, confirming a tendency of this treatment to relieve the chilliness of the body.( UMIN000036209) Foundation YASOUKOUSO Co., Ltd. -
濃縮紅麹カプセルの摂取によるコレステロール調節効果の評価における健常領域被験者に限定した層別解析―ランダム化二重盲検プラセボ対照並行群間比較―
48巻2号(2020);View Description Hide DescriptionIn this study, we did the stratified analysis in the previous report(For the purpose of examining the effect of serum cholesterol regulation when we consecutively administered concentrated red malt containing 3.75 mg of Monacoline K per 2 capsules/day for 12 weeks, a randomized double-blind placebo-controlled parallel group comparison study was conducted with healthy 30 to 59 years old male and female who are high in serum cholesterol.),1) the data of the healthy subjects which are LDL-cholesterol less than 140 mg╱dL. We confirmed that LDL-cholesterol, the main item, and total cholesterol, a secondary item, were reduced. Furthermore, since HDL-cholesterol was also elevated. We could reconfirm the cholesterol regulating action. -
Lactobacillus plantarum PIC—NBN22 株とフラクトオリゴ糖の同時継続摂取による体脂肪低減効果の検証―ランダム化二重盲検プラセボ対照並行群間比較試験―
48巻2号(2020);View Description Hide DescriptionObjectives A research of an intake of supplements containing Lactobacillus plantarum PIC-NBN22(PIC-NBN22)and Fructo-oligosaccharides(FOS)was performed, and the change of human body fat mass was analyzed. Methods A randomized, double-blind, placebo-controlled, parallel-group trail was performed. 50 Japanese subjects aged from 30 to 65, with a Body Mass Index(BMI)of 23-30 were randomly divided into two groups(the test group=26, the placebo group=24)and provided test food(containing PIC-NBN22(2.0×108 cells/day)and FOS(1.5 g/day))or placebo food for once in a day throughout 12 weeks. Results After the supplements intake of 12 weeks, there wasnʼt a significant change between the two groups. However, in the comparison except for individuals with obesity(both BMI≳25 and visceral fat area≳100 cm2), the test group showed a significant decrease in BMI and body weight. Furthermore, the area value of abdominal body fat significantly decreased in the test group(the test group: Δ=-16.2±6.4, the placebo group: Δ=1.9±6.0, P=0.048). Conclusions In the present study, it indicated that the supplementation of PIC-NBN22 and FOS could have a reduction effect on abdominal fat mass to Japanese who have a tendency to obesity. Trial registration UMIN-CTR:UMIN000032404 -
Lactobacillus plantarum PIC—NBN22 とフラクトオリゴ糖の摂取が便秘傾向の健康成人における便通および腸内細菌叢に及ぼす効果の検証―ランダム化プラセボ対照二重盲検クロスオーバー比較試験―
48巻2号(2020);View Description Hide DescriptionObjectives and Methods The aim of evaluating the effect of intake of Lactobacillus plantarum PIC-NBN22(Pne-12)and fructo-oligosaccharides(FOS)on bowel movement and intestinal flora, healthy adults with a tendency toward constipation (stool frequency:3 to 5 times/week)a randomized, double-blind, crossover comparative study was conducted on 30 subjects(stratified analysis subjects:28 men(10 males, 18 females), 45.6±2.1 years(mean ±standard error)). Results A significant increase in the number of times of defecation at 2 weeks of ingestion(P <0.05)was observed by intake of the test food, and an increasing trend of Bifidobacterium in feces(P<0.1)(next generation sequencing method)was confirmed. Conclusions It was speculated that an increase in the intestinal Bifidobacterium is involved in the increase in the frequency of defecation due to the intake of the test food admitted in this study. Trial registration UMIN-CTR:UMIN000032411 -
正常高値血圧者に対するα—リノレン酸含有油脂の摂取が与える影響―プラセボ対照二重盲検並行群間比較試験―
48巻2号(2020);View Description Hide DescriptionThe objective of the present study was to investigate the effect of α-linolenic acid ingestion on blood pressure(BP)in Japanese with high-normal BP. A double-blind, parallel, placebo-controlled study was conducted. In study 1, 2.6 g/day of α-linolenic acid was ingested daily for 12 weeks, and in study 2, 7.8 g/day of α-linolenic acid was ingested for 4 weeks. Eligible subjects for study 1 had high-normal BP and grade Ⅰhypertension, and for study 2, eligible subjects had normal BP or high-normal BP, and grade Ⅰ hypertension. The subjects who enrolled were divided into two groups. In the two studies, the diet was controlled such that the nutrients intake was