Deciphering suppressive effects of Lianhua Qingwen Capsule on COVID-19 and synergistic effects of its major botanical drug pairs / 中国天然药物

The COVID-19 pandemic has resulted in excess deaths worldwide. Conventional antiviral medicines have been used to relieve the symptoms, with limited therapeutic effect. In contrast, Lianhua Qingwen Capsule is reported to exert remarkable anti-COVID-19 effect. The current review aims to: 1) uncover the main pharmacological actions of Lianhua Qingwen Capsule for managing COVID-19; 2) verify the bioactive ingredients and pharmacological actions of Lianhua Qingwen Capsule by network analysis; 3) investigate the compatibility effect of major botanical drug pairs in Lianhua Qingwen Capsule; and 4) clarify the clinical evidence and safety of the combined therapy of Lianhua Qingwen Capsule and conventional drugs. Numerous bioactive ingredients in Lianhu Qingwen, such as quercetin, naringenin, β-sitosterol, luteolin, and stigmasterol, were identified to target host cytokines, and to regulate the immune defence in response to COVID-19. Genes including androgen receptor (AR), myeloperoxidase (MPO), epidermal growth factor receptor (EGFR), insulin (INS), and aryl hydrocarbon receptor (AHR) were found to be significantly involved in the pharmacological actions of Lianhua Qingwen Capsule against COVID-19. Four botanical drug pairs in Lianhua Qingwen Capsule were shown to have synergistic effect for the treatment of COVID-19. Clinical studies demonstrated the medicinal effect of the combined use of Lianhua Qingwen Capsule and conventional drugs against COVID-19. In conclusion, the four main pharmacological mechanisms of Lianhua Qingwen Capsule for managing COVID-19 are revealed. Therapeutic effect has been noted against COVID-19 in Lianhua Qingwen Capsule.

Botanical drug clinical trial: Common issues and future options

In order to understand this disparity between human use and drugs approved by regulatory agencies, we analyzed botanical drug clinical trials registered at ClinicalTrial.gov to detect trends in current trials and guide future trials. A total of 195 botanical drug clinical trials were registered from 2016 to 2019, of which 81 are phase II or phase II/III. 95% of all phase II and II/III studies were designed with 100 or less participants per arm, indicating a more observational nature due to the limited power to detect differences in outcomes between treatment and control groups. Due to the limited number of participants, efficacy outcome from results may be highly subjective. 14% of the total trials were phase I studies. For botanical drugs with well-documented or extensive history of human use, phase I may not provide significant additional information, and may, therefore, not be necessary. For the trial design, we suggest added-on studies when botanical drugs are used as part of a combination treatment. Additionally, we believe standardized data collection methods and criteria are critical to utilizing the vast collection of human experience as quality evidence to support regulatory approval.

Andrographis Paniculata HMPL-004, An Old Medicine with New Story / 世界科学技术-中医药现代化

In June 2004,the US Food and Drug Administration (FDA) issued Guidance for Industry:Botanical Drug Development,which opened a new path for the internationalization of traditional Chinese medicine (TCM).In October 2006,the first botanical drug product Veregen TM was approved by the FDA.The regulatory policy for botanical and herbal medicine coincides with the internationalization strategy of Hutchison MediPharma Ltd.(hereinafter referred to as Hutchison).In 2006,Hutchison's first herbal mixture medicine andrographis paniculata HMPL-004 successfully obtained Investigational New Drug (IND) from the US.From 2006 to 2014,there are eight clinical studies of HMPL-004 being conducted in Europe and the US,from Phase 1 safety study to proof-of-concept trials in ulcerative colitis (UC) and Crohn's disease.To strengthen HMPL-004 development on a global scale,Hutchison made business alliance with Nestle Health Science in clinical development as well as basic research.Due to futile outcome of an interim analysis,the Phase Ⅲ registration study in UC was terminated.However,valuable lessons were learned with the birth of the generation botanical drug product HMPL004-6599.

Brief Introduction and Comment on the Final Revised Vision of Botanical Drug Development Guidance for Industry Issued by FDA / 中国药学杂志

Botanical Drug Development Guidance for Industry, replaced the Guidance for Industry on Botanical Drug Products issued in June 2004, was issued at December 2016. With the understanding and experience acquired in the reviews of NDAs and INDs for botanical drugs, specific recommendations have been modified and new sections have been added in this new edition. Compared new version with the old, "loose requirement" policy in early IND on consideration of prior human experience of botanical products was unchanged, but the requirements of quality and the rapeutic consistency on botanical raw material, drug substance and finished product in late-phase development and NDA submission for botanical drugs was very strict, especially, requirement to ensure that different marketing batches, with their variations, have the therapeutic effect consistent with those of the batches used in the phase 3 clinical studies. The new analytical methods, such as"totality of the evidence" approach, biological assays, mass balance of all ingredients, multiple batch analyses and dose-response effect, were introduced to ensure the quality and therapeutic consistency. The manufacturing of botanical drug substance should be in compliance with both GACP and CGMPs may be warranted to cover the way in which the botanical raw material is grown, collected, processed and stored.

