[Guidelines for post-marketing research on clinical effectiveness of Chinese patent medicines].

Due to the lack of specialized guidance, the post-marketing research on clinical effectiveness of Chinese patent medicines demonstrates varied quality and lacks high-quality evidence, failing to meet the demands of policy-making, clinical decision-making, and industrial decision-making. To address this issue, this project gathered experts in clinical medicine, clinical pharmacy, evidence-based medicine, drug epidemiology, medical ethics, and policy and regulation in China. They referred to the model of international post-marketing research on medicines and developed Guidelines for post-marketing research on clinical effectiveness of Chinese patent medicines under the framework of relevant laws and regulations and technical guidance documents in China. The guidelines were developed with consideration to the characteristics of Chinese patent medicines, China's national conditions, and all the stakeholders including marketing authorization holders, clinical researchers, drug administration, and users. The development of the guidelines followed the requirements for developing group standards set by the China Association of Chinese Medicine. The guidelines fully implement the concept of full life-cycle research, emphasizing the combination of traditional Chinese medicine(TCM) theory, human use experience, and clinical trials and pay attention to the compliance, scientificity, and ethics of research. The guidelines clarify the topic selection and decision-making path of the post-marketing research on effectiveness of Chinese patent medicines through six steps: determining research purpose, analyzing drug characteristics, evaluating research basis, proposing clinical orientation, clarifying research purpose, and implementing classified research. The general principles of research design and implementation were clarified from eight aspects: research type, research objects, sample size, efficacy indicators, bias, missing data, evidence level, and practicality. It focuses on the research on the TCM syndrome-based efficacy evaluation, clinical value-oriented mechanism of action, and the effectiveness of Chinese patent medicines with different routes of administration. The guidelines provide a universal methodological basis for the post-marketing research on clinical effectiveness of Chinese patent medicines.

[Research and development strategy of new traditional Chinese medicine drugs for syndromes based on human use experience].

Chinese drug registration laws and regulations have always reserved a place for the new traditional Chinese medicine(TCM) drugs for syndromes, but so far no such new drugs have been approved for registration. This paper expounded on the relevant policies, regulations, and technologies of new TCM drugs for syndromes in China and pointed out that the application of the animal model of TCM syndromes to carry out pharmacodynamics research and clinical efficacy evaluation criteria of TCM syndromes were the main technical difficulties in the research and development of new TCM drugs for syndromes. Not all syndromes are suitable for developing new drugs, and the indications for new TCM drugs should be constant syndromes. Among the three research and development models of simple syndrome, syndrome-unified disease, and combined disease and syndrome, the research and development model of combined disease and syndrome is recommended. Clinical positioning is the key to new TCM drugs for syndromes. It is encouraged to conduct high-quality human use experience studies to determine the clinical positioning of new TCM drugs for syndromes, as well as the target population, dose, course of treatment, and initial therapeutic and safety, and apply for exemption from non-clinical effectiveness studies. Clinical trials of new TCM drugs for syndromes should take the target symptoms or signs as the main efficacy index and the efficacy of TCM syndromes as the secondary efficacy index. Clinical research program design should implement the "patient-centered" concept and introduce clinical outcome evaluation indicators. In the clinical safety evaluation, special conditions such as characteristic syndromes and changes should be considered. With the construction of the human use experience technology system and the promotion of the TCM registration and evaluation evidence system featuring the "combination of TCM theory, human use experience, and clinical trials", it is believed that many high-quality new TCM drugs for syndromes will be developed in the future.

[Meta-analysis and trial sequential analysis of Tanreqing Injection in treatment of severe pneumonia in elderly].