similar except for the different intakes of α-linolenic acid. Measurements of BP were performed as the primary outcome, plus physical measurements, blood collection, and urine collection. The data obtained were anonymized and stratified with normal-range BP and grade Ⅰ hypertension subjects, and analyses were performed. In study 1, high-normal BP subjects had a significant antihypertensive effect on systolic and diastolic BP(P<0.05), but grade Ⅰ hypertension subjects had no significant effect. There were no clinically significant changes in the indicators of body weight, blood, and urine, in either study 1 or study 2. In conclusion, these results suggest that α-linolenic acid ingestion in high︱normal BP subjects has a significant antihypertensive effect on both systolic and diastolic BPs, but that even if the intake is increased by a factor of three, it might have no significant clinical impact. -
Regular Intake of Japanese Traditional Rice Fermented Beverage, Koji Amazake for 4 weeks Decreases Systolic Blood Pressure ―A Randomized, Double—blind,Placebo—controlled, Parallel—group Comparative Study―
48巻2号(2020);View Description Hide DescriptionBackground Japanese traditional beverage koji amazake is made by the fermentation of rice by filamentous fungi, Aspergillus oryzae, koji. Though the history of the fermented beverage is long in Japanese culture and its health-promoting effects have been widely believed, there have been only a few researches showing the effects to human health. Methods We performed a randomized, double-blind, placebo-controlled parallel-group comparative study to evaluate the health-promoting effects of the fermented beverage. We also investigated the chemical components and their activities from the amazake extracts. Results Twenty participants were allocated into two groups of 10 subjects. Each subject took either 160 g koji amazake or placebo in a day for 4 weeks. We found significant decrease in systolic blood pressure after the regular intake of amazake, while we did not find any changes in the diastolic blood pressure and pulse. The water- and ethanol extracts from the beverage used in the clinical study have an ACE inhibition activity. Comparing their inhibition rates with that of Valyl-Tyrosine, a dipeptide which is known to have an ACE inhibition activity, we estimated that drinking of 80 mL amazake in a day is enough to obtain the clinical effect of decrease in systolic blood pressure. The koji amazake also contains much glucose and various amino acids, which provide energy for our activities. Conclusion These results suggest that daily intake of koji amazake has great possibilities to improve our health-related quality of life(QOL), and that Japanese traditional diet is worth reevaluated for the health promotion. -
ひざ関節に違和感がある健常者を対象としたラブダン型ジテルペン類化合物含有食品の摂取によるひざ関節の違和感に対する影響
48巻2号(2020);View Description Hide DescriptionBackground The knee joint problem is one of the major problems for elder people. Labdane, which is contained in white turmeric leaf, has demonstrated to inhibit degradation of hyaluronic acid(HA). Since HA is important for lubricating joints, Labdane is expected to have a role to maintain good joint health. Objectives This study aimed at validating the effects of Labdane on discomfort in the knee joint. Methods In a single-arm open-label trial, 33 healthy subjects(ages 44 to 93 years) with a discomfort in the knee joint received 6.4 mg of the Labdane per day for 12 weeks. The discomfort of the knee joint was measured every 4 weeks from the start of intake until 12 weeks after beginning the test food ingestion using visual analogue scale(VAS). Results The results of each VAS score were 5.2±2.6 at 0 weeks, 3.8 ±3.0 at 4 weeks, 2.7± 2.5 at 8 weeks and 2.5±2.9 at 12 weeks. Significant differences were observed at 4 weeks (P=0.002), 8 weeks(P<0.001)and 12 weeks (P<0.001)against the 0 weeks of intake. Conclusions This study concluded that taking the Labdane 6.4 mg/day for 4, 8, 12 weeks in healthy adult men and women with a discomfort in the knee joint is significantly effective.
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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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