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Traditional use and safety evaluation of combination Traditional Chinese Medicine in European registration: with XiaoYao Tablets as an example. 中药复方在欧注册中的传统使用及安全性评价——以逍遥片为例
Pub Date : 2022-04-10 DOI: 10.1691/ph.2022.1227
Qiong Wang, Shenghan Gao, Wensheng Zhang, Yunxia Zhao, Yi He, W. Sun, Feng-Na Zhang, Tong Yu, Lihong Zhou, Zheng-Rong Ye, Jian-ming Su, Shunnan Zhang, Yongfa Chen
Mental health disorders such as stress, anxiety, depression and insomnia caused by COVID-19 have attracted worldwide attention. Traditional Chinese medicines (TCMs) have been proven to be a safe and effective option for treating mental health disorders. Recently, after assessing its efficacy and safety fully, the Netherlands Medicines Evaluation Board approved XiaoYao Tablets as a traditional herbal medicinal product (THMP), indicated for an alternative self-care for patients in Europe to relieve the symptoms of mental stress and exhaustion. Despite the fact that TCMs have gradually become one of the therapeutic choices worldwide, to-date, only a few TCMs have been successfully registered in the European Union (EU) as THMPs, and XiaoYao Tablets is the first successfully registered combination TCM from China. In this article, traditional use efficacy and clinical safety of XiaoYao Tablets in the treatment of mental health disorders were summarized and analyzed from the perspective of traditional use registration (TUR). Additionally a safety evolution pathway of combination TCMs was established. This article will not only seek to enhance our understanding about traditional use efficacy and clinical safety of XiaoYao Tablets, but also summarize the experience of XiaoYao Tablets as the first successfully registered combination TCM from China, which could serve as role model for the others to overcome registration difficulties in the EU.
新冠肺炎引发的压力、焦虑、抑郁、失眠等精神健康障碍引起了全世界的关注。中药(tcm)已被证明是治疗精神健康障碍的安全有效的选择。最近,在对其有效性和安全性进行了全面评估后,荷兰药品评估委员会批准了止痛片作为传统草药产品(THMP),作为欧洲患者缓解精神压力和疲惫症状的替代自我保健。尽管中药已逐渐成为世界范围内的治疗选择之一,但迄今为止,只有少数中药在欧盟(EU)成功注册为thmp,逍遥片是中国第一个成功注册的复方中药。本文从传统用药登记(TUR)的角度,对逍遥片治疗精神健康障碍的传统用药疗效及临床安全性进行总结分析。建立了复方中药的安全性演化路径。本文旨在增进我们对中药复方药的传统使用疗效和临床安全性的认识,同时总结中药复方药作为中国首个成功注册的中药复方药的经验,为其他中药复方药在欧盟克服注册困难提供借鉴。
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引用次数: 2
MiR-513a-3p promotes radiation-induced apoptosis of human lung cells by inhibiting glutathione S-transferase P1. MiR-513a-3p通过抑制谷胱甘肽s -转移酶P1促进辐射诱导的人肺细胞凋亡。
Pub Date : 2022-04-10 DOI: 10.1691/ph.2022.1872
Hui Zhou, Binghua Yao, L. Qian, Haozhong Hu, Qingning Duan
Radiotherapy is a common treatment for lung cancer. However, radiation pneumonitis caused by radiotherapy can affect the quality of life and prognosis of lung cancer patients. miR-513a-3p has been found to sensitize human lung adenocarcinoma cells to chemotherapy by targeting glutathione S-transferase P1 (GSTP1). Here, we found that x-ray induced the apoptosis of BEAS-2B and miR-513a-3p expression in a dose- and time-dependent manner, and miR-513a-3p-mimic significantly increased x-ray induced apoptosis, while miR-513a-3p-inhibitor significantly decreased x-ray induced apoptosis. Dual luciferase gene reporter system showed that miR-513a-3p targeted to inhibit the expression of GSTP1 in BEAS-2B cells. Moreover, knockdown of GSTP1 significantly increased, while overexpression of GSTP1 decreased the apoptosis of BEAS-2B induced by x-ray. Importantly, overexpression of GSTP1 significantly reduced miR-513a-3p-mimic elevated x-ray -induced apoptosis in BEAS-2B cells. In conclusion, x-ray caused increased expression of miR-513a-3p, and miR-513a-3p promoted x-ray-induced apoptosis of human lung cells by inhibiting GSTP1.