This study aimed to systematically evaluate the effectiveness and safety of Tanreqing Injection in the treatment of severe pneumonia in the elderly. Eighteen randomized controlled trials(RCTs) involving 1 457 elderly patients with severe pneumonia were included in the study after conducting searches in both Chinese and English databases as well as clinical trial registration platforms. The quality of the included studies was assessed using the Cochrane risk of bias assessment tool. Meta-analysis were conducted using RevMan 5.4 and Stata 17 software, and trial sequential analysis(TSA) was performed using TSA 0.9.5.10 beta software. Meta-analysis results showed that compared with conventional western medicine treatment, Tanreqing Injection + conventional western medical significantly improved the clinical effectiveness in elderly patients with severe pneumonia(RR=1.26, 95%CI[1.20, 1.32], P<0.000 01), arterial oxygen partial pressure(SMD=6.23, 95%CI[3.29, 9.18], P<0.000 1), oxygenation index(SMD=11.72, 95%CI[4.41, 19.04], P=0.002), reduce procalcitonin(SMD=-6.16, 95%CI[-8.10,-4.21], P<0.000 01), C-reactive protein(SMD=-8.50, 95%CI[-11.05,-5.96], P<0.000 01), white blood cell count(SMD=-4.56, 95%CI[-5.73,-3.39], P<0.000 01), and shortened the duration of fever(SMD=-3.12, 95%CI[-4.61,-1.63], P<0.000 1), cough(SMD=-4.84, 95%CI[-6.90,-2.79], P<0.000 01), lung rales(SMD=-0.99, 95%CI[-1.54,-0.44], P=0.000 4), and mechanical ventilation time(SMD=-3.26, 95%CI[-5.03,-1.50], P=0.000 3), increase CD4~+ T-cell levels(SMD=6.73, 95%CI[5.23, 8.23], P<0.000 01) and CD8~+ T-cell levels(SMD=7.47, 95% CI[5.32, 9.61], P<0.000 01) with no significant adverse reactions. TSA confirmed the stability and reliability of the results related to clinical effectiveness. This study suggests that Tanreqing Injection, as a Chinese medicinal preparation, has a significant therapeutic effect and good safety profile in the treatment of severe pneumonia in elderly patients. Due to the limited quality of the included studies, high-quality RCT is still needed to provide evidence support for the above conclusions.

[Pharmaceutical changes and countermeasures for transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on human use experience].

Traditional Chinese medicine(TCM) preparations in medical institutions, as a unique and important form of preparations in China, have a long history of human use and serve as a bridge between clinical experience prescriptions and new Chinese medicine preparations. The state encourages medical institutions to transform their preparations into new traditional Chinese medicines, emphasizing their role as "incubators". Since the proposal of the traditional Chinese medicine registration and evaluation evidence system with the integration of TCM theory, human use experience(HUE), and clinical experience, the idea of transforming preparations used in medical institutions into new drugs based on HUE has been increasingly valued by drug research and development organizations. In the transformation process, pharmaceutical changes should be concerned from multiple aspects. This paper discusses the pharmaceutical changes and countermeasures based on the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE from the aspects of excipients, dosage forms, production technology, production scale, packaging materials and containers, production sites, and registration standards. It is emphasized that scientific decisions should be made according to the characteristics and clinical needs of drugs to ensure the stability of drug quality. The impacts of pharmaceutical changes on drug quality should be objectively assessed based on appropriate evaluation indexes and detection methods. The layout should be carried out in advance, and the key pharmaceutical information of the preparations should be kept stable, so as to underpin the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE.

The Fracture Incidence and Safety of Teriparatide and Bisphosphonate in Postmenopausal Women With Osteoporosis: A Meta-Analysis.

Objective: To evaluate the anti-fracture effect and adverse effects of teriparatide versus bisphosphonate on postmenopausal osteoporosis. This study will provide evidence-based practice for the clinical selection of more effective and safer drugs for these patients. Methods: We searched PubMed, Embase, and the Cochrane Library from database inception to July 2022. The keywords included "fracture"; "teriparatide", "bisphosphonate", "postmenopausal women", and "osteoporosis". Randomized controlled trials (RCTs) comparing teriparatide versus bisphosphonates on the risk of fracture and adverse effects in postmenopausal osteoporosis were included in the analysis. Results: Finally, 3376 participants were recruited in all 5 RCTs. The results revealed that teriparatide could decrease the rate of clinical vertebral fracture (OR=1.97, 95% CI=1.43-2.73, I2 = 0%, P < .0001) and new vertebral fractures (OR=2.44, 95% CI=1.70-3.50, I2 = 0%, P < .00001) compared with bisphosphonate. AE results refer to the type and frequency of adverse effects related to drug treatment. The rate of treatment discontinuous due to AEs (OR=0.63, 95% CI=0.48-0.83, I2 = 44%, P = .0009) with teriparatide was significantly greater than that with bisphosphonate. However, there was no significant difference in the incidence of adverse events to death (OR=0.59, 95% CI=0.30-1.18, I2 = 0%, P = .13). The proportion of patients reporting adverse events in the teriparatide versus bisphosphonate groups was consistent across subgroups, except for the rate of dizziness (OR=0.53, 95% CI=0.31-0.90, I2 = 49%, P = .02). Conclusions: Among postmenopausal women with osteoporosis, clinical vertebral fractures and new vertebral fractures decreased more in patients receiving teriparatide than in those receiving bisphosphonate. Although there were no differences in adverse events across subgroups, patients receiving teriparatide had a higher rate of dizziness than those receiving bisphosphonate.The results of this work will provide a reference for clinicians to select appropriate anti-osteoporosis drugs by comprehensively considering individual differences such as fracture risk and dizziness tolerance.