Botanical Drug Development-Guidance for Industry and Expert Views on Botanical Drug Development in the US / 世界科学技术-中医药现代化

The definition of new drugs in China and the US has no major differences on chemical drugs and biologics.However,Chinese medicines,which are regulated as over-the-counter (OTC) or prescription drugs in China,are mostly regulated as food and/or dietary supplements without FDA approved medicinal use for marketing.The FDA Guidance for Industry-Botanical Drug Products (2004) and the recently revised Guidance for Botanical Drug Development (2016) paved the way for Chinese herbal medicine and other botanical mixtures to be further developed as new drugs through clinical trials and other nonclinical studies.FDA recognizes the value of traditional medicines as part of the previous human experiences to support the safety and speed up early phase clinical trials of botanical products under investigational new drug (INDs) applications.The revised Guidance included addition recommendations for late phase development,like phase 2 trials and new drug applications (NDA),to resolve some of the unique challenges on batch-tobatch consistency (e.g.,a totality of evidence approach,including raw material control,bioassays,multiple-batch and multiple-dose clinical trials,and etc.).The approval of Veregen and Fulyzaq (now Mytesi) are new molecular entity / new chemical entity type of new drugs,treasured fruits from several hundred INDs studying botanicals.With those NDA examples,it is expected that further study of Chinese herbal medicines as new botanical drugs through further clinical and nonclinical development will be fruitful.On the other hand,long-term commitments are universal for new drug development.And it will also be true for bringing Chinese herbal medicines as botanical new drugs to international markets.It still takes time to see whether artesunate tablets can be verified through further clinical trials and achieve the same level of Coartem.

Focuses and difficulties in clinical study of botanical drugs based on revised guidance for Industry by FDA / 药学学报

This paper was prepared to analyze and discuss the main content of the Botanical Drug Development Guidance for Industry by United States FDA's (the draft version of the 2015), especially focused on the guidelines for clinical research (mainly in late-stage clinical studies) recommendations and requirements sectiones. The key and difficult issues in the late clinic study were analyzed and discussed, and a series of countermeasures were proposed in this paper. At the same time, combined with the case of approved botanical drug products, analysis of the guidelines for the development of plant drug regulations, the enlightenment were presented in the last part, to guide the research and development of traditional Chinese medicine and the internationalization of Chinese medicine.

European Union regulatory and quality requirements for botanical drugs and their implications for Chinese herbal medicinal products development / 中国中药杂志

This paper introduces regulatory pathways and characteristic quality requirements for marketing authorization of herbal medicinal products in the European Union（EU）, and the legal status and applications of "European Union list of herbal substances, preparations and combinations" and "European Union herbal monographs". Also introduced are Chinese herbs that have been granted the EU list entry, those with EU herbal monographs, and registered EU traditional herbal medicinal products with Chinese herbs as active ingredients. Special attention is paid to the technical details of three authorized EU herbal medicinal products (Veregen, Sativex and Episalvan) in comparison with Andrographis paniculata extract HMPL-004 that failed the phase Ⅲ clinical trial for ulcerative colitis. The paper further emphasizes the importance of enriching active fractions of herbal extracts and taking regulatory and quality considerations into account in early stage of botanical drug development.

Ginkgo biloba: A ‘living fossil’ with modern day phytomedicinal applications.

Ginkgo biloba has survived for over 200 million years now. With other members of this gymnosperm extinct, it is considered as a ‘living fossil’. Yinxing, as it is called in Chinese, is very popular in East Asia as a remedy for lung congestion, ischemia and asthma. In modern day medical practice, growing consideration is given to the extract from this tree as a line of treatment in many cancer conditions partly due to the side effects of conventional drugs of therapy. The extract has also anti-diabetic, anti-inflammatory and cardio- and hepatoprotective roles. These and other numerous recent applications of this important botanical drug are discussed in this review.

Establishing of Good Extracting Practice of the Traditional Chinese Medicine and Facilitating the Stan-dardization of Chinese Botanical Extracts / 中国药房

OBJECTIVE:In order to enhance the quality control of Chinese botanical extracts and to facilitate the entry of Chinese botanical drugs and traditional Chinese medicine into the international market.METHODS:The market overview of the botanical extracts was expounded,problems existed in the quality control of the Chinese botanical extracts were analyzed,and the significance and key points in establishing Good Extracting Practice(GEP)of the traditional Chinese medicine were discussed.RESULTS&CONCLUSION:The quality control of the Chinese botanical extracts must be emphasized,which means to establish the feasible quality standard;the production process should be optimized and the corresponding‘Standard Operating Procedure’should be formed;advanced technology and facilities should be adopted to improve the content of hi-tech,the toxic substances should be strictly controlled;the quality of the raw material should be guaranteed,the connection between which and the‘Good Agricultural Practice for Chinese Crude Drugs'should be strengthened.