放射治疗是治疗肺癌的常用方法。然而,放疗引起的放射性肺炎会影响肺癌患者的生活质量和预后。已经发现miR-513a-3p通过靶向谷胱甘肽s -转移酶P1 (GSTP1)使人肺腺癌细胞对化疗敏感。在这里,我们发现x射线以剂量和时间依赖的方式诱导BEAS-2B和miR-513a-3p的表达凋亡,miR-513a-3p-mimic显著增加x射线诱导的细胞凋亡,而miR-513a-3p-inhibitor显著降低x射线诱导的细胞凋亡。双荧光素酶基因报告系统显示miR-513a-3p靶向抑制BEAS-2B细胞中GSTP1的表达。GSTP1的下调明显增加,而GSTP1的过表达减少了x射线诱导的BEAS-2B的凋亡。重要的是,GSTP1的过表达显著降低了miR-513a-3p-mimic在BEAS-2B细胞中x射线诱导的升高的凋亡。综上所述,x射线导致miR-513a-3p表达增加,miR-513a-3p通过抑制GSTP1促进x射线诱导的人肺细胞凋亡。
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引用次数: 0
Cytotoxic benzylidene hydrazides of terephthalic acid and related compounds. 对苯二甲酸的细胞毒性苄基酰肼及其相关化合物。
Pub Date : 2022-04-10 DOI: 10.1691/ph.2022.11072
M. Hossain, S. C. Hall, P. J. Wiggington, S. Roth, S. Das, U. Das, P. K. Roayapalley, J. Dimmock
The present investigation involved the synthesis of a number of novel benzylidene hydrazides as candidate cytotoxic agents. The preparation of these compounds from terephthalic acid and isophthalic acid proceeded satisfactorily. However, the reaction of phthalic acid hydrazide with various aryl aldehydes was unsuccessful in general. Some of the unexpected products were identified. The shapes and also the distances between the centers of the aryl rings designated B and C of three representative compounds 1b, 2b and 3b were determined. The compounds designated 1a-e, 2a-e and 3b were screened against human HCT116 and HT29 colon cancer cells as well as human CRL1790 non-malignant colon cells which revealed the tumor-selective toxicity displayed by these compounds.
本研究涉及合成一些新型苄基肼作为候选细胞毒性药物。以对苯二甲酸和间苯二甲酸为原料制备这些化合物的过程令人满意。然而,邻苯二甲酸肼与各种芳醛的反应一般都不成功。发现了一些意想不到的产品。测定了三个具有代表性的化合物1b、2b和3b的芳基环B和C中心的形状和距离。对化合物1a-e、2a-e和3b进行了抗人HCT116和HT29结肠癌细胞以及人CRL1790非恶性结肠癌细胞的筛选,发现这些化合物具有肿瘤选择性毒性。
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引用次数: 1
Development and optimization of Clinacanthus nutans liquid spray using a two-level full factorial design. 采用两水平全因子设计开发和优化山楂液体喷雾剂。
Pub Date : 2022-04-10 DOI: 10.1691/ph.2022.1236
K. Huanbutta, K. Thanawuth, L. Sutthapitaksakul, S. Piriyaprasarth, K. Cheewatanakornkool, S. Maksup, K. Theeratanapartkul, P. Sathorn, P. Phusamlee, T. Kwanjaiphanich, T. Sangnim, P. Sriamornsak
This study aimed to develop and optimize a topical Clinacanthus nutans liquid spray that dries quickly after spraying and has low stickiness. An experimental design was adopted to evaluate the effects of the amounts of polyvinylpyrrolidone (X1) and glycerol (X₂) and the ratio of acetone:ethanol (X₃) on the stickiness (Y1 ), solution viscosity (Y₂), evaporation rate (Y₃), and spray coverage radius (Y₄) of the solution. Results revealed that all independent factors had a substantial effect on Y1 -Y₃. In this model, the synergistic effect was uncommon. The optimized formulation consisted of X1 of 0.1%, X₂ of 1.0%, and X₃ of 59:41. The response values of Y1, Y₂, Y₃, and Y₄ were 92.24 mN, 4.63 cP, 0.0959%, and 9.40 cm, respectively. The actual results were close to those predicted by the experimental design model. Therefore, the optimized topical spray formulation can be used in actual practice.
