群体药物代谢动力学原理及应用进展

群体药物代谢动力学(PPK)在西方国家已有将近40年的发展和应用历史,越来越广泛地用于临床合理用药和个体化给药中。本文简要介绍了PPK基本原理,求算PPK参数的有关方法,重点阐述了目前较常应用的非线性混合效应模型法,并列举了群体药物代谢动力学在常规治疗药物监测、个体化给药以及上市前新药研究中的应用实例。     

Research Progress on Reversing Multidrug Resistance in Tumors by Using Chinese Medicine

Multidrug resistance (MDR) is a major cause of cancer chemotherapy failure, and it is important to develop suitable reversal agents to overcome MDR. A majority of chemical reversal agents have acceptable reversal effects. However, the toxicity and adverse reactions associated with these agents restricts their clinical use. Chinese medicines (CMs) have lower toxicities and adverse reactions and are associated with multiple components, multiple targets and reduced toxicity. CMs have several advantages and could reverse MDR, decrease drug dosage, enhance patient compliance and increase efficacy. This review summarizes the current progress of CM reversal agents..     

拉莫三嗪的药代动力学研究进展

拉莫三嗪是新一代抗癫痫药物,本文综述近年来其传统和群体药代动力学（药动学）的研究现状,基因多态性和联合用药对其药动学的影响,并阐明其在特殊人群的药动学特点,为临床更科学地制定给药方案,提高合理用药水平提供参考。     

Quality Assessment of Clinical Research on Liver Cancer Treated by Intra-Arterial Infusion of Chinese Medicine

Objective：To assess the methodological quality of clinical research on Chinese medicine（CM）applied by infra-arterial infusion in treating primary liver cancer（PLC）.Methods：Cochrane Central Register of Controlled Trials（CENTRAL）,PubMed,and three Chinese databases,including Chinese BioMedical Database（CBM）,China National Knowledge Infrastructure（CNKI）and China Academic Journal（VIP）were searched.Chinese articles were also searched manually in 16 journals.Two reviewers independently selected studies,the quality of literatures were assessed according to the Cochrane Collaboration method of quality assessment.Results：A total of 14 articles met the inclusion criteria for this review.Only three of these articles described the randomization method used.None of the studies was blinded.All of the articles didn＇t report the calculation of the sample size.Only six studies mentioned adverse reactions.All of the studies were of grade C according to the Cochrane Collaboration method.Six studies reported results of survival,and only two of these reported better efficacy in the treatment groups.Conclusions：The quality of studies concerned intra-arterial infusion of CM in treating with PLC was poor and the exact effect of these medicines still need evaluation.Well designed RCTs with large sample sizes,adequate follow-up data and reliable methods of assessment are needed to better appraise the real effect of CMs in the treatment of PLC patients.     

Chinese Medicine in Fighting against Covid-19: Role and Inspiration

Covid-19 pandemic has caused hundreds of thousands deaths and millions of infections and continued spreading violently.Although researchers are racing to find or develop effective drugs or vaccines,no drugs from modern medical system have been proven effective and the high mutant rates of the virus may lead it resistant to whatever drugs or vaccines developed following modern drug development procedure.Current evidence has demonstrated impressive healing effects of several Chinese medicines(CMs)for Covid-19,which urges us to reflect on the role of CM in the era of modern medicine.Undoubtedly,CM could be promising resources for developing drug candidates for the treatment of Covid-19 in a way similar to the development of artemisinin.But the theory that builds CM,like the emphasis of driving away exogenous pathogen(virus,etc.)by restoring self-healing capacity rather than killing the pathogen directly from the inside and the'black-box'mode of diagnosing and treating patients,is as important,yet often ignored,an treasure as CM herbs and should be incorporated into modern medicine for future advancement and innovation of medical science.     

