中药复方制剂临床试验申请的非临床研究关注要点

中药复方制剂新药是最能体现中医药理论特色和人用经验的中药创新药。近年来，在中药创新药临床试验（investigational new drug，IND）申请中，中药复方制剂占大部分。非临床研究对于中药创新药IND申请的获益风险评估具有重要作用，中药复方制剂IND申请之前需根据品种的特点和临床定位，完成必要的药效学研究和毒理学研究。根据非临床有效性和安全性结果，结合品种的特点和人用经验，综合评估品种初步的获益-风险和潜在的临床价值。结合案例分析，探讨中药复方制剂IND申请中的非临床研究关注点，以及通过获益-风险评估对品种能否进入临床试验进行的决策考虑，以期为中药研发和注册申报提供参考。     

Traditional Chinese medicine for prevention and treatment of hepatocellular carcinoma: A focus on epithelial-mesenchymal transition

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant cancers worldwide. Epithelial-mesenchymal transition (EMT), which endows epithelial cells with mesenchymal properties, plays an important role in the early stages of metastasis. Conventional cancer therapies have promising effects, but issues remain, such as high rates of metastasis and drug resistance. Thus, exploring and evaluating new therapies is an urgent need. Traditional Chinese medicines (TCMs) have been acknowledged for their multi-target and coordinated intervention effects against HCC. Accumulating evidence indicates that TCM can inhibit the malignancy of cells and the progression of EMT in HCC. However, studies on the effects of TCM on EMT in HCC are scarce. In this review, we summarized recent developments in anti-EMT TCMs and formulae, focusing on their underlying pharmacological mechanisms, to provide a foundation for further research on the exact mechanisms through which TCM affects EMT in HCC.     

基于配伍相互作用的中药合理用药研究进展及监管思考

安全性及有效性是合理用药的重要前提及首要目标。中药配伍及配伍禁忌研究与中药安全及有效性密切相关,是中药临床应用需关注的重点问题。近年来中药临床应用出现诸多问题,使中药监管体系面临挑战,监管科学的兴起为促进中药合理用药的发展提供了契机。聚焦中药配伍理论的传统阐释与现代机制的研究进展,围绕效应成分的相互作用,从中药体外效应成分相互作用、体内药动学相互作用和体内生物效应相互作用3个方面对中药配伍及配伍禁忌的作用机制进行综述。同时,总结中药临床应用常见问题并提出监管建议,以期为促进中药临床合理、安全用药和改善监管效果提供参考。     

Development of High Performance Liquid Chromatography and Mass Spectrometry: a Key Engine of TCM Modernization

Traditional Chinese Medicine (TCM) has been popular for thousand years in prevention and treatment of chronic diseases synergistically with Western medicine while producing mild healing effects and lower side effects. Although many TCMs have been proven effective by modern pharmacological studies and clinical trials, their bioactive constituents and the remedial mechanisms are still not well understood. Researchers have made great efforts to explore the real theory of TCM for many years with different strategies. Development of high performance liquid chromatography (HPLC) and mass spectrometry within recent decade can provide scientists with robust technologies for disclosing the mysterious mask of TCM. In this paper, important innovations of HPLC and mass spectrometry are reviewed in the application of TCM analysis from single compound identification to metabolomic strategy.     

Interactions Between Traditional Chinese Medicine and Anticancer Drugs in Chemotherapy

Herbal medicines, including traditional Chinese medicines(TCMs), have been used in Eastern countries for treating diseases such as cancer for thousands of years. With the growing knowledge of tumorigenesis and cancer therapy, some natural compounds have been developed as clinical anticancer drugs. In addition, many compounds and TCMs have been characterized as complementary and alternative treatments,with synergetic effects on enhancing the efficacy or reducing the side effects of the therapeutics. In this review, we summarized the recent studies focusing on the combination of natural compounds or TCM decoction with chemotherapeutics. The detailed mechanisms of action of the combinations and the application of analytical methods on TCM development are also discussed.     

