薬理と治療
Volume 45, Issue 6, 2017
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扉・目次
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TOPICS 第16回CRCと臨床試験のあり方を考える会議2016 IN 大宮
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- シンポジウム11/治験にかかるコストを考える~適切な分業を目指して~
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- シンポジウム12/品質管理について正しく理解し実践するために
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ICH‒E6(R2)におけるRBA を利用した品質マネジメントシステムについて―製薬企業・SMO・医療機関がより良い関係を築くために
45巻6号(2017);View Description Hide Description
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OPINION
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REVIEW
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ダビガトラン特異的中和剤・イダルシズマブの特性および作用機序
45巻6号(2017);View Description Hide DescriptionFour direct oral anticoagulants(DOACs)including direct thrombin inhibitor dabigatran and direct Xa inhibitors rivaroxaban, apixaban and edoxaban are available for the prevention of stroke in patients with non-valvular atrial fibrillation(NVAF)in Japan. Although DOACs are associated with less life-threatening bleeding, in particular less intracranial hemorrhage, some patients still have serious hemorrhages; moreover, trauma, and clinical situations requiring urgent surgery or intervention can occur in which specific reversal agents with an immediate onset of action could be helpful in managing the emergency. Therefore, some reversal agents for DOACs are in development. Idarucizumab is a specific reversal agent for dabigatran, which is registered in many countries including Japan. Idarucizumab is a humanized monoclonal antibody fragment and binds irreversible to dabigatran with an affinity more than 300-fold higher than the affinity of dabigatran for thrombin. Therefore, idarucizumab binds specifically and potently to dabigatran and neutralizes the anticoagulant effect of dabigatran. The dabigatran neutralizing effect of idarucizumab was shown in nonclinical studies both in vitro with human plasma and in animal models looking at anticoagulation and bleeding. These dabigatran neutralizing effects of idarucizumab have been shown in nonclinical studies to be unaffected by other agents that may be combined with dabigatran and idarucizumab, including PCC, RBC, volume expanders, rt-PA, other anticoagulants, or antiplatelets. The nonclinical study results described in this report are supported by the results in the interim report of the RE-VERSE AD study, in which idarucizumab has been shown to be beneficial for patients undergoing emergency surgery and patients with hemorrhage.
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ORIGINAL ARTICLES
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自然発症高血圧ラットにおけるCilnidipine およびValsartan 併用の血圧および心拍数に対する作用―Amlodipine およびValsartan 併用との効力比較―
45巻6号(2017);View Description Hide Description背景・目的Calcium channel 拮抗薬(calcium channelblocker; CCB)とangiotensinⅡtype︱1 受容体拮抗薬(angiotensinⅡreceptor blocker; ARB)との併用療法は「高血圧治療ガイドライン2014」で推奨される降圧薬の組合わせである。しかし,cilnidipine およびvalsartan の併用とそれ以外の組合わせのCCB とARB の併用の,心血管系疾患のリスクファクターの一つである反射性の心拍数上昇作用を比較検討した結果は報告されていない。そこで本研究では,自然発症高血圧ラット(SHR)を用い,cilnidipine およびvalsartan の併用による降圧作用に伴う心拍数上昇作用を,amlodipine およびvalsartan を併用した場合とで比較検討した。さらに,心拍数上昇の作用機序を解析した。方法覚醒下のSHR にcilnidipine およびvalsartan,あるいはamlodipine およびvalsartan を経口投与し,テレメトリーシステムを使用して収縮期血圧および心拍数を測定した。また,別試験において,CCB とARB を併用したときの,交感神経活性化の指標の一つである尿中norepinephrine(NE)排泄量を定量した。結果Cilnidipine およびvalsartan の併用は,amlodipineおよびvalsartanの併用と比較して,降圧作用は同程度であったにもかかわらず,心拍数上昇は有意に下回るものであった。また,cilnidipine およびvalsartanの併用ではamlodipine およびvalsartan の併用と比較して,尿中NE排泄量が有意に低値を示した。結論Cilnidipine およびvalsartan の併用はamlodipineおよびvalsartan の併用と比較して,心拍数上昇が軽度であることが示唆された。また,その作用機序の一つとして,cilnidipine およびvalsartan の併用は交感神経活性化の程度が軽度であることが示唆された。本研究で得られた結果から,cilnidipine およびvalsartan の併用は,amlodipine およびvalsartan の併用と比較して心血管系に対して好ましい特徴を有する,有益な高血圧治療の手段となる可能性が考えられた。 -
新規非ステロイド性抗炎症薬,S—flurbiprofen 含有貼付剤の光安全性評価
