Enlightenment of COVID-19 Treated by Botanical Drugs on the Development of Drugs for Rare Diseases in China

Objective To study the feasibility of developing botanical drugs to treat intractable diseases and play an important role in dealing with major public health crises.Methods From January 1990 to May 2021,a bibliographic search was carried out on the use of botanical drugs,rare disease drugs,related registration management policies and regulations in PubMed and CNKI.The following keywords were searched in the database:Rare disease policies and regulations,orphan drugs,botanical drugs for intractable diseases,botanical drugs for the treatment of new coronary pneumonia,traditional Chinese medicine,and emergency guidelines for major public health crisis.Other data were obtained from“Chinese Pharmacopoeia”and relevant Chinese government websites for sorting and analysis.Results and Conclusion Based on 39 Chinese corresponding policies and regulations,challenges and opportunities of developing and researching drugs for treating rare diseases were found out after the analysis and comparison.Based on the study of national policies on drugs for rare diseases,the priority review and approval procedures in the drug registration,as well as China’s emergency guidelines and policies for major public health events,some problems in the use of drugs for rare diseases are found out.Therefore,it is recommended to actively adopt the property rights protection system,explore the folk prescriptions of traditional Chinese medicine and the potential of hospital preparations,and the registration review strategy of giving priority to the use of botanical drugs for rare diseases.Thus,the international status of botanical drugs for rare disease and the influence of responding to major public health events can be enhanced.

New botanical drug, HL tablet, reduces hepatic fat as measured by magnetic resonance spectroscopy in patients with nonalcoholic fatty liver disease: A placebo-controlled, randomized, phase Ⅱ trial

AIM To evaluate the efficacy and safety of HL tablet extracted from magnolia officinalis for treating patients with nonalcoholic fatty liver disease(NAFLD).METHODS Seventy-four patients with NAFLD diagnosed by ultrasonography were randomly assigned to 3 groups given high dose(400 mg) HL tablet, low dose(133.4 mg) HL tablet and placebo, respectively, daily for 12 wk. The primary endpoint was post-treatment change of hepatic fat content(HFC) measured by magnetic resonance spectroscopy. Secondary endpoints included changes of serum aspartate aminotransferase, alanine aminotransferase(ALT), cholesterol, triglyceride, free fatty acid, homeostasis model assessment-estimated insulin resistance, and body mass index(BMI).RESULTS The mean HFC of the high dose HL group, but not of the low dose group, declined significantly after 12 wk of treatment(high dose vs placebo, P = 0.033; low dose vs placebo, P = 0.386). The mean changes of HFC from baseline at week 12 were-1.7% ± 3.1% in the high dose group(P = 0.018),-1.21% ± 4.97% in the low dose group(P = 0.254) and 0.61% ± 3.87% in the placebo group(relative changes compared to baseline, high dose were:-12.1% ± 23.5%, low dose:-3.2% ± 32.0%, and placebo: 7.6% ± 44.0%). Serum ALT levels also tended to decrease in the groups receiving HL tablet while other factors were unaffected. There were no moderate or severe treatment-related safety issues during the study.CONCLUSION HL tablet is effective in reducing HFC without any negative lipid profiles, BMI changes and adverse effects.

Pharmacological Effects of Botanical Drugs on Myocardial Metabolism in Chronic Heart Failure

Although there have been significant advances in the treatment of heart failure in recent years,chronic heart failure remains a leading cause of cardiovascular disease-related death.Many studies have found that targeted cardiac metabolic remodeling has good potential for the treatment of heart failure.However,most of the drugs that increase cardiac energy are still in the theoretical or testing stage.Some research has found that botanical drugs not only increase myocardial energy metabolism through multiple targets but also have the potential to restore the balance of myocardial substrate metabolism.In this review,we summarized the mechanisms by which botanical drugs(the active ingredients/formulas/Chinese patent medicines)improve substrate utilization and promote myocardial energy metabolism by activating AMP-activated protein kinase(AMPK),peroxisome proliferator-activated receptors(PPARs)and other related targets.At the same time,some potential protective effects of botanical drugs on myocardium,such as alleviating oxidative stress and dysbiosis signaling,caused by metabolic disorders,were briefly discussed.

Deciphering suppressive effects of Lianhua Qingwen Capsule on COVID-19 and synergistic effects of its major botanical drug pairs

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 to2019,of which 81 are phaseⅡor phaseⅡ/Ⅲ.95%of all phaseⅡandⅡ/Ⅲstudies were designed with100 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 phaseⅠstudies.For botanical drugs with well-documented or extensive history of human use,phaseⅠmay 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.

Screening Test for Antibiotics in Medicinal Plants(STAMP):Using Powdered Plant Materials Instead of Extracts

Plants are a rich source of antibiotics, but screening all the existing plant species for biological activity using current methods can be time and resource consuming. The present study is to investigate whether powdered plant materials would perform as well as plant extracts in the screening of plants with antimicrobial activity. In the new method proposed (STAMP), we compared in vitro antimicrobial activity of powdered plant materials from 12 species against bacteria and fungi. We confirmed these results with their corresponding aqueous (wet) and hydro-alcoholic extracts and one species testing the antimicrobial activity of two isolated compounds. Compared with hydro-alcoholic extracts, screening using the powdered plant materials correctly identified the majority of the species with antimicrobial activity against Candida albicans (sensitivity 91%, specificity 86%), C. parapsilosis (sensitivity 100%, specificity 67%), and Staphylococcus aureus (sensitivity 64%, specificity 86%). For bacteria, the method performed better in a pH of 9.0. The antimicrobial activity of two compounds isolated from one species (maytenin and netzahualcoyone) confirmed the results. In conclusion, the use of powdered plant materials for screening plants with antimicrobial properties is a cheap, widely available, technically easy, time sparing, reproducible, and sensitive method and can significantly shorten the time and money spent during drug development.

Status and Thoughts of Chinese Patent Medicines Seeking Approval in the US Market

Veregen^TM and Fulyzaq are