本研究旨在开发和优化一种喷雾后快速干燥、低粘性的外用山棘液体喷雾剂。采用实验设计,考察了聚乙烯吡罗烷酮(X1)和甘油(X₂)的用量以及丙酮:乙醇(X₃)的比例对溶液黏度(Y1)、溶液黏度(Y₂)、蒸发率(Y₃)和喷雾覆盖半径(Y₄)的影响。结果表明,所有的独立因素对Y1 -Y₃都有很大的影响。在该模型中,协同效应并不常见。优化后的配方为X1 = 0.1%, X₂= 1.0%,X₃= 59:41。Y1、y2、Y₃、Y₄的响应值分别为92.24 mN、4.63 cP、0.0959%、9.40 cm。实际结果与实验设计模型的预测结果接近。因此,优化后的外用喷雾配方可用于实际。
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引用次数: 0
Human placental mesenchymal stem cell derived exosomes exhibit anti-inflammatory effects via TLR4-mediated NF-κB/MAPK and PI3K signaling pathways. 人胎盘间充质干细胞来源的外泌体通过tlr4介导的NF-κB/MAPK和PI3K信号通路表现出抗炎作用。
Pub Date : 2022-04-10 DOI: 10.1691/ph.2022.11082
Yiwei Hu, Huiting Qu, Jie He, Hongyao Zhong, Shoukai He, P. Zhao, Leyao Zhang, Jinghua Chen, Chao Deng
Exosomes are a type of nanoparticles in 40-200 nm extracellular vesicles secreted from living cells, containing a plurality of biologically active substances, which can be used as carriers of intercellular delivery signals. Among them, mesenchymal stem cell (MSC)-derived exosomes have been reported to play important roles in injury repair, alleviating inflammation; thus, MSC-derived exosomes have become hot spot in noncellular therapies. The role of human placental MSC-derived exosomes (hplMSC-Exos) in inflammation and their potential mechanisms are unclear. Therefore, we investigated the anti-inflammatory effects of hplMSC-Exos in lipopolysaccharide (LPS)-induced RAW264.7 cells and their intrinsic mechanisms. Our data demonstrated that hplMSCs-Exos can adjust inflammation by regulating TLR4-mediated NF-κB/MAPK and PI3K signaling pathways, indicating that hplMSCs-Exos can act as a new strategy for inflammatory treatment.