[Clinical centralized safety monitoring and evaluation of traditional Chinese medicine formula granules].

Traditional Chinese medicine(TCM) formula granules are highly praised for the advanced, convenient, and modern use of Chinese medicinal materials. The safety of TCM formula granules has long been a concern of regulatory authorities and the medical industry. A multi-center, prospective, open, non-interventional, and centralized monitoring was carried out for the patients treated with TCM formula granules in 252 medical institutions from February 5, 2020 to April 19, 2022. All the case data and the incidence of adverse drug reactions/events were recorded. This study evaluated the safety of TCM formula granules, aiming to provide a reference for the clinically use. A total of 20 547 patients were included in this study. Four adverse events were recorded, including 3 adverse drug reactions with an adverse drug reaction rate of 0.015%, all of which occurred in the digestive system. There was no serious adverse event, and no factors related to adverse drug reactions/events were identified. The incidence of adverse drug reactions/events associated with China Resources Sanjiu Medical & Pharmaceutical Co., Ltd. TCM formula granules was rare, which proved their safety in clinical use. A comprehensive data mining and objective analysis was carried out for the medicines with high frequency in TCM formula granules, the commonly used medicine pairs and combinations, and departmental medication. The drug use characteristics, prescription rules, and departmental use of TCM formula granules were summarized, which can shed light on the prescription compatibility and clinical application.

[Quality requirements of human use experience research on traditional Chinese medicine].

The human use experience of traditional Chinese medicine(TCM) is of great significance for the development of new traditional Chinese medicine. In 2023, the National Medical Products Administration(NMPA) issued the Special Regulations on Registration Management of Traditional Chinese Medicine, which explicitly encouraged the conduct of high-quality human use experience research on TCM clinical practice to obtain sufficient evidence for registration support. It also required that human use experience research should comply with relevant requirements and undergo registration verification. The quality of human use experience research on TCM directly determines the reliability of the evidence. This article discussed the quality requirements for human use experience research on TCM from the perspectives of basic requirements, organizational management, key pharmaceutical information, scientific research, risk management, ethical compliance, and study implementation and proposed differential treatment in quality requirements and registration verification focus based on different research purposes, stages, and types of studies. While ensuring the authenticity of data, retrospective studies should pay particular attention to the integrity of the data, and prospective studies should focus on the normativity of the data, which may affect the research conclusions. Human use experience research, as part of drug registration materials, falls within the scope of relevant regulatory oversight. Researchers should have a strong awareness of regulations to avoid serious quality issues. The standardized conduct of human use experience research on TCM requires joint efforts from regulatory authorities, applicants, research institutions, and researchers to establish a research quality management system based on the clinical characteristics of TCM.

[Construction of clinical efficacy evaluation system based on optimal clinical experience].