中药新药药效学试验设计的关注要点与思考

药效学研究是中药新药研发中的重要环节,通过前期的药理毒理试验来考察成药性,为后期临床试验提供支持性数据,可减少后期研发风险。近年来中药药效学研究不断发展和进步,但是仍存在一些问题,影响了药效学研究在中药新药研发中作用的发挥。科学合理的设计是实现药效学试验价值与目标的基础。该文总结了审评工作中中药药效学试验设计方面存在的常见缺陷,包括试验项目、检测指标、给药剂量、给药时间、对照、检测时间点等方面的缺陷。在此基础上,提出了中药药效学试验设计的总体思路、关注要点以及具体要求,并提出一些思考。     

Advances in heroin addiction treatment with traditional Chinese medicine: a systematic review of recent Chinese language journals

The aim of this review is to critically examine the clinical trial research on Traditional Chinese Medicine (TCM) as an intervention in treating heroin addiction in People's Republic of China. This review examines Chinese-language-only publications for the patent medicines: Shenfu Tuodu, Fukang Pian, and Shifu Sheng. Other compound medicines will be reviewed in future publications. A systematic review of the literature was conducted in Western and Chinese databases. Most trials were excluded because they did not declare randomization and had poor methodology or reporting. The majority of clinical evidence in the random controlled trials demonstrates good evidence for TCM patent medicines in heroin addiction treatment. When compared to typical Western medications, TCMs demonstrate fewer side-effects, in addition to equal measures of treatment efficacy and safety.     

基于"三要素"的中药药性认知模式构建与实践

中药药性理论是中药基本理论研究的重点和难点,药性概念、构成及表征的复杂性长期困扰着研究人员,亟需研究视角和方法的创新。从认知科学角度看,中药药性理论的产生就是人们在与疾病斗争的医疗实践中面对中药及其作用的感官信息,在中国传统哲学思维指导下进行储存、提取、重建、总结,进而形成有关药物疗效性质概念的认知学过程;中药药性认知过程具有其特殊的认知要素和认知策略。本研究遵循中药临床应用特点,明晰其特殊认识要素,结合现代化学、生物学、数学研究手段,在本室5年前期工作基础上,构建基于"三要素"的中药药性认知模式,并以辛热药为示例进行实践,以期实现传统中药药性的现代科学解读,为阐明药性本质提供思考,为临床合理用药提供指导。     

新形势下中药创新药物的发现与研发

该文根据近年来生命科学的快速发展和我国对中药创新药物审批要求的不断提升,在分析基于中医药理论和天然产物资源的创新药物发现的优势以及当前中药新药研发存在的问题的基础上,从基于中药资源的活性化合物发现、中药有效部位及其复方制剂的发现、基于经典名方的中药创新药物的研发、基于名优中成药的创新药物研发以及临床有效方剂的新药转化等5个方面,系统介绍了新形势下中药创新药物的发现和研发思路,并就加快我国中药创新药物的发展提出五点建议,为中药创新药物的研发提供参考。     

确保盲法实施的中药安慰剂制备和评价关键问题

近年来,随着安慰剂作为优先考虑的中药临床评价的对照方式,对中药安慰剂的制作水平和评价技术要求也逐步提高。作为一种模拟制剂,中药安慰剂与受试制剂的相似性直接影响了临床盲法的实施效果,需要确保其无药效的适用性才能准确评估受试制剂的真实药效;作为一种临床应用的制剂,对中药安慰剂的安全性、可控性也有要求。目前很多临床试验中安慰剂的应用已经无法保证临床试验的盲法实施,因此对中药安慰剂的质量控制水平尚待进一步提升。通过分析近10年来相关临床研究中安慰剂的研究状况,结合研究实践,对中药安慰剂制备和评价的一系列关键问题进行探讨,为中药安慰剂的研究水平提升和法规制定提供参考。     

中药性味理论的现代研究进展

中药药性理论是中医药理论体系的重要组成部分和中药理论中的核心内容。其中,中药的四性五味作为中药的核心药性在中医临床诊治过程中起着关键性的指导作用。近年,国家科技部、国家中医药管理局、国家自然科学基金委等先后立项支持性味理论相关项目的深化研究,旨在进一步从分子水平解析中药四性五味理论的现代科学内涵,使其更好地服务于中医临床和药学体系。本文对近20年来有关中药四气五味相关文献的整理分析,从生物效应、物质基础等方面对中药四气五味的研究状况进行了系统回顾和概述,结合课题组中药药性研究中的发现和体会,剖析了目前中药药性研究中存在的问题和不足,为深入开展中药性味理论的科学实质研究提供借鉴和参考。     