沙库巴曲缬沙坦钠在基层心血管疾病临床应用的专家共识

沙库巴曲缬沙坦钠作为全球首个血管紧张素受体脑啡肽酶抑制剂类药物,在治疗心力衰竭和高血压方面疗效确切且安全性良好,同时在急性心肌梗死及心律失常等心血管疾病中表现出潜在的治疗效果。由于沙库巴曲缬沙坦钠在我国上市时间不长,目前临床医生,特别是基层全科医生对该药的临床应用经验较少,故中国医师协会全科医师分会组织14位心血管内科、全科医学领域的专家,基于循证医学证据和国内外相关指南、共识,结合基层的临床实际制定《沙库巴曲缬沙坦钠在基层心血管疾病临床应用的专家共识》,主要包括沙库巴曲缬沙坦钠的药理学特点与作用机制、循证医学证据和相关指南推荐及临床应用方法,以期指导基层全科医生合理规范化应用沙库巴曲缬沙坦钠。     

肾移植患者西罗莫司的群体药代动力学模型研究

目的：建立肾移植患者口服西罗莫司片的群体药代动力学模型,研究西罗莫司在人体内的药动学特点,为实施个体化用药提供理论支持。方法：以111例肾移植术后采用西罗莫司进行免疫抑制治疗的患者为研究对象,回顾性收集患者常规监测的西罗莫司稳态血药浓度及相应的实验室检查数据,运用Phoenix NLME药动学软件建立西罗莫司的群体药动学模型,分析影响药动学参数的因素。最终模型采用Bootstrap法和可视化预测检查进行内部验证。结果：西罗莫司符合一级消除动力学一室模型。发现红细胞比容对清除率有影响,碱性磷酸酶对分布容积有影响,获得的最终模型CL/F值为10.8 L/h,V/F为1 011 L。Bootstrap验证和可视化预测检查的评价结果表明模型预测结果可靠。结论：本研究成功建立了肾移植患者西罗莫司的群体药动学模型,考察了年龄、体重、性别、合并用药以及各生化指标对模型的影响,为实现西罗莫司的临床合理用药提供参考。     

中药内服联合维A酸类药治疗痤疮文献质量评价

目的：研究中药内服联合维A酸类药治疗痤疮的文献中科研方法学的目前状况及其存在问题。方法：按照临床流行病学/DME方法学的原则和方法,检索2000—2010年间中药内服联合维A酸类药治疗痤疮的临床研究文献,对临床研究类型及方法学,一般情况,疾病诊断及纳入、排除标准,样本含量,疗效判定标准,随访,不良反应及安全性等进行评价。结果 ：入选的52篇文献,大多数尚缺乏统一的诊断标准、纳入标准、排除标准和疗效判定标准;随机化质量、盲法的应用、失访与退出病例的记录与分析等方面描述不清楚;有接近一半的文献未能事先确定统计学方法,不良反应的数据也未能进行统计学处理。结论：目前中药内服联合维A酸类药治疗痤疮文献质量不高,制定规范化的临床研究设计方案迫在眉睫,以便为临床医生选择药物提供客观依据。     

To Be, Or Not To Be: The Calculated Politics of Acupuncture in JAMA

Ten acupuncture-related articles were published in The Journal of the American Medical Association (JAMA) between 1998 and 2017. Five studies showed positive results in terms of the effectiveness of acupuncture/Chinese medicine (CM); five studies showed negative results. This article summarizes the acupuncturerelated clinical trials published over the last 20 years in JAMA, and addresses what seems to be a fundamental ambivalence in Western medical journals regarding the scientific validity of acupuncture/CM. As yet there has been no consensus on the role of acupuncture in healthcare in Western countries. This is hardly surprising, considering the conflicting evidence found in published studies. Skepticism regarding acupuncture/CM is largely grounded in the fact that an accurate model for assessing the true clinical effects of acupuncture has yet to be created. This article discusses some of the pitfalls which result from applying Western-based scientific principles to CM, and suggests that in many cases, "negative" studies have been misinterpreted. The clinical experience of acupuncture practitioners is often in direct conflict with many of the negative conclusions published in journals. We are in need of an accurate model for sham and placebo treatments, and must analyze all published studies for design flaws and faulty conclusions.     