Evidence-based medicine plays an important role in promoting the scientific nature of clinical decision-making. Howe-ver, there is a problem where evidence derived from clinical research may not necessarily be applicable to individual patients. Evidence-based medicine has been introduced into the field of traditional Chinese medicine(TCM) for over 20 years, and although certain achievements have been made, the overall level of clinical research evidence based on the principles of evidence-based medicine in TCM is not high. The acceptance of TCM diagnosis and treatment guidelines developed based on evidence-based medicine methods is generally low. As revealed by the analysis of the problems in the application of evidence-based medicine in the field of TCM, it is found that there is a structural contradiction between clinical randomized controlled trial(RCT) of TCM and the characteristics of TCM clinical practice. They cannot comprehensively, objectively, and truthfully reflect the clinical efficacy and safety of TCM. Conducting clinical RCTs of TCM in pursuit of "evidence" actually means giving up the advantages of TCM in clinical treatment based on syndrome differentiation, prescription changes along with syndromes, and treatment in accordance with three categories of disease cause, which leads to sacrificing some clinical effectiveness of TCM. Based on the concept of evidence-based medicine, this article proposed the construction of "clinical syndrome-based medicine" based on the optimal clinical experience, which was suitable for the characteristics of TCM clinical practice. The key to clinical syndrome-based medicine is the optimal clinical experience, and the core elements of the optimal clinical experience are regularity and reproducibility. Real-world research methods are recommended as a reference for obtaining the optimal clinical experience. Clinical syndrome-based medicine, combining the characteristics of TCM clinical practice and incorporating the concept of evidence-based medicine, is the product of integrating TCM into evidence-based medicine. It is dedicated to improving the clinical efficacy of TCM along with evidence-based medicine.

[Hydnocarpin inhibits malignant progression of triple negative breast cancer via CNOT4-mediated ubiquitination and degradation of YAP].

This study aims to investigate the effect and mechanism of hydnocarpin(HC) in treating triple negative breast cancer(TNBC). Cell counting kit-8(CCK-8), xCELLigence real-time cellular analysis(RTCA), and colony formation assay were employed to determine the effects of HC on the proliferation of two TNBC cell lines: MDA-MB-231 and MDA-MB-436. The effects of HC on the migration and invasion of TNBC cells were detected by high-content analysis, wound-healing assay, and Transwell assay. The changes in the epithelial-mesenchymal transition(EMT) and the expression of invasion-and migration-associated proteins [E-cadherin, vimentin, Snail, matrix metalloproteinase-2(MMP-2), and MMP-9] were detected by Western blot. Western blot and RT-qPCR were employed to determine the protein and mRNA levels of Yes-associated protein(YAP) and downstream targets(CTGF and Cyr61). TNBC cells were transfected with Flag-YAP for the overexpression of YAP, and the role of YAP as a key target for HC to inhibit TNBC malignant progression was examined by CCK-8 assay, Transwell assay, and wound-healing assay. The pathway of HC-induced YAP degradation was detected by the co-treatment of proteasome inhibitor with HC and ubiquitination assay. The binding of HC to YAP and the E3 ubiquitin ligase Ccr4-not transcription complex subunit 4(CNOT4) was detected by microscale thermophoresis(MST) assay and drug affinity responsive target stability(DARTS) assay. The results showed that HC significantly inhibited the proliferation, colony formation, invasion, and EMT of TNBC cells. HC down-regulated the protein and mRNA levels of CTGF and Cyr61. HC down-regulated the total protein level of YAP, while it had no effect on the mRNA level of YAP. The overexpression of YAP antagonized the inhibitory effects of HC on the proliferation, migration, and invasion of TNBC cells. HC promoted the degradation of YAP through the proteasome pathway and up-regulated the ubiquitination level of YAP. The results of MST and DARTS demonstrated direct binding between HC, YAP, and CNOT4. The above results indicated that HC inhibited the malignant progression of TNBC via CNOT4-mediated degradation and ubiquitination of YAP.

Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

[Technical points of human use experience of ethnic medicine].

