薬理と治療
Volume 51, Issue 6, 2023
Volumes & issues:
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扉・目次
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TOPIC 第22回CRCと臨床試験のあり方を考える会議 2022 in 新潟
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- シンポジウム5/治験施設費用について考える─現状の課題の解決と今後向かっていく道─
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治験施設費用の問題点─東京都病院薬剤師会 治験に関する意見交換会から─
51巻6号(2023);View Description Hide Description筆者の所属する,東京都病院薬剤師会臨床試験小委員会では,毎年,治験業務に関する意見交換会(以下,「意見交換会」)を開催している。令和4 年3 月12 日には第20 回をWEB にて開催した。第20 回のテーマは,「改めて知りたい治験に関わる費用について~ベンチマーク算定・マイルストーン払い・保険外併用療養費・負担軽減費など~」である。意見交換会のプログラムは,講演,参加者からの意見のまとめ,スモールグループディスカッション,総合討論となっている。55 名が参加し,その内訳は医療機関所属が58%,SMO 所属が27%,依頼者所属が15%であった。本意見交換会参加者からの事前アンケートおよび当日の総合討論における問題点(ジレンマ)から,治験依頼者側,治験実施側のそれぞれの考える問題点を紹介する。意見交換会では,たくさんの問題点があげられた。それらを,下記の五つの項目に分類した。また,意見交換会で回答が得られたものもあったため,回答が得られたものについてはそれも紹介する。1 負担軽減費2 保険外併用療養費3 治験費用の算定方法4 治験費用の請求方法5 ベンチマーク算定,マイルストーン払いなど -
海外での治験費用算定方法の考え方と日本の問題点および日本でのベンチマーク型コスト算定の実施経験
51巻6号(2023);View Description Hide Description2007 年に厚生労働省より「国際共同治験における基本的考え方」が発出されて以降,医薬品開発における国際共同治験の治験届出数は増加をたどり,2022 年には届出の6 割を超えた1)。今や国際共同治験が医薬品開発の主流であり,新薬へのアクセスの観点から世界同時開発を行うには,日本の国際共同治験への参加は欠かせないものとなっている。この間GCP 省令は幾度もの改正がなされ,日本の治験の実施に係る多くの手順が国際的に共通化されてきたが,治験費用算定プロセスは国際的なハーモナイゼーションの議論からやや取り残されてきた感がある。その結果,国内では20 年以上にわたり現在もなおポイント表に基づく独自の費用算定が利用されている。一方,海外では米国をはじめとしてFair Market Value:市場適正価格(以下FMV)の原則が浸透し,FMV に基づくベンチマーク型コスト算定(以下ベンチマーク型コスト算定)が日本を除く世界80 ヵ国以上で標準的に利用されており,治験費用の透明性が確保されている2)。
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ORIGINAL ARTICLES
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オキサリプラチンを含む化学療法を施行した患者における過敏反応の発現に関する研究
51巻6号(2023);View Description Hide DescriptionObjective Oxaliplatin(L–OHP)is a platinum complex antineoplastic agent that is used as a first–line drug for the treatment of colorectal, pancreatic, and gastric cancer. However, hypersensitivity reactions often occur during or after L–OHP administration. In the present study, we investigated the incidence of hypersensitivity reactions among patients who received a chemotherapy regimen including L–OHP at the Fukuoka University Chikushi Hospital. Methods Patients with colorectal, pancreatic, and gastric cancer who underwent chemotherapy including L–OHP at our hospital from January 2017 to December 2018 were enrolled in this study. The patients were classified into two groups, i. e., those who developed hypersensitivity reactions during chemotherapy containing L–OHP and those who did not. Patient information, clinical laboratory data, the chemotherapy regimens used, history of use of molecularly targeted drugs, total L–OHP dose, and L–OHP dose intensity were compared in this cohort. In addition, patients with hypersensitivity reactions were graded using the Common Terminology Criteria for Adverse Events v5.0(CTCAE v5.0). Results Five out of the 74 patients enrolled in the present study(6.8%)developed hypersensitivity reactions. No significant differences were observed between two groups. The severity of the hypersensitivity reactions was of grade 1 or 2 in one case each and of grade 3 in three cases. Conclusions Patients who receive chemotherapy including L–OHP should be monitored carefully by a pharmacist from the onset of the administration of the drug; moreover, patient guidance should be offered and symptomatic therapy administered when hypersensitivity reactions occur.(Jpn Pharmacol Ther 2023;51:807‒12) -
非侵襲毛細血管顕微鏡を用いたウロリチン A 含有ザクロ抽出発酵物(ウロリッチ®)摂取に伴う毛細血管変化と内皮機能評価―ランダム化プラセボ対照二重盲検並行群間比較試験―
51巻6号(2023);View Description Hide DescriptionBackground Urolithin A, produced by the gut microbial metabolism from ellagic acid, and has many physiological functions including inducing mitophagy, antioxidant effect, and anti–inflammatory effect and Sirtuin activation. Various health benefits of urolithin A have been proposed, such as extending lifespan, increasing muscle metabolism, anticancer effect, neuroprotective effect. However, its effects to human health have been still uncertain. In the previous clinical study, ingestion of a supplement containing 10 mg urolithin A once a day for 12 weeks increased the flow–mediated dilation(FMD), which indicates the improvement in the vascular endothelial function. To assess the detailed effects on the vascular functions, we examined the effects of the same supplement on the vascular morphology by the observation with a capillary microscope. Methods We performed a randomized, placebo–controlled, double–blind, clinical study with 32 healthy subjects, divided into test and placebo groups. Subjects in each group took one supplement containing 10 mg urolithin A