艾滋病中药治疗现状分析

人类免疫缺陷病毒感染与获得性免疫缺陷综合征(艾滋病)作为一种新发的传染病,中医学没有明确的记载,经过近30年医家们运用中医药的临床实践,取得了显著的临床疗效,研发出了大量的有效方药,但在中药新药研发方面进展缓慢,目前治疗艾滋病的中药新药仅唐草片一个品种,在一定程度上限制了中医药防治艾滋病作用的发挥。笔者通过对治疗艾滋病中药研究现状的分析,探讨限制治疗艾滋病中药新药研发的瓶颈,如缺少理想的动物模型,艾滋病的中医临床研究混杂因素过多,提出在深入开展动物模型研究的基础上,注重中医复方作用机制研究,尤其体外抗病毒、免疫调节活性成分筛选,为更好的研发治疗艾滋病中药新药提供证据。     

Prediction of quality markers of traditional Chinese medicines based on network pharmacology

Network pharmacology is a powerful tool to reflect the pharmacologically active effects, mechanism of action and toxic activity of traditional Chinese medicines (TCMs). The ingredients of TCMs, associated with quality control of TCM products, are those fundamental chemicals that exhibit biological activities. A great amount of effort has been made by scientists in that field in order to improve the quality of TCMs, though the approaches to determine their quality and the TCM theory and compatibility rules remain ambiguous. Now some methods and technologies must be applied to predict and explore the quality marker (Q-marker) for quality control, as well as to clarify the factors affecting the quality of TCM, which may give new insight into rational ground of establishment of appropriate quality control and assessment system. In this review paper, authors focus on the prediction of quality markers of TCMs by network pharmacology based on three aspects: (1) from network medicine to network pharmacology, (2) complex network system of traditional Chinese medicine, and (3) predicting TCM quality markers based on network pharmacology. Authors proposed the research pattern on network pharmacology based on biological and medical networks, and further TCM network pharmacology based on substantial basis of TCM formulae, and the idea of “effect-ingredient-target-fingerprint” to predict and recognize the TCM Q-marker was the ultimate goal. In addition, authors yet noted how to make full use of the advantages of network toxicology to provide new ideas for the toxicity study of complex TCM systems and the prediction of TCM toxicity markers.     

斑马鱼在中药研究中的应用

斑马鱼模型作为一个整体的动物模型,其体积小、高通量、费用低、周期短,且实验结果可靠,在药物研究领域广泛应用。中药是一个复杂的系统,其有效成分及作用机制是中药现代化发展的研究热点之一,随着先进技术和方法的不断改进,斑马鱼在中药研究中的应用逐渐深入,并且已经在活性筛选、毒理、代谢研究等方面表现出优越性。该文主要介绍了近年来斑马鱼在中药研究中应用的概况,以期能为中药基础研究提供新的思路和方法。     

中药肾毒性成分及其毒性机制研究进展

近年来,随着我国医药产业的稳步发展,中药作为补充和替代医学制剂在世界各地赢得了认可和信赖。然而,随着对中药的广泛应用和深入研究,中药的肾脏毒性引发了国内外学者的广泛关注。为保障中药临床应用的安全性,有必要深入研究并整理中药肾毒性成分及其毒性机制。在查阅近30年国内外常见中药肾毒性相关文献的基础上,对中药肾毒性成分及其毒性机制进行了总结与分析,以期为中药肾毒性深入研究提供思路,为中药安全合理应用提供参考。     

基于多学科交叉的中药药效物质基础研究方法和思路概述

中药药效物质是揭示中药作用本质奥秘的关键,是中药安全性和质量控制的基础和核心,而中药及其复方多组分、多靶点、整体调节的作用特点,使其药效物质基础不明成为中医药现代化和国际化发展进程中的瓶颈之一.近年来,随着各学科研究方法和技术手段的不断发展和成熟,众多学科包括分析化学、中药药物化学、药理学、细胞生物学、系统生物学、生物信息学等不断引入中药研究.多学科的交叉整合实现了各学科之间的交流和良性互动,加速了中药研究和中药现代化的进程.该文通过对中药复方药效物质基础研究方法的探讨和总结,对多学科交叉整合的研究模式在中药药效物质基础研究中的应用进行综述,为中药及其复方药效物质基础的辨识提供参考.     