45巻6号(2017);View Description Hide DescriptionS-flurbiprofen plaster(SFPP)は強力なシクロオキシゲナーゼ抑制作用を有する非ステロイド性抗炎症薬であるS︱flurbiprofen(SFP)を含有した新規の外用貼付剤である。外用薬は光にさらされる皮膚に適用されることから,光に対する安全性を評価することは重要である。そこで本検討ではSFPP の外用貼付剤としての適性を確認する目的でSFP およびSFPP の光安全性を評価した。評価は,SFP では紫外可視吸収スペクトル測定およびマウス線維芽細胞を用いたin vitro 3T3 neutral red uptake phototoxicity 試験(NRUP)により,SFPP はモルモットを用いた光毒性および皮膚光感作性試験により行った。SFPのモル吸光係数(測定波長:290~700 nm)は1000L╱(mol cm)未満で光吸収を示さず,NRUP では1000μg╱mL の高濃度においても光毒性はないと判定された。SFPP のモルモット光毒性および皮膚光感作性試験では,紫外線照射の有無にかかわらず,投与部位に皮膚反応は認められなかった。これらの結果は,本試験条件下において,SFP は光毒性および皮膚光感作性ポテンシャルを有さないこと,SFPP の光毒性学的リスクは低いことを示唆している。 -
ジエノゲストの子宮腺筋症患者における臨床評価―多施設共同ランダム化プラセボ対照二重盲検並行群間用量反応比較試験―
45巻6号(2017);View Description Hide DescriptionObjectives To evaluate the efficacy, safety, and recommended dosage of dienogest(DNG), a progestational 19︱norsteroid, in the treatment of painful symptoms in patients with adenomyosis in Japan. Methods In this study, 158 patients diagnosed with adenomyosis were enrolled and randomized into three groups, and were orally administered placebo, 1 or 2 mg╱day of DNG for 16 weeks. The primary endpoint for efficacy was the change from baseline to post-treatment in the pain score which was assessed by a verbal rating scale defining pain symptoms associated with adenomyosis. The primary endpoint for safety was adverse events occurring after treatment. In addition, serum estradiol levels were monitored. Results The mean change from baseline to post-treatment in pain scores were -1.4, -3.3 and -3.1 for placebo, 1 and 2 mg╱day of DNG, respectively. A dose-response relationship was found and the decrease in pain score was significantly greater in the 1 and 2 mg╱day DNG group than in the placebo group, respectively. Metrorrhagia was the most frequent adverse drug reaction for this drug. However, the bleeding was tolerable in these groups. No serious adverse events occurred. Serum estradiol levels showed a statistically significant dose-response relationship, and the mean levels were 59.2 pg╱mL, 57.7 pg╱mL, and 26.4 pg╱mL for placebo, 1 and 2 mg╱day of DNG, respectively. Conclusion The study demonstrated for the first time that DNG showed high efficacy and tolerability in the treatment of adenomyosis and that the recommended dose of DNG is 2 mg╱day. -
アミノ酸等含有サプリメントの長期摂取が睡眠,疲労,ストレスに与える影響―二重盲検クロスオーバープラセボ対照試験―
45巻6号(2017);View Description Hide DescriptionObjective Improving the sleep quality is an important factor to recover early from fatigue and stress and to maintain a healthy lifestyle. The amino acid-containing supplement used in this study contains arginine, ornithine, and lysine (the amino acids), glycogen, zinc, magnesium, selenium, vitamin B6, and the powder of kanka extract. Arginine, ornithine, and lysine are known to promote the secretion of growth hormone, playing an important role in recovery from fatigue. This study aimed to verify the effects of the amino acid-containing supplement in improving sleep quality and fatigue and stress conditions. Methods Adult volunteers(29 subjects) who were feeling fatigued and stressed daily were enrolled in this double-blind, crossover, placebo-controlled study. The amino acid-containing supplement and placebo were taken for 12 weeks continuously. The sleep status was evaluated using the Japanese version of the Pittsburgh Sleep Quality Index(PSQI-j). Fatigue and stress were evaluated using the Short form of Profile of Mood States(POMS-S). Results The global score of PSQI-j after 12-week intake was significantly decreased with amino acid-containing supplement intake compared with that with placebo intake. The amount of change in the global score from before the intake to 4 and 12 weeks after the intake was also significantly lower with amino acid-containing supplement intake than with placebo intake. On POMS-S, the measured values of anger-hostility(8th week)and the changes from pre-trial values of depression(4th week), anger-hostility(8th week), and confusion(12th week)showed significant improvement with amino acid-containing supplement intake compared with those with placebo intake. Conclusions It was suggested that the amino acid-containing supplement may be effective in improving sleep quality and fatigue and stress conditions. -
SC—2 乳酸菌,コラーゲンペプチド,スフィンゴミエリン含有食品の摂取は肌の角層水分量を増加させる―ランダム化プラセボ対照二重盲検並行群間比較試験―