Ethnic medicine has a rich history of application. Because of the large number of ethnic groups, wide geographical distribution, and unique medical systems in China, the research on the human use experience(HUE) of ethnic medicine should combine the characteristics of ethnic medicine, be based on practical experience, and respect folk practice and tradition. The clinical positioning of ethnic medicine should consider three factors, i.e., population region, dominant diseases, and clinical demand. We should consider the development of traditional preparations that meet the needs of ethnic regions and encourage the development of new drugs that can be popularized and used nationwide for the dominant diseases of ethnic medicines. Attention should be paid to the problems such as a large number of customary articles or substitutes of ethnic medicinal materials, the phenomena of foreign bodies with the same name and different names for the same substance, the different standards of medicinal materials, and the poor processing standards. The name, processing method, source, medicinal parts, and dosage of ethnic medicinal materials or decoction pieces should be determined, and resources should be carefully evaluated to ensure the safety of medicinal resources and ecology. The preparation of ethnic medicine is mostly in the form of pills, powder, ointment, etc., with simple processing technology. The problems of low-quality stan-dards of some preparations, different prescriptions with the same name, and inconsistent processing technology should be overcome, and the process route and main process parameters should be clarified to lay the foundation for the subsequent empirical research on HUE. In the collection and analysis of the HUE data of ethnic medicine, the core guiding ideology of "patient-centered" should be established, and the experience data of patients should be collected. The problems of weak links existing in the inheritance of ethnic medicine should be solved, and flexible and diverse methods should be adopted. Meanwhile, on the premise of complying with the requirements of the principles of medical ethics, we should respect the religion, culture, and customs of ethnic areas to obtain the key HUE information of ethnic medicine. On the basis of the patient preference information and differences in regional disease epidemiology, population characteristics, and medical practice, whether the HUE conclusions of ethnic medicine can be extrapolated to patients outside the region is evaluated from the aspects of clinical benefits, risk tolerance, risk acceptance, etc. The HUE research on ethnic medicine is carried out in a clear way to guide the research and development of new ethnic medicines.

Lobetyolin Alleviates Ferroptosis of Skeletal Muscle in 5/6 Nephrectomized Mice via Activation of Hedgehog-GLI1 Signaling.

BACKGROUND: Muscle wasting increases morbidity and mortality and is related to chronic kidney disease (CKD) and dialysis. It is still unclear whether ferroptosis occurs during this progression and whether it is a potential intervention target for the treatment of CKD-related muscle injury. PURPOSE: The objective is to identify potential compounds for treating ferroptosis and muscle wasting and explore the potential mechanisms in vivo/in vitro. METHODS: Initially, we explored whether ferroptosis is present in the skeletal muscle of 5/6 nephrectomized (NPM) mice via RNA-Seq analysis, TUNEL staining, Oil red O staining, MDA/GSH/GSSG level detection and real-time quantitative PCR (qPCR). Subsequently, utilizing our established molecular phenotyping strategy, we screened potential traditional Chinese herb-derived compounds for alleviation of muscle wasting and ferroptosis. HE staining, Oil red O staining, TUNEL staining, immunofluorescence staining, MDA/GSH/GSSG level detection, Fe level detection, western blotting and qPCR were applied to assess the effects of the identified compound on muscle wasting and ferroptosis and explore the potential mechanism. Furthermore, RNA-Seq analysis, ChIP-Seq analysis and further experiments in vitro were performed to determine the role of Hedgehog signaling in the effect of Lobetyolin (LBT) on ferroptosis. RESULTS: In NPM mice, skeletal muscle dysfunction, lipogenesis, reduced GSH/GSSG ratio, decreased GSH content, increased MDA production and and higher levels of ferroptosis markers were observed. LBT treatment (30 mg/kg or 50 mg/kg) significantly alleviates skeletal muscle injury by inhibiting ferroptosis. Additionally, in an in vitro investigation, C2C12 cells exposed to Indolyl sulfate (IS) induced ferroptosis and LBT treatment (20 µM and 50 µM) protected C2C12 from such injury, consistent with the results from the in vivo analysis. Furthermore, it was found LBT increased the levels of protein involving Hedgehog signaling pathway (SMO and GLI1), and rescue analysis revealed that this pathway played a crucial role in the regulation of ferroptosis. Further experiments demonstrated that LBT upregulated a series of suppressors of ferroptosis by activating Gli1 transcription. CONCLUSION: LBT alleviates CKD-induced muscle injury by inhibiting ferroptosis through activation of the Hedgehog signaling pathway.

[Guideline for clinical comprehensive evaluation of Chinese patent medicine (2022 version)].