or a placebo in a day for 12 weeks, respectively. Capillaries in the fingertip of the subjects were non–invasively imaged by the capillary microscope “Kekkan–bijin”in every 4 weeks. Blood pressure, pulse and weight of the subjects were also checked at the same time. Its anti–aging effects were also examined by the questionnaire. Results Comparison between test and placebo group suggested that the capillary length in the test group became statistically significantly longer than that in the test group after 12 weeks. Interestingly the optical response characteristics of extravascular interstitial fluid of the capillary images in the test group increased more than that of the placebo group. Weight of the test group subjects significantly decreased compared to the placebo group, and the questionnaire indicated the significant improvements of the visibility only in the test group after 8 weeks of the trial. Conclusions These results suggest that intake of the test product containing 10 mg urolithin A once a day changed the morphology of the capillary in the finger tips, which is expected to be associated with improvements in the capillary functions. We showed that the non–invasive observation with the capillary microscope can easily provide useful insights into the health–promoting effects(. UMIN ID: UMIN000049134)(Jpn Pharmacol Ther 2023;51:813‒29) -
米ぬか発酵物含有食品の摂取によるLDL コレステロールの減少効果―ランダム化二重盲検プラセボ対照並行群間比較試験―
51巻6号(2023);View Description Hide DescriptionObjective The purpose of this study was to verify the effect of food consisting of rice bran fermented product containing 3–(4–hydroxy–3–methoxyphenyl)propionic acid(HMPA)on LDL cholesterol. Methods A randomized, double–blind, placebo–controlled, parallel–group study was conducted in 40 healthy adults aged 20 to 64 years whose serum LDL Cholesterol levels were between 120 and 139 mg/dL. The participants took either a test food consisting of rice bran fermented product containing HMPA, or placebo for 12 weeks. The primary outcome was the change from 0 week of serum LDL cholesterol levels and the secondary outcome were total cholesterol, non–HDL cholesterol HDL cholesterol, arteriosclerotic index(LDL cholesterol/HDL cholesterol ratio)and triglyceride. Results The changes in LDL cholesterol levels from 0 week by the intake of the test food containing of rice bran fermented product was significantly lower than those of placebo in 12 weeks. No adverse events were observed in this study. Conclusion These results suggested that rice bran fermented product containing HMPA reduces LDL cholesterol levels.(Clinical trial registration: UMIN000048588)(Jpn Pharmacol Ther 2023;51:831‒40) -
微粉砕脱脂ごま粉末(リピスマート®)の日本人健常成人に対する長期安全性の検討―プラセボ対照無作為化二重盲検並行群間比較試験―
51巻6号(2023);View Description Hide DescriptionObjective The safety of 12 week intake of pulverized defatted sesame powder was evaluated in healthy Japanese subjects. Methods In this randomized, placebo–controlled, double–blind trial, 24 healthy subjects (male n=12; female n=12)were enrolled and assigned by randomization to receive the 600 mg of pulverized defatted sesame powder capsule or placebo capsule for 12 weeks. Hematological tests, blood biochemical tests, urine tests, physical measurements, physical examination, interview, and physical condition check through logbooks were conducted prior to the intake, 4 weeks, 8 weeks, 12 weeks after intake, and 4 weeks after the intake period ended. Results No deviation from the normal test values or adverse effects associated with the intake of pulverized defatted sesame powder were observed. Conclusion The present study suggests that 12 weeks intake of pulverized defatted sesame powder is safe for healthy Japanese individuals.(Jpn Pharmacol Ther 2023;51:841‒52) -
松樹皮抽出物含有食品が血圧に与える影響―プラセボ対照ランダム化二重盲検並行群間比較試験―
51巻6号(2023);View Description Hide DescriptionObjective The aim of this randomized, double–blind, placebo–controlled, parallel–group study was to investigate the effects of supplementing foods with pine bark extract on blood pressure. Methods Forty healthy participants were randomly assigned to either the test food group or the placebo group. For 12 weeks, the participants consumed either test foods containing pine bark extract (adjusted to provide 2.4 mg/day of procyanidin B1 and procyanidin B3)or placebo foods(similar foods without pine bark extract). The primary outcome(blood pressure)was evaluated before and 8 and 12 weeks after the start of the experimental diet and at the post–observation period. Results The individuals in the test food group had significantly lower systolic blood pressure values than those in the placebo food group after the initiation of the experimental diets(P< 0.05). By contrast, there was no significant difference in diastolic blood pressure values between the two groups. Moreover, no adverse events attributable to the test foods were observed during the study period. Conclusion Foods containing pine bark extract may suppress systolic blood pressure increase in healthy adults.(UMIN–CTR ID: UMIN000048172)(Jpn Pharmacol Ther 2023;51:853‒9) -