中药血清药物化学研究概况及其理论和方法拓展

中药血清药物化学是从中药/方剂口服给药后的血中移行成分中筛选药效物质基础的研究设计,其理念及方法符合中药整体作用模式,并体现了人体对药物的代谢、转化作用和药物在体内的相互作用,现已成为公认并被普遍应用的研究中药药效物质基础的有效方式。该文对以往中药血清药物化学的研究内容和研究方法进行梳理,在进一步认识中药复方给药形式的特殊性及方证对应疗效的专属性基础上,提出整合系统生物学的中药血清药物化学新研究策略:以证候为切入点,以方剂为研究对象,在利用系统生物学方法阐明证候生物标记物的前提下,评价方剂整体效应,在有效的状态下,筛选与效应生物标记物高度关联的中药血清移行成分,发现并确定中药的药效物质基础。通过整合系统生物学方法,中药血清药物化学的理论与方法进一步扩展,将开启诠释中医药理论的新篇章。     

中药注册申报中非临床研究资料常见问题探讨

近年来,我国陆续出台中药产业支持政策,对中药新药研发带来了新的发展机遇,2020年9月国家药品监督管理局发布了《中药注册分类和申报资料要求》,对中药注册申报提出了新的要求。非临床研究资料作为在中药注册申报资料重要的组成部分,是中药开展临床试验或上市重要的有效性和安全性的依据。本文结合《中药注册分类和申报资料要求》,对中药注册申报资料中发现的常见问题进行分析和探讨,以期为中药研发和注册申报提供参考。     

中药质量控制和新药研发的思路和方法

中药现代化的主要目标是中药的安全、有效和质量稳定、可控。作者在近年来的部分研究工作的基础上,本文对中药质量控制和以科学实证为基础的创新中药研究进行了探讨。中药质量控制的两个关键点就是分析技术的建立和化学对照品的运用。分析技术方面在继承形态组织学方法的基础上,发展DNA分子技术和色谱技术鉴别药材,建立各种现代色谱联用技术定量评价药材及其制剂的内在质量。加强高质量中药化学对照品的研制,提高质量控制水平：新药研究首先应针对传统中医药有治疗特色的疾病开展研究。可以在中医理论指导下对古方或验方进行二次开发,强调复方配伍,也可利用高通量筛选先导化合物。实证研究既注重分子、细胞、器官和整体动物药效学机理研究以及新制剂工艺的研究,还要强调随机、双盲和安慰剂对照的临床验证。本文还对当前中药质量控制和创新药物研发中存在的问题进行了讨论。     

Randomized Clinical Trials of Traditional Chinese Medicines for Treating Ulcerative Colitis: A Scoping Review

Objective: Traditional Chinese medicines (TCMs) are efficacious against ulcerative colitis (UC). In recent years, the number of randomized clinical trials (RCTs) of TCM has increased. Thus, it is very important to summarize the basic characteristics, quality, and types of TCM interventions in published RCTs. This scoping review was performed to systematically identify and describe the current situations about RCTs of TCMs for treating UC. Hope to express the focus and specifics of nowadays research in TCM interventions in RCTs and evaluate their common disadvantages exposed to help advance in TCM researching. Materials and Methods: Ascoping review was conducted according to the PRISMA extension for scoping reviews. We searched two English databases and four Chinese databases from the date of establishment of each database to January 2020. Data from RCTs focusing on any TCM treatment for patients with UC were extracted and evaluated. Selection and characterization were performed by two independent reviewers using predefined forms. All discrepancies were resolved by consensus discussion with a third reviewer. Microsoft Excel 2010 was used to extract the following data from the included studies: (1) basic information of the included studies including research ID, article title, publication language, journal, year of publication, and funding information; (2) patient information including gender, age, disease course, disease stage, severity, sample size; and (3) information on intervention measures, types of intervention measures, drug dosage forms, and treatment courses. Results: The search identified 2225 RCTs published between 1987 and 2020. These studies covered 36 provinces in China. The time frame of the RCTs was <28 days in approximately one-third of the RCTs (647, 29.08%). Only one RCT was published in English. Nearly three-quarters of RCTs (1665, 74.83%) did not report the severity of the disease. Three types of interventions were included in the RCTs: pharmacotherapy (2028, 91.15%), nonpharmacotherapy (57, 2.56%), and a combination of the two (140, 6.29%). The administration modes of the intervention groups were evaluated. Drug therapy involved 12 types of TCM dosage forms, which were decoctions, troches, powders, capsules, granules, pills, suppositories, ointments, injections, gels, oral liquids, and substitute tea according to the frequency of use. Nondrug intervention measures involved 10 treatment options, namely, acupuncture, moxibustion, hemospasia, auricular point, acupoint catgut embedding, acupoint injection, scrapping, tuina, acupoint application, and five?tone therapy according to the frequency of use. Most studies included in this review were low in quality. This underscores the need for improvement in the quality of trial methodology in TCM RCTs.