Currently,the research or publications related to the clinical comprehensive evaluation of Chinese patent medicine are increasing,which attracts the broad attention of all circles. According to the completed clinical evaluation report on Chinese patent medicine,there are still practical problems and technical difficulties such as unclear responsibility of the evaluation organization,unclear evaluation subject,miscellaneous evaluation objects,and incomplete and nonstandard evaluation process. In terms of evaluation standards and specifications,there are different types of specifications or guidelines with different emphases issued by different academic groups or relevant institutions. The professional guideline is required to guide the standardized and efficient clinical comprehensive evaluation of Chinese patent medicine and further improve the authority and quality of evaluation. In combination with the characteristics of Chinese patent medicine and the latest research achievement at home and abroad,the detailed specifications were formulated from six aspects including design,theme selection,content and index,outcome,application and appraisal,and quality control. The guideline was developed based on the guideline development requirements of China Assoication of Chinese medicine. After several rounds of expert consensus and public consultation,the current version of the guideline has been developed.

Plantamajoside attenuates cardiac fibrosis via inhibiting AGEs activated-RAGE/autophagy/EndMT pathway.

Advanced glycation end products (AGEs) have been identified to transduce fibrogenic signals via inducing the activation of their receptor (RAGE)-mediated pathway. Recently, disrupting AGE-RAGE interaction has become a promising therapeutic strategy for chronic heart failure (CHF). Endothelial-to-mesenchymal transition (EndMT) is close to the cardiac fibrosis pathological process. Our previous studies have demonstrated that knockout RAGE suppressed the autophagy-mediated EndMT, and thus alleviated cardiac fibrosis. Plantamajoside (PMS) is the major bioactive compound of Plantago Asiatica, and its activity of anti-fibrosis has been documented in many reports. However, its effect on CHF and the underlying mechanism remains elusive. Thus, we tried to elucidate the protective role of PMS in CHF from the viewpoint of the AGEs/RAGE/autophagy/EndMT axis. Herein, PMS was found to attenuate cardiac fibrosis and dysfunction, suppress EndMT, reduce autophagy levels and serum levels of AGEs, yet did not affect the expression of RAGE in CHF mice. Mechanically, PMS possibly binds to the V-domain of RAGE, which is similar to the interaction between AGEs and RAGE. Importantly, this competitive binding disturbed AGEs-induced the RAGE-autophagy-EndMT pathway in vitro. Collectively, our results indicated that PMS might exert an anti-cardiac fibrosis effect by specifically binding RAGE to suppress the AGEs-activated RAGE/autophagy/EndMT pathway.

Technical points of human use experience of ethnic medicine / 中国中药杂志

Ethnic medicine has a rich history of application. Because of the large number of ethnic groups, wide geographical distribution, and unique medical systems in China, the research on the human use experience(HUE) of ethnic medicine should combine the characteristics of ethnic medicine, be based on practical experience, and respect folk practice and tradition. The clinical positioning of ethnic medicine should consider three factors, i.e., population region, dominant diseases, and clinical demand. We should consider the development of traditional preparations that meet the needs of ethnic regions and encourage the development of new drugs that can be popularized and used nationwide for the dominant diseases of ethnic medicines. Attention should be paid to the problems such as a large number of customary articles or substitutes of ethnic medicinal materials, the phenomena of foreign bodies with the same name and different names for the same substance, the different standards of medicinal materials, and the poor processing standards. The name, processing method, source, medicinal parts, and dosage of ethnic medicinal materials or decoction pieces should be determined, and resources should be carefully evaluated to ensure the safety of medicinal resources and ecology. The preparation of ethnic medicine is mostly in the form of pills, powder, ointment, etc., with simple processing technology. The problems of low-quality stan-dards of some preparations, different prescriptions with the same name, and inconsistent processing technology should be overcome, and the process route and main process parameters should be clarified to lay the foundation for the subsequent empirical research on HUE. In the collection and analysis of the HUE data of ethnic medicine, the core guiding ideology of "patient-centered" should be established, and the experience data of patients should be collected. The problems of weak links existing in the inheritance of ethnic medicine should be solved, and flexible and diverse methods should be adopted. Meanwhile, on the premise of complying with the requirements of the principles of medical ethics, we should respect the religion, culture, and customs of ethnic areas to obtain the key HUE information of ethnic medicine. On the basis of the patient preference information and differences in regional disease epidemiology, population characteristics, and medical practice, whether the HUE conclusions of ethnic medicine can be extrapolated to patients outside the region is evaluated from the aspects of clinical benefits, risk tolerance, risk acceptance, etc. The HUE research on ethnic medicine is carried out in a clear way to guide the research and development of new ethnic medicines.