外泌体是活细胞分泌的一种位于40-200 nm细胞外囊泡内的纳米颗粒,含有多种生物活性物质,可作为细胞间传递信号的载体。其中,间充质干细胞(MSC)衍生的外泌体已被报道在损伤修复、减轻炎症;因此,msc来源的外泌体已成为非细胞治疗的热点。人胎盘间充质干细胞来源的外泌体(hplMSC-Exos)在炎症中的作用及其潜在机制尚不清楚。因此,我们研究了hplMSC-Exos在脂多糖(LPS)诱导的RAW264.7细胞中的抗炎作用及其内在机制。我们的数据表明,hplMSCs-Exos可以通过调节tlr4介导的NF-κB/MAPK和PI3K信号通路来调节炎症,这表明hplMSCs-Exos可以作为炎症治疗的新策略。
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引用次数: 5
Influence of concurrent and staggered dosing of semi-solid nutrients on the pharmacokinetics of orally administered carbamazepine in rats. 同时和交错给药半固体营养物对大鼠口服卡马西平药代动力学的影响。
Pub Date : 2022-04-10 DOI: 10.1691/2022.1756
K. Nagai, S. Fukuno, R. Moriwaki, H. Kuroda, S. Omotani, T. Miura, Y. Hatsuda, M. Myotoku, H. Konishi
In the present study, we examined the effects of concurrent and staggered dosing of PG-soft ace-MP TM (PG), novel semi-solid enteral nutrients, on the pharmacokinetics of orally administered carbamazepine (CBZ) in rats due to the high possibility of drug interaction during the absorption process. The pharmacokinetic behavior of CBZ was considerably altered when administered concurrently with PG. The maximum serum CBZ concentration (Cmax) significantly decreased and the mean residence time (MRT) significantly increased. The elimination constant (ke) also significantly increased, but there were no significant changes in the area under the serum CBZ concentration versus time curve (AUC) and the time to reach Cmax (Tmax). However, these changes in the pharmacokinetic parameters were eliminated by waiting 20 min, the time interval equivalent to the Tmax described above, between CBZ administration and PG dosing. This study suggested that PG interferes with CBZ absorption from the digestive tract, although staggered administration of CBZ and PG prevented their interaction.
在本研究中,我们研究了同时和交错给药PG-soft ace-MP TM (PG),一种新型半固体肠内营养物质,对大鼠口服卡马西平(CBZ)的药代动力学的影响,因为在吸收过程中药物相互作用的可能性很高。与PG同时给药时,CBZ的药动学行为明显改变,血清CBZ最大浓度(Cmax)显著降低,平均停留时间(MRT)显著增加。消除常数(ke)也显著升高,但血清CBZ浓度-时间曲线下面积(AUC)和到达Cmax的时间(Tmax)无显著变化。然而,在CBZ给药和PG给药之间等待20分钟(相当于上述Tmax的时间间隔),这些药代动力学参数的变化被消除了。本研究表明PG干扰CBZ从消化道的吸收,尽管CBZ和PG的交错给药阻止了它们的相互作用。
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引用次数: 0
Community pharmacists' measurement of health-related quality of life in outpatients taking high-risk drugs. 社区药师对门诊高危用药患者健康相关生活质量的测量。
Pub Date : 2021-09-13 DOI: 10.21203/rs.3.rs-858889/v1
T. Ichimura, C. Ogawa, Hayato Murata, K. Miyahara, Satoshi Yuge, R. Tsukioka, Keisuke Kado, Tomonobu Yoshimura, Kenichi Suzuki, H. Nomura, Hisanori Shimizu
Patients experiencing severe side effects when taking high-risk drugs may have a significantly reduced health-related quality of life (QOL); therefore, it is important to identify changes in the health-related QOL in these patients. This study aimed to determine the health-related QOL in community pharmacy outpatients taking high-risk drugs. This prospective observational study was conducted in 29 community pharmacies with 71 pharmacists in 12 regions and cities in Japan from October to December 2020 and 760 patients were enrolled. Using descriptive questionnaires of EuroQOL-5-dimensions-5-levels (EQ-5D-5L), community pharmacists obtained health-related QOL data from outpatients taking high-risk drugs. The mean health-related QOL of all outpatients was 0.869. The health-related QOL decreased with increasing age. The outpatient health-related QOL was 0.700, 0.763, 0.785, and 0.817 when taking antiepileptic, antidepressant, digitalis, and antiarrhythmic drugs, respectively, which was lower than the average health-related QOL of all outpatients. Mobility and pain/ discomfort accounted for a large proportion of the decline in the health-related QOL with increasing age. There were no significant differences in personal care with increasing age; however, the number of outpatients with mobility, normal activity, and pain challenges decreased with age. In contrast, outpatients aged <65 years with anxiety/depression showed a lower than overall average health-related QOL. To the best of our knowledge, this is the first study in Japan to report an investigation by community pharmacists regarding health-related QOL assessment in outpatients taking high-risk drugs.