45巻6号(2017);View Description Hide DescriptionObjectives The aim of this study was to clarify whether long-term ingestion of fermented milk containing SC-2 lactic acid bacteria, collagen hydrolysates, and sphingomyelin increase skin hydration in healthy human participants with dry skin. Methods A randomized, double-blind, placebo-controlled study was carried out for 94 women. Subjects ingested the active drink(fermented milk containing SC-2 lactic acid bacteria, collagen hydrolysates, and sphingomyelin)or the placebo drink(acidified skim milk)for 28 days. Skin hydration on the forearm and the cheek was analyzed before and after the ingestion of test drink. Results The change of skin hydration on the forearm was significantly increased in the group fed active drink as compared with the group fed placebo drink. Conclusions These results suggested that long-term ingestion of fermented milk containing SC-2 lactic acid bacteria, collagen hydrolysates, and sphingomyelin increased skin hydration. -
A Study for Evaluating the Effect of the Supplement Containing Glucosamine on Joint Performance and Daily Physical Performance ―A Randomized, Double—blind, Placebo—controlled, Study Mainly Evaluated by Subjects—oriented Questionnaire―
45巻6号(2017);View Description Hide DescriptionObjective The objective of this research was to investigate the effect of the supplement containing glucosamine(750 mg per day)on joint performance and daily physical performance of healthy people, and evaluate the safety of the tablet. Methods In this randomized, double-blind, placebo-controlled study, 44 subjects were randomized. To evaluate this objective, the locomotive syndrome risk test(a 25- question risk assessment“, LSRT”and the two-step test), and questionnaire on the condition of the knees, elbows, and low back(“QKEL”)were observed as the primary outcome. LSRT and the two-step test were devised by Japanese Orthopaedic Association(JOA). QKEL was developed by the principle investigator, which was based upon J- KOOS(Japanese Knee Injury and Osteoarthritis Outcome Score)and JKOM(Japanese Knee Osteoarthritis Measure)for knee, HAQ (Health Assessment Questionnaire)for elbows, and ODI (Oswestry Disability Index)for low back. And to evaluate the safety of the test food, adverse events were collected by means of a written questionnaire during the study as the secondary outcome. Results The study showed the improvement (including the improvement tendency)in 5 out of 26 items of LSRT among the test group compared to Placebo. In addition, the two-step test showed the significant difference in the between-group comparison. As for QKEL, among the total of 48 items, the result indicated significant difference in 10 items and tendency in 3 items. Furthermore, no adverse effects associated with the test products were observed in 16-week ingestion. Conclusion We found out that the ingestion of the supplement containing glucosamine (750 mg per day)for 16 weeks contributed to improvement of joint performance and daily physical performance of healthy people. In addition, no safety︱related matters occurred during the 16-week test period. -
複合成分配合サプリメント摂取が肥満に及ぼす作用についての検討―無作為化二重盲検プラセボ対照並行群間比較臨床試験―
45巻6号(2017);View Description Hide DescriptionObjectives Previously we reported that the plant extract from the genus Salacia in the Hippocrateaceae family has property to inhibit sugar absorption and alter the intestinal microbiota. Here, we focused on the effects of two composite supplements contained salacinol that is a characteristic chemical component of Salacia extract on obesity. Composite supplement A contained salacinol, green tea extract, enzymatically modified rutin and dietary fiber. Composite supplement B contained salacinol, green tea extract, enzymatically modified rutin, dietary fiber and polyphenol derived from seaweed. We evaluated the effects of daily ingestion of these supplements on visceral fat area, subcutaneous fat area, total fat area, body weight, and waist circumference in this study. Methods We conducted a randomized, double-blind, placebo-controlled, parallel-group study on healthy subjects aged 20 to 65 years with a body mass index of 25 to below 30. They were randomly assigned into three groups, and ingested either supplement A, B or placebo. Results Both tested groups showed the reduced visceral and total fat area, body weight and BMI. Furthermore, the group that consumed supplement B showed the reduced subcutaneous fat area and waist circumference. No adverse effects were observed in this study. Conclusions These results indicated that the ingestion of composite supplements A and B decreased body weight and BMI by reducing body fat. -