Guideline for clinical comprehensive evaluation of Chinese patent medicine (2022 version) / 中国中药杂志

Currently,the research or publications related to the clinical comprehensive evaluation of Chinese patent medicine are increasing,which attracts the broad attention of all circles. According to the completed clinical evaluation report on Chinese patent medicine,there are still practical problems and technical difficulties such as unclear responsibility of the evaluation organization,unclear evaluation subject,miscellaneous evaluation objects,and incomplete and nonstandard evaluation process. In terms of evaluation standards and specifications,there are different types of specifications or guidelines with different emphases issued by different academic groups or relevant institutions. The professional guideline is required to guide the standardized and efficient clinical comprehensive evaluation of Chinese patent medicine and further improve the authority and quality of evaluation. In combination with the characteristics of Chinese patent medicine and the latest research achievement at home and abroad,the detailed specifications were formulated from six aspects including design,theme selection,content and index,outcome,application and appraisal,and quality control. The guideline was developed based on the guideline development requirements of China Assoication of Chinese medicine. After several rounds of expert consensus and public consultation,the current version of the guideline has been developed.

A molecular phenotypic screen reveals that lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting osteopontin.

BACKGROUND: Cardiovascular diseases are the major cause of mortality in patients with advanced chronic kidney diseases. The predominant abnormality observed among this population is cardiac dysfunction secondary to myocardial remodelings, such as hypertrophy and fibrosis, emphasizing the need to develop potent therapies that maintain cardiac function in patients with end-stage renal disease. AIMS: To identify potential compounds and their targets as treatments for cardiorenal syndrome type 4 (CRS) using molecular phenotyping and in vivo/in vitro experiments. METHODS: Gene expression was assessed using bioinformatics and verified in animal experiments using 5/6 nephrectomized mice (NPM). Based on this information, a molecular phenotyping strategy was pursued to screen potential compounds. Picrosirius red staining, wheat germ agglutinin staining, Echocardiography, immunofluorescence staining, and real-time quantitative PCR (qPCR) were utilized to evaluate the effects of compounds on CRS in vivo. Furthermore, qPCR, immunofluorescence staining and flow cytometry were applied to assess the effects of these compounds on macrophages/cardiac fibroblasts/cardiomyocytes. RNA-Seq analysis was performed to locate the targets of the selected compounds. Western blotting was performed to validate the targets and mechanisms. The reversibility of these effects was tested by overexpressing Osteopontin (OPN). RESULTS: OPN expression increased more remarkably in individuals with uremia-induced cardiac dysfunction than in other cardiomyopathies. Lobetyolin (LBT) was identified in the compound screen, and it improved cardiac dysfunction and suppressed remodeling in NPM mice. Additionally, OPN modulated the effect of LBT on cardiac dysfunction in vivo and in vitro. Further experiments revealed that LBT suppressed OPN expression via the phosphorylation of c-Jun N-terminal protein kinase (JNK) signaling pathway. CONCLUSIONS: LBT improved CRS by inhibiting OPN expression through the JNK pathway. This study is the first to describe a cardioprotective effect of LBT and provides new insights into CRS drug discovery.

[Expert consensus on human use experience research of traditional Chinese medicine].

Human use experience(HUE) is important for the research and development of Chinese medicine. For the sake of more reliable data, the Professional Committee for Clinical Evaluation of Chinese Medicine of Chinese Pharmaceutical Association drafted the Expert Consensus on Human Use Experience Research of Traditional Chinese Medicine. It highlights that the research on HUE should have clear purposes, describe the theoretical basis of traditional Chinese medicine(TCM) for the clinical indications and prescriptions and the clinical value of prescriptions, especially the advantages or characteristics in clinical orientation and target population, evaluate the dosages and number of medicinals of prescriptions, verify the accordance with the preparation process of new Chinese medicine, analyze feasibility of the process for large-scale production and the rationality of the dosage form, and assess the medicinal material resources. Moreover, such research should have reasonable protocol and the collection of clinical data on HUE must comply with medical ethics and avoid conflicts of interest. The collection method should be selected depending on the characteristics of clinical data. Quality control measures should be formulated to ensure the authenticity, accuracy, completeness, reliability, and traceability of clinical data. The definitions on the clinical data should be uniform and clear, and methods should be adopted to avoid bias. The data can be statistically analyzed after the processing. Through the study of HUE, the clinical orientation, target population, commonly used dosage, course of treatment, preliminary efficacy and safety of Chinese medicine prescriptions will be clarified. On this basis, the data on the HUE should be discussed and conclusions will be drawn. Finally, a standardized report will be formed.