Therapeutic evaluation on complex interventions of integrative medicine and the potential role of data mining

It is a common view that the integration of Chinese medicine （CM） and modern Western medicine is an efficient way to facilitate the development of CM. Integrative medicine is a kind of complex interventions. Scientific therapeutic evaluation plays a crucial role in making integrative medicine universally acknowledged. However, the modern method of clinical study, which is based on the concept of evidence-based medicine, mostly focuses on the population characteristics and single interventional factor. As a result, it is difficult for this method to totally adapt to the clinical features of CM and integrative medicine as complex interventions. One possible way to solve this issue is to improve and integrate with the existing method and to utilize the evaluation model on complex interventions from abroad. As an interdisciplinary technique, data mining involves database technology, artificial intelligence, machine learning, statistics, neural network and some other latest technologies, and has been widely used in the field of CM. Therefore, the application of data mining in the therapeutic evaluation of integrative medicine has broad prospects.     

Recent Highlights of Chinese Medicine for Advanced Lung Cancer

Owing to its unique superiority in improving quality of life and prolonging survival time among advanced lung cancer patients, Chinese medicine (CM) has, in recent years, received increased attentions worldwide. We utilized a bibliometric statistical method based on MEDLINE/GoPubMed to conduct a comprehensive analysis of the current application status of CM in lung cancer, by including annual and accumulated publications, origin distribution of countries and journals, and keywords with a higher frequency score. Then the relevant clinical trials and mechanistic studies were systematically summarized within the field according to research types. We have raised potential problems and provided potentially useful reference information that could guide similar studies in the future. The basic experimental results are highly consistent with clinical trials, leading us to conclude that CM can offer better overall therapeutic benefits when used in combination with routine Western medicine for patients with advanced lung cancer.     

多西他赛在乳腺癌病人中群体药代动力学模型的验证

目的探讨已建立的不同多西他赛群体药代动力学（PPK）模型对国内乳腺癌群体的适用性,从而为建立合适的国内乳腺癌病人最终PPK模型提供依据。方法计算机检索PubMed、Embase、Web of Science、中国知网和万方等数据库中多西他赛PPK模型的文献,提取文献基本信息,收集国内乳腺癌病人应用多西他赛的血药浓度数据,利用Phoenix非线性最大混合效应模型软件进行拟合,根据模型拟合的观测浓度-预测浓度诊断图与可视化预测检验评估已有模型对乳腺癌病人血药浓度的拟合效果。结果共收集39例乳腺癌病人108个血药浓度数据作为外部验证数据集进行多西他赛PPK模型验证。最终纳入研究的文献有6篇。对建立的PPK模型进行拟合后发现LAUNAY-ILIADIS模型拟合效果最佳（-2LL=933.34,AIC=993.34）,BRUNO模型次之（-2LL=945.13,AIC=1007.13）,其余模型拟合效果较差。结论国内多西他赛治疗乳腺癌的血药浓度数据与大多数文献报道的多西他赛PPK模型拟合效果不佳,为研究国内多西他赛治疗乳腺癌病人的药动学特征,有必要建立多中心、大样本的国内乳腺癌多西他赛PPK模型。     

血管紧张素Ⅱ和血小板源生长因子对血管平滑肌和心肌细胞细胞周 …

目的 观察血管紧张素Ⅱ（ＡｎｇⅡ）和血小板源生长因子ＢＢ（ＰＤＧＦ－ＢＢ）对血管平滑肌细胞和心肌细胞中细胞周期素和Ｐ２７蛋白表达量的不同影响,方法 培养的血管平滑肌细胞或乳鼠心肌细胞,加入ＡｎｇⅡ１０＾－６ｍｏｌ／Ｌ,ＰＤＧＦ－ＢＢ２０ｎｇ／ｍｌ后２４小时收集细胞,用碘化丙啶（ＰＩ）标记细胞ＤＮＡ,以确定细胞所处的周期,用细胞周期素（ＣｙｃｌｉｎＤ,ＣｙｃｌｉｎＥ,ＣｙｃｌｉｎＡ）或Ｐ２７蛋白的单     