チョコレート形態で摂取したLactobacillus brevisNTT001 のヒト消化管での生存性―オープン試験―
45巻6号(2017);View Description Hide DescriptionObjectives Previously we reported that chocolate have property to protect probiotics from simulated digestive juice, indicating chocolate may be a useful tool to deliver them to intestine alive. To evaluate the survival of Lactobacillus brevis(L. brevis)NTT001 in human gastrointestinal tract, we performed an open trial whether live L. brevis was detected from feces after ingestion of chocolate containing L. brevis NTT001. Methods Thirty healthy volunteers were given 28 g of test chocolate containing live L. brevis NTT001(1.0⊠109 cfu╱28 g)for one day. Feces were sampled at before ingestion, first day, second day, and seventh day after ingestion of test chocolate. After incubation of diluted feces on the mLBS plate, L. brevis-specific PCR and restriction enzyme analysis was done with DNA extracted from colony. Results Before ingestion of test chocolate, L. brevis was not detected in the feces of all subjects(below detection limit). At first day or second day after ingestion, live L. brevis was detected in the feces of almost subjects(26╱29), and the number of L. brevis in the feces(log10 cfu╱g)was 5.2, 4.7, respectively. At seventh day after ingestion, L. brevis was not detected in the feces of all subjects(below detection limit). Conclusions We demonstrated that L. brevis NTT001 can survive transit through the gastrointestinal tract when ingested via chocolate. -
健常中高年者におけるイチョウ葉エキス含有食品の認知機能に及ぼす効果および安全性―無作為化二重盲検,プラセボ対照,並行群間比較試験―
45巻6号(2017);View Description Hide DescriptionObiective To determine whether a Ginkgo biloba extract(GBE)-containing supplement improves cognitive function and is safe in healthy, cognitively intact middle-aged to older adults. Methods The trial was conducted as a 8-week, randomized, double-blind, placebo-controlled, parallel-group study. Forty-four healthy volunteers aged between 47 and 69 years with memory complaints were randomized, 22 each into the placebo group and the GBE group (GBE 168 mg╱day). Safety and compliance were monitored over the 8-week intervention period. To evaluate participantʼs cognitive function the rey auditory-verbal learning test (RAVLT)was administered to them prior to the initiation of the intervention(baseline)and after 4 and 8 weeks of the intervention. The following 6 RAVLT parameters were used to assess the efficacy of GBE-containing supplement for different aspects of cognitive function:(1)short-term memory(STM);(2)total immediate memory(TIM);(3)verbal learning abilities(VLA);(4) reverse interference(RI);(5)delayed recall; and(6)delayed recognition. Results Analysis of the total evaluable population showed that compared to the baseline , all of the 6 parameters were significantly improved after 4 and╱or 8 weeks in the GBE group. However, no significant intergroup differences were found probably because of the presence of similar improvement in the placebo group. The subgroup analysis with the older-age participant population(≥55 years of age)revealed that an intergroup difference in delayed recall was significant(P=0.038) and intergroup differences in delayed recognition, as well as in RI, were near-significant, in favor of GBE. No GBE-induced side effects were observed during the study. Conclusion In this study, the GBE group did not differ from the control group in terms of efficacy for enhancing cognitive function in cognitively intact middle-aged to older adults. However, it looks likely that the GBE-containing supplement tested may improve the long-term memory in the older population aged above 55 years. -
健常者を対象としたLactococcus lactis subsp. cremorisFC 含有食品摂取による整腸効果の検証―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―