在服用高风险药物时出现严重副作用的患者可能会显著降低与健康相关的生活质量(QOL);因此,确定这些患者健康相关生活质量的变化非常重要。本研究旨在了解社区药房门诊高危用药患者与健康相关的生活质量。本前瞻性观察研究于2020年10月至12月在日本12个地区和城市的29家社区药店进行,共有71名药剂师,纳入760名患者。社区药师采用euroqol -5维-5水平描述性问卷(EQ-5D-5L),获取门诊高危用药患者健康相关生活质量数据。门诊患者健康相关生活质量平均值为0.869。健康相关生活质量随年龄增长而下降。门诊患者服用抗癫痫药、抗抑郁药、洋地黄、抗心律失常药的健康相关生活质量分别为0.700、0.763、0.785、0.817,均低于门诊患者的健康相关生活质量平均值。随着年龄的增长,与健康相关的生活质量下降的主要原因是活动能力和疼痛/不适。个人护理水平随年龄增长无显著差异;然而,有活动能力、正常活动和疼痛挑战的门诊患者数量随着年龄的增长而减少。相比之下,年龄<65岁的焦虑/抑郁门诊患者的健康相关生活质量低于总体平均水平。据我们所知,这是日本第一个报告社区药剂师对门诊高危药物患者健康相关生活质量评估的研究。
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引用次数: 1
Antimicrobial drugs involved in potential drug-drug-interactions in cardiosurgical patients 心脏外科患者中潜在药物相互作用的抗菌药物
Pub Date : 2021-01-01 DOI: 10.1691/PH.2021.0774
I. Samardžić, I. Marinović, I. Matković, I. Mamic, V. Vrca
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引用次数: 1
Notoginsenoside R1: A systematic review of its pharmacological properties. 三七皂苷R1:药理性质的系统综述。
Pub Date : 2019-11-01 DOI: 10.1691/ph.2019.9534
Shasha Guo, Xiaozhi Xi, Jia Jia
Notoginsenoside R1 is one of major bioactive compounds extracted from Panax notoginseng (Burk.) dry roots and rhizomes of F.H. Chen, which has been increasingly used for enhancing cognition and physical health worldwide. The objective of this study was to review the pharmacological effects of notoginsenoside R1 in a systematic manner. We performed searches on databases including MEDLINE (Pubmed), Google Scholar and Web of Science, the System for Information on to select the original research publications reporting the biological and pharmacological effects of notoginsenoside R1 from in vitro and in vivo studies regardless of publication language and study design. Notoginsenoside R1 exhibited potent characteristics of neuroprotective, anti-inflammatory, anti-apoptosis and anti-ischemia-reperfusion injury properties etc. The cytotoxic effects of notoginsenoside R1 were dependent on different types of cell lines. Other pharmacological effects including accumulation of lipopolysac chaired-induced microcirculation, endothelial injury, hypoxia-reoxygenation injury effects have been mentioned, but the results were considerably diverged. A higher quality of evidence on clinical trial studies is highly recommended to confirm the efficacy of notoginsenoside R1.