Q方法在专家经验分类及理解中应用的可行性分析

The Q method, combining qualitative and quantitative methods, refers to the qualitative analysis of Q-sorts based on quantitative techniques. It is used to research individual subjective experience, analyzing consensus and divergence to identify and categorize subjects＇ viewpoints. The sorting process is completely performed by the subjects, independent of study researchers. The Q method in medical research has been applied in many fields, including nursing care, clinical studies, doctor and patient＇s perceptions, health evaluation and decision making. The authors used the Q method to research Chinese medicine （CM） group decision making, exploring its practical feasibility in this important field. Four primary domains are addressed： （1） integration of expert opinion; （2） expert classification; （3） ascertaining the entire viewpoint orientation of a certain type of expert; and （4） comparison of expert opinion using an additional perspective. The essence of the Q method caters to the CM thinking model and should be introduced into CM and explored more deeply.     

复合应用型临床药学专业人才培养方案的构建与实施

为达到培养复合应用型临床药学人才的目的,通过对临床药学专业人才的需求分析,构建了复合应用型药学专业人才培养方案,提出了以培养医药兼备,能够从事临床合理用药、治疗药物检测、新药临床评价及临床药学研究等方面工作的复合应用型药学人才培养的基本建设思路,并就方案的实施,在课程体系的优化、教学内容改革、教学方法改革、实验教学的改革及临床和药学实践能力的培养五个方面进行了对策研究。     

癫癎儿童拉莫三嗪群体药代动力学模型的研究

目的采用USC＊PACK软件建立中国癫癎儿童拉莫三嗪的群体药代动力学（PPK）模型,促进个体化用药。方法回顾性收集60例癫癎患儿应用拉莫三嗪（LTG）的临床数据,并根据联合用药情况,将114个血药浓度点分成LTG＋丙戊酸（VPA）组（n=56）、LTG＋肝药酶诱导剂（EI）组（n=26）、LTG＋EI＋VPA组（n=16）及单用LTG组（n=16）。血药浓度均为临床常规监测的稳态浓度。应用USC＊PACK软件中的非参数最大期望程序（NPEM Program）,推算最优的PPK参数值,并建立模型。应用此模型和USC＊PACK软件中的贝叶斯拟合程序（Bayesian fitting program）,对患儿的血药浓度进行预测;求算平均预测误差（MPE）,预测误差均方（MSPE）判断预测的准确度和精密度,验证PPK模型。结果最大似然值为-192．87,LTG的最佳PPK参数值为：Ka=（1．97±1．66）h^-1;Vs=（1．07±0．89）L／kg;Kel=（0．05±0．05）h^-1。血药浓度拟合值与观测值的相关系数r=0．99,回归方程为YOBS=,=-0．09＋1．05×YPRED（R^2=0．98,P〈0．001）。MPE为-0．16μg／mL,MSPE为0．28（μg／mL）^2。结论在USC＊PACK软件中,应用自行建立的PPK模型和Bayes法,估算个体PK参数,再进一步算出半衰期、峰谷浓度以及调药后的峰谷浓度,甚至可以模拟出调药前后的药时曲线,满足临床上的多种需求,使得临床用药从传统的经验用药模式提高到科学的个体化用药模式。     

Progress of experimental study on treatment of psoriasis by Chinese medicinal monomer and single or compound recipe in Chinese materia medica