45巻6号(2017);View Description Hide DescriptionObjectives The aim of this study was to evaluate the effect of Lactococcus lactis subsp. cremoris FC on fecal properties and fecal microflora in healthy subjects prone to constipation. Methods In total, 50 volunteers(seven men and 43 women)were randomized into two groups and given 100 mg of L. lactis subsp. cremoris FC(test)or dextrin(placebo)daily for 2 weeks in a double-blind, placebo-controlled, cross-over study. The fecal microflora was analyzed using the DNA extracted from feces and a real-time polymerase chain reaction. Results Compared with the ingestion of placebo, the defecation frequency significantly increased(days╱week, P<0.05; times╱week, P<0.001)with the ingestion of L. lactis subsp. cremoris FC. The total bacterial count(log)and Lactobacillus sp. bacterial count(log)significantly(P<0.05)increased 2 weeks after the ingestion of test. Conclusion These results suggest that the continuous ingestion of L. lactis subsp. cremoris FC caused changes in intestinal microflora, improving defecation status and fecal characteristics in healthy subjects prone to constipation. -
クリルオイルの摂取が膝関節の痛みにかかわるQOL 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―
45巻6号(2017);View Description Hide Description目的本研究は,健常者を対象にクリルオイルの摂取が膝関節の痛みに関わるQOL に与える影響をランダム化プラセボ対照二重盲検並行群間比較試験にて検証した。方法医師の判断により,膝関節に痛みを感じている健常な日本人男女81 名を選抜した。試験参加者を,クリルオイル低用量群,クリルオイル高用量群とプラセボ群に無作為に27 名ずつ割り付けた。試験参加者は試験食品を1 日4 カプセル,4 週間摂取した。摂取前および摂取4 週後にJKOM,JOA,高感度CRP の評価によって,膝関節の痛みに関わるQOL を検証した。安全性については,身体測定・理学検査,尿検査,血液検査にて評価した。結果全試験参加者81 名のうち,試験食品の摂取不足によりクリルオイル高用量群から1 名が試験から脱落した。よって,最終解析対象はクリルオイル低用量群では計27 名,クリルオイル高用量群では計26 名,プラセボ群では計27 名であった。試験食品摂取4 週間後において,高感度CRP は,プラセボ群と比較してクリルオイル低用量群では有意に改善した(P=0.034)。JKOM およびJOA の評価では,クリルオイルによる影響は認められなかった。安全性評価項目として設定した身体測定・理学検査,尿検査,血液検査においては,試験食品摂取に伴う医学的に問題のある変化認められなかった。結論クリルオイルの継続摂取は,膝関節に痛みを感じている健常な成人日本人男女のQOLを改善し,膝関節の痛みを和らげることが示唆された。また,本研究の条件下では安全な食品であった。【COI】本試験は,三生医薬㈱が第三者機関である㈱オルトメディコに試験を委託して実施した。また,委託の際に試験食品と試験実施費用を㈱オルトメディコに提供した。 -
酵母SM—10 を含む食品の膝関節痛を有する被験者の関節機能に対する有効性に関する研究―無作為化二重盲検プラセボ対照並行群間比較試験―
45巻6号(2017);View Description Hide DescriptionObjectives The objective of this study was to investigate the effect of a dietary supplement containing Yeast SM-10 on joint functions of individuals with knee joint pain. Methods A randomized double-blind placebo-controlled clinical study was conducted in 57 subjects with knee joint pain but without the diagnosis of osteoarthritis. They were randomly assigned to two groups and administered with either a test supplement containing 600 mg Yeast SM-10(Yeast SM-10 group)or a placebo(placebo group)per day for 12 weeks, and joint functions were evaluated with the diagnostic tools for locomotive syndrome(the 25-question geriatric locomotive function scale, standing test and two-step test)as well as JOA score. Results The results indicated that the subscales for the diagnostic tools for locomotive syndrome and JOA score were not significantly different between the placebo(n=29)and Yeast SM-10(n=28)groups during the intervention, when all the subjects containing those with mild hip joint pain and low back pain were analyzed. Then, the subjects without or with weak hip joint pain and low back pain(VAS scales of JHEQ and JLEQ<10 mm)were further analyzed. Notably, the two-step test was significantly improved in the Yeast SM -10 group(n=15)compared with the placebo group(n=8)at 12 weeks during the intervention. Similarly, the subscales of JOA score(pain on walking, pain on ascending or descending stairs and total)were improved in the Yeast SM-10 group compared with the placebo group at 12 weeks during the intervention. Conclusions These observations suggest that the daily administration of a test supplement containing 600 mg Yeast SM-10 is effective for improving walking ability of healthy subjects with joint pain. -
機能性大麦BARLEYmax(Tantangara)による整腸効果について―ランダム化二重盲検並行群間比較試験―
45巻6号(2017);View Description Hide DescriptionBARLEYmax 含有食品(ショートバー形体で,BARLEYmax の摂取量として12 g/day に設計)の摂取が便通に及ぼす影響を確認するために,便秘傾向の女性28 名,36.8±9.08 歳)を対象として試験を行った。試験はプラセボ対照ランダム化二重盲検並行群間比較法にて実施した。対象者は,BARLEYmax含有食品(ショートバー形体で,BARLEYmaxの摂取量として12 g/day に設計)を4 週間摂取し,その結果BARLEYmax摂取群では,プラセボの小麦摂取群と比較して排便回数,排便量が有意に改善される効果があることが確認された。本試験結果よりBARLEYmax 含有食品の摂取は,便秘傾向者の便通改善に役立つことが示唆された。
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