歯茎への触圧刺激(歯茎マッサージ)による日常生活下の主観的ホットフラッシュ症状に対する改善効果についての探索的研究
51巻6号(2023);View Description Hide DescriptionObjective Hot flashes are one of the symptoms of menopause, characterized by a sudden feeling of facial heating and sweating. Hot flashes are related to a reduced quality of life. We have previously revealed that somatosensory stimulation to the gums(i. e., gum massage with oneʼs finger)reduced the subjective frequency of hot flashes over a certain period under calculation task. Menopausal women are deeply concerned about the sudden onset of hot flashes in daily life. Thus, this study aimed to examine the effect of gum massage on the occurrence of hot flashes in daily life. Methods This study instructed 19 females experiencing hot flashes at least once a day to perform gum massage at home by 10:00 a. m. and to record the frequency of subjective hot flashes until bedtime. The Visual Analogue Scale(VAS)was used to measure subjective hot flash symptom feelings. Results The frequency of subjective hot flashes was considerably lower in a gum massage condition than in a non–massage condition(gum massage condition: 1.41±0.45 times/day, non–massage condition: 2.69±0.45 times/day, P<0.01). VAS scores about feelings of hot flash symptoms for the day revealed similar results as that of the frequency of the subjective hot flashes(P<0.01).Conclusions This pilot study suggested that gum massage could improve subjective hot flash frequency in daily life. Therefore, gum massage may help develop new non–hormonal therapy for hot flashes.(Jpn Pharmacol Ther 2023;51:861‒9) -
Randomized controlled trial of the effects of Tongkat Ali intake on physical and psychological fatigue in healthy Japanese adults
51巻6号(2023);View Description Hide DescriptionBackground Tongkat Ali has been used in medical treatments in South–East Asian countries and the health benefits with their products consumption have been well reported, but few studies have reported the effect of Tongkat Ali supplementation on fatigue. Objectives The aim of the present study was to assess the efficacy of the intake of Tongkat Ali supplement, compared with the placebo, over a 4–week period, on fatigue in healthy Japanese adults, using the Chalder Fatigue Scale(CFS). Methods We conducted a clinical parallel, double–blind, placebo–controlled trial study to assess the efficacy of the Tongkat Ali supplement on fatigue in healthy Japanese adults. 38 healthy adults aged 30 to 60 years were divided by age and body mass index(BMI)at baseline, into the Tongkat Ali group, in which the participants consumed the Tongkat Ali supplements, and the placebo group, in which the participants consumed placebo tablets. The fatigues were assessed using the CFS. Results A participant was excluded due to the anthropometric condition. A significant reduction in the score between 0 week to 4 weeks in psychological fatigue was observed only in the Tongkat Ali group(P<0.01), although at week 4, significant reductions in the score from baseline(week 0)in physical fatigue of CFS were observed in both groups(P<0.01 in both groups).Conclusions The study indicated the intake of Tongkat Ali supplements has the potential to reduce some kind of fatigue in healthy Japanese adults. (UMIN000044295)(Jpn Pharmacol Ther 2023;51:871‒5) -
カカオフラバノールエキス末の健常成人における 90 日間安全性試験―オープン試験―
51巻6号(2023);View Description Hide DescriptionObjective The aim of this study was to evaluate the safety of cacao flavanol extract in adult humans. Methods In this open–label trial, 19 healthy adult volunteers(37.5±3.4 years old)took the test tablet containing 600 mg of cacao flavanol extract(containing 100 mg of cacao flavanol) daily for 90 days. Ames test using the preincubation method with bacteria was performed on the powder to verify the gene mutagenicity of cacao flavanol extract powder. Results There were no adverse events during the study. 15 subjects completed the study without any abnormal changes in physical examinations, hematological analyses, blood biochemical tests, nor urinary analyses. Conclusion These results suggest that the cacao flavanol extract does not show genetic toxicity, and that the extract containing 100 mg of cacao flavanol was safe. (UMIN–CTR000049370)(Jpn Pharmacol Ther 2023;51:877‒92) -