Psoriasis is a common,chronic,recurrent inflammatory skin disorder whose etiology is still unknown.It is believed that a multiple-gene inheritance is involved and it also involves various factors such as immunity,inflammation,cell proliferation,apoptosis,neural media,etc.Since cytokines are key mediators in inflammation,a number of Chinese medicines(CMs)have been reported to have certain antagonist effects on pro-inflammatory cytokines such as tumor necrosis factor-α(TNF-α),platelet active factor(PAF)and interleukin-8(IL-8).Some researches on CMs have made significant breakthroughs in psoriasis by intervening with cytokines.Abnormalities with keratinocyte proliferation and apoptosis are considered to be present in patients with psoriasis and a number of studies show that the mechanism of CMs on psoriasis may be through the inhibition of the keratinocyte proliferation and induction of apoptosis.Other studies also show that the inhibition of fibroblast-secreted cytokines could regulate keratinocyte proliferation and differentiation and reduce the level of Calcitonin gene-related peptide(CGRP)in plasma and in lesions so as to slow down the process of inflammation and proliferation in psoriasis.The most commonly used models for psoriasis are the scaled tails or the vaginal epithelium of mice in China.They were used to observe the histopathological changes after the model mice were treated with CMs with the inhibition on the mitosis of vaginal epithelium or promotion of granular layer in rat tail taken as the indices of clinical efficacy.A variety of signs occur in psoriasis patients with TCM blood-stasis syndrome type and the effect of CMs in activating blood circulation to remove blood stasis on psoriasis suggested that the mechanism of CMs may be partially correlated to hemorrheology and microcirculation.Along with the continuous development of the biosciences,some TCM theories for psoriasis have been confirmed by laboratory studies.However,the exploration into traditional Chinese medicines'biomechanics in psoriasis and the therapeutic mechanism of CMs by integrative medicine still requires further studies.     

Arterioles in cerebral amyloid angiopathy and vascular dementia

Background Small cerebrovascular lesions are one of the most important factors in cerebral amyloid angiopathy （CAA） and vascular dementia （VaD）. We analyzed the difference of arteriolar pathology between CAA patients （CAAs） and vascular dementia patients without CAA （VaDs）. Methods Ten deceased CAAs and twelve deceased VaDs were available for this study. Five deceased patients without known cerebrovascular diseases served as controls. These patients were all autopsy cases. All transversely cut arterioles in the gray matter and white matter with an external diameter equal to or larger than 30 um and with a maximum of 300 um were examined. The internal and external diameters of arterioles were measured. Results The external diameter of gray matter arterioles in the CAAs was significantly greater than in controls. In gray matter arterioles, the diameter of the lumen in VaDs was markedly smaller than in the CAAs, whereas there was no significant difference between CAAs and controls. CAAs and VaDs may cause remarkable thickening of the arteriolar walls in either white matter or gray matter. The sclerotic index of arterioles in VaDs was significantly greater than in CAAs and controls. Conclusions Stenosis of arterioles occurred in both CAA and VaD, but the tendency was greater in VaD. Arterioles of CAA were also expanded in gray matter, which may be related to lobar hemorrhage. The loss and/or degeneration of vascular smooth muscle cells was predominant in CAA, while the over-proliferation of vascular smooth muscle cells was areater in VaD.     

Chinese medicine pattern diagnosis could lead to innovation in medical sciences

Chinese medicine(CM) pattern diagnosis(Bianzheng or syndrome differentiation),as another patient classification approach,has been incorporated with biomedicine diagnosis in clinical practice in China,and the clinical experience has proven that the integration of biomedicine and CM is better in the treatment of many diseases.CM pattern diagnosis is completely different from the diagnosis in biomedicine,and it must take an active role in innovation for medical sciences.This paper is trying to discuss how CM pattern diagnosis lead to innovations in basic research,clinical research and new drug discovery.Scientific basis of CM pattern in innovation of basic research,clinical efficacy and safety,CM pattern based clinical trial design,CM pattern and clinical practice guideline in innovation of clinical study, CM pattern based indication finding,and CM pattern based network pharmacology in innovation of new drug discovery have been discussed.     

Insights of Chinese Medicine on Ventricular Remodeling: Multiple-Targets, Individualized-Treatment

Ventricular remodeling (VR) can be induced by myocardial injury, leading to progressive cardiac dysfunction and heart failure, and is associated with high morbidity and mortality. Despite being studied for more than 3 decades, current therapeutic strategies still remain unsatisfactory in effificacy, expensive, and with side effects and drug resistances. Chinese medicine (CM) has been used to treat heart diseases for thousands of years. This article reviews the published studies on the mechanisms and therapeutic applications of CM in VR. The major aspects include: mechanistic studies of VR, molecular biology and myocardial functional studies of CM therapies on VR, and mechanism of CM therapies on VR.