Notoginsenoside R1是从三七干根和根茎中提取的主要生物活性化合物之一,在世界范围内越来越多地用于增强认知和身体健康。本文对三七皂苷R1的药理作用进行了系统的综述。我们对MEDLINE (Pubmed)、Google Scholar和Web of Science、the System for Information on等数据库进行了检索,从体外和体内研究中选择了报道三七皂苷R1生物学和药理作用的原始研究出版物,而不考虑出版物的语言和研究设计。三七皂苷R1具有较强的神经保护、抗炎、抗细胞凋亡、抗缺血再灌注损伤等特性。三七皂苷R1对不同类型细胞系的细胞毒作用不同。其他药理作用包括脂溶酶积累、诱导微循环、内皮损伤、缺氧再氧化损伤作用,但结果分歧很大。强烈建议在临床试验研究中有更高质量的证据来证实三七皂苷R1的功效。
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引用次数: 18
Efficacy of montelukast sodium chewable tablets combined with inhaled budesonide in treating pediatric asthma and its effect on inflammatory factors. 孟鲁司特钠咀嚼片联合吸入布地奈德治疗小儿哮喘的疗效及对炎症因子的影响。
Pub Date : 2019-11-01 DOI: 10.1691/ph.2019.9582
Yu Zhang, Hai Wang
The aim of this study was to explore the clinical effect of montelukast sodium chewable tablets combined with inhaled budesonide in the treatment of pediatric asthma and its influence on inflammatory factors. One hundred and thirty-five asthmatic children were randomly divided into montelukast sodium group, budesonide group and combined group. Clinical symptoms, lung function, inflammatory factors and immune related indices of patients in each group were observed and recorded. After treatment, the times to disappearance of wheezes, dyspnea, asthma and hospital stay in the combined group were significantly shorter than those in the single-drug group (all p < 0.001). Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF) were significantly higher than those before treatment, and in the combined group value were significantly higher than in the single-drug group in the same period (all p < 0.001). Tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-8 and hypersensitive C-reactive protein (hs-CRP) were significantly lower than before treatment, and the combined group was significantly lower than the single-drug group in the same period (all p < 0.05). The number of CD4+ and CD3+ cells in the combined group was significantly higher than that in the single-drug group, while the number of CD8 + cells and the expression level of immune globulin E (IgE) were significantly lower (all p < 0.05). There was no difference in the incidence of adverse reactions between the groups during treatment (p > 0.05). Six months after treatment, the incidence of asthma in the combined group was significantly lower than that in the single-drug group (both p < 0.05). Montelukast sodium chewable tablets combined with inhaled budesonide can shorten the discomfort duration of asthmatic children and help them restore lung function. Moreover, it reduces the level of inflammatory factors and increases the resistance of children, which is worthy of further promotion and application.
本研究旨在探讨孟鲁司特钠咀嚼片联合吸入布地奈德治疗小儿哮喘的临床疗效及对炎症因子的影响。135例哮喘患儿随机分为孟鲁司特钠组、布地奈德组和联合组。观察并记录各组患者的临床症状、肺功能、炎症因子及免疫相关指标。治疗后,联合用药组喘息、呼吸困难、哮喘消失次数及住院时间均显著短于单药组(p < 0.001)。用力肺活量(FVC)、第一秒用力呼气量(FEV1)、呼气峰流量(PEF)均显著高于治疗前,且联合用药组同期均显著高于单药组(p < 0.001)。肿瘤坏死因子-α (TNF-α)、白细胞介素-4 (IL-4)、IL-8、超敏c反应蛋白(hs-CRP)均显著低于治疗前,且同期联合用药组显著低于单药组(均p < 0.05)。联合用药组CD4+、CD3+细胞数量显著高于单药组,CD8 +细胞数量及免疫球蛋白E (IgE)表达水平显著低于单药组(均p < 0.05)。两组患者治疗过程中不良反应发生率比较,差异无统计学意义(p > 0.05)。治疗6个月后,联合用药组哮喘发病率显著低于单药组(p < 0.05)。孟鲁司特钠咀嚼片联合吸入布地奈德可缩短哮喘患儿的不适持续时间,帮助患儿恢复肺功能。而且降低了炎症因子水平,增加了儿童的抵抗力,值得进一步推广应用。
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引用次数: 10
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