サウナ浴による健常成人熱中症脱水モデルにおけるアクエリアス経口補水液の水・電解質補給効果―ランダム化二重盲検プラセボ対照クロスオーバー比較試験―
51巻6号(2023);View Description Hide DescriptionObjective The aim of this study was to evaluate the effect of AQUARIUS–ORS(sample)water and electrolytes supplementation in healthy adults with sauna induced dehydration of heatstroke. Methods A randomized, double–blind, placebo–controlled crossover comparison study was conducted in 15 healthy men subjects. All participants were instructed to remain in a dry sauna for 10 minutes period×3 times. After completing the three periods, subjects were instructed to consume an amount of sample or Mineral Water(placebo)comparable to the amount of water lost through sweating in the sauna as calculated by weight loss over 30 minutes. Body weight, body weight change and rate of body weight change, serum and urinary electrolytes concentrations, hematological parameters, and blood chemistry values were assessed before and after sauna bathing and up to 4 hours after ingestion of the sample or placebo. Results After sauna bathing, the sample intake group replenished fluids and electrolytes more quickly and maintained than the placebo intake group until the end of the study. Body weight, blood, and electrolytes in urine showed statistically significant improvements in the sample group compared to the placebo group after 2 hours of ingestion. No adverse events related to the study food were identified during the study period. Conclusions AQUARIUS–ORS, an oral rehydration solution, was confirmed to be more effective for water and electrolytes supplementation in healthy adults with sauna–induced dehydration of heatstroke.( UMIN ID: UMIN000043913)(Jpn Pharmacol Ther 2023;51:893‒907) -
Efficacy of undenatured collagens(type Ⅱ and Ⅺ) derived from salmon nasal cartilage on knee discomfort in healthy volunteers―A randomized, double—blind, placebo—controlled intergroup trial―
51巻6号(2023);View Description Hide DescriptionObjectives This trial was conducted to investigate whether intake of undenatured type Ⅱ and Ⅺ collagen derived from salmon nasal cartilage can ameliorate discomfort in the knee joints in healthy individuals. Methods In a randomized, double–blind, placebo–controlled, intergroup trial, the subjects were randomly allocated to receive a 10 mg/day of undenatured collagen or placebo for 16 weeks. The primary outcomes included visual analogue scale(VAS)scores in five different situations. The secondary outcomes were scores on 10–time–repeated exercise tests and the levels of type Ⅱ collagen degradation/synthesis biomarkers—CPⅡ, CTX–Ⅱ, and C1, 2C. Results Each group consisted of 25 subjects. After the 16 weeks, there was a significant difference in changes from baseline in the VAS score at walking between the undenatured collagen group and the placebo group(P=0.04). Hierarchical analyses for the subjects ≥50 years of age(excluding those with no pain or strong discomfort at week 0)indicated the efficacy of undenatured collagen with between–group differences in changes in VAS scores at going up and down stairs(P=0.01)and in the squat scores of 10–time–repeated exercise tests(P= 0.04). A CTX–Ⅱ/CPⅡ ratio also showed a between–group difference(P=0.04). Conclusions This trial showed that the intake of undenatured collagen derived from salmon nasal cartilage can ameliorate and prevent discomfort in the knee joints at walking, as well as discomfort caused by bending and stretching of the knee joints, such as using stairs and doing squat, in persons 50 years of age or older. This efficacy was supported by the results of biomarker assessment and was suggested to be resulted from normalization of the balance of synthesis and degradation of the joint cartilage.(UMIN ID: UMIN000041641)(Jpn Pharmacol Ther 2023;51:909‒20) -
The effects of melinjo seed extract on uric acid levels―A randomized double—blind placebo—controlled parallel—group study―
51巻6号(2023);View Description Hide DescriptionObjectives We designed a clinical study in order to evaluate the effects on uric acid levels and the safety with regard to melinjo seed extract(MSE). Methods This study was a randomized double–blind, placebo–controlled, parallel–group clinical trial. Sixty participants were randomly assigned into three groups, MSE 750 mg/day group, MSE 375 mg/day group and placebo group. Twenty participants in each group took MSE 750 mg/day or MSE 375 mg/day or placebo for 12 weeks. Statistical analyses were performed in order to compare biomarkers between MSE groups and placebo group. Finally, 19 participants in each group completed the trial. Results MSE decreased uric acid levels in participants who had high uric acid levels(5.5–7.0mg/dL)by taking MSE 750 mg/day. There were no safety issues with taking MSE. Conclusions This study revealed that MSE decreases uric acid levels in human with high uric acid levels.(UMIN000040821)(Jpn Pharmacol Ther 2023;51:921‒8) -
マカエキス含有食品摂取による睡眠の質および疲労感の改善効果―無作為化二重盲検プラセボ対照並行群間比較試験―
51巻6号(2023);View Description Hide DescriptionObjectives Maca(Lepidium meyenii Walp)extract is suggested to have the effect for fatigue recovery. This study aims to evaluate the efficacy on quality of sleep and fatigue of a supplement containing Maca extract. Methods A randomized, double–blind, placebo–controlled, parallel–group study was conducted with 60 participants middle–aged and elderly who were concerned about fatigue. Participants were randomly assigned to receive either the test product containing 600 mg of Maca extract(containing 8.28μg of macapyrrolidione and 1.08 mg of pyroglutamic acid)or placebo daily for 12 weeks. Participants were evaluated using Profile of Mood States 2nd Edition (POMS2), OSA sleep inventory for middle age and aged(OSA–MA), Visual Analogue Scale questionnaire on fatigue feeling and salivary s–IgA concentration and secretion rate. Results In analysis of the total evaluable population, there was no significant improvement in POMS2 between the test food group and the placebo group. However, factor V(Perception of sleep length upon awaking)score of OSA–MA was significantly improved in the test group compared with the placebo group at week 12. Furthermore, in the strong fatigued group, the vitality–energy score of POMS2 was significantly improved in the test food group compared with the placebo group. Conclusions These results suggested that ingestion of Maca extract–containing foods improves the quality of sleep in middle–aged and elderly people who are concerned about fatigue. Furthermore, it was also confirmed that it helps to improve the vitality of people with strong fatigue, and that the feeling of fatigue is reduced.(UMIN ID: UMIN000047170)(Jpn Pharmacol Ther 2023;51:929‒40) -
Effects of food containing heat—killed Lactobacillus rhamnosus CRL1505 on immune function and physical conditions―A randomized, double—blinded placebo—controlled, parallel—group study―
51巻6号(2023);View Description Hide DescriptionObjectives A randomised, double–blind, placebo–controlled, parallel–group study was conducted to evaluate the effect of food containing heat–killed Lactobacillus rhamnosus CRL1505 (HkLr05)on the immune function and physical condition of healthy subjects. Methods Eighty healthy subjects were enrolled in this study. The subjects were randomly divided into two groups and ingested either food containing HkLr05 or placebo for 8 weeks. Immune function was evaluated by the expression levels of HLA–DR and CD86 in peripheral blood mononuclear cells as the activity of plasmacytoid dendritic cells(pDC)was measured at baseline and at 4 and 8 weeks after ingestion. Physical conditions were evaluated using a questionnaire during the intake period. Results After 8 weeks, with respect to the suppression of HLA–DR expression from the baseline, the HkLr05 group exhibited significantly lower suppression than the placebo group(P< 0.05). The HkLr05 group showed a significantly lower cumulative incidence of days with symptoms of physical condition. No adverse events attributable to the test food were observed during the study period. Conclusions These results indicated that food containing HkLr05 improves the activity of pDC and the physical condition of healthy subjects. (UMIN–CTR ID: UMIN000046351)(Jpn Pharmacol Ther 2023;51:941‒9)
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REVIEW
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SGLT2 阻害薬カナグリフロジンの腎保護効果―CREDENCE 試験の結果からわかってきたこと―
51巻6号(2023);View Description Hide DescriptionThe CREDENCE trial provided evidence that patients with type 2 diabetes mellitus and chronic kidney disease treated with canagliflozin have a lower risk of kidney failure and cardiovascular events compared with placebo. In this review, in order to better understand the renoprotective effects of sodium glucose co–transporter 2(SGLT2)inhibitors and their mechanisms, the results of various stratified and exploratory analyses performed on this trial are summarized. (Jpn Pharmacol Ther 2023;51:951‒8)
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COLUMN
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INFORMATION
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