[Evaluation for druggability of traditional Chinese medicine preparations in medical institutions based on human use experience].

Traditional Chinese medicine(TCM) preparations in medical institutions are an important source of research and development(R&D) of TCM new drug. With years of usage in therapy, these preparations' safety and effectiveness have generally been validated in clinic. However, there are still a few disadvantages in TCM new medicine development, such as similar prescriptions, excessive prescription ingredients, too broad clinical orientation, lack of solid clinical data, issue in pharmaceutical quality control, and intellectual property disputes. Nowadays, the Three-Combined Evaluation System has strengthened policy support for the new TCM R&D. In order to improve the success rate of TCM R&D, due to the difficulties within, this paper proposes the process of transforming TCM preparations in medical institutions into new TCM and advocates the evaluation for druggability based on Human Use Experience(HUE). The potencial preparations ought to follow traditional Chinese Medical theory, sufficient HUE data in indication, syndrome type of TCM, target population, usage, dosage, and course of treatment are required. Particular attention should be paid to the source, evolution, and improvement process of prescription, and evaluate the dosage, ingredients, and herb resources of prescription. To assess the feasibility of mass production, it is necessary to determine whether the pharmaceutical process is mostly consistent with the new drug and whether the dosage form is reasonable. By summarizing the clinical application of the preparations, the whole picture of its clinical application would be reveal as much as possible. It is beneficial to evaluate its clinical value and R&D prospect. In consideration of the lack of clinical safety data of preparations, safety profile needs to be collected according to the prescription. The quality of clinical data needs to be evaluated by focusing on the integrity and accuracy of data to reduce bias and confusion. Significant care should be paid to intellectual property protection to avoid legal disputes.

Zhen-Wu decoction and lactiflorin, an ingredient predicted by in silico modelling, alleviate uremia induced cardiac endothelial injury via Nrf2 activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiorenal syndrome type 4 (CRS type 4), with high rates of morbidity and mortality, has become a social and economic problem worldwide over the last few decades. Zhen-Wu decoction, a traditional medicine used in East Asia, has been widely used in the treatment of cardiovascular disease and kidney disease, and has shown potential therapeutic effects for the clinical treatment of CRS type 4. However, the underlying mechanism has not been extensively explored. AIM OF THE STUDY: The purpose of this study was to investigate the effect and underlying mechanism of Zhen-Wu decoction on uremic cardiomyopathy, offering a potential target for clinical treatment of CRS type 4. MATERIALS AND METHODS: Five/six nephrectomized mice were utilized for experiments in vivo. The cardioprotective effects of Zhen-Wu decoction were evaluated by echocardiography and tissue staining. RNA-Seq data were used to investigate the potential pharmacological mechanism. The prediction of targets and active components was based on our previous strategy. Subsequently, the protective effect of the selected compound was verified in experiments in vitro. RESULTS: Zhen-Wu decoction alleviated cardiac dysfunction and endothelial injury in 5/6 nephrectomized mice, and the mechanism may involve the inflammatory process and oxidative stress. The activation of the Nrf2 signaling pathway was predicted to be a potential target of Zhen-Wu decoction in protecting endothelial cells. Through our machine learning strategy, we found that lactiflorin as an ingredient in Zhen-Wu decoction, alleviates IS-induced endothelial cell injury by blocking Keap1 and activating Nrf2. CONCLUSIONS: The present study demonstrated that Zhen-Wu decoction and lactiflorin could protect endothelial cells against oxidative stress in mice after nephrectomy by activating the Nrf2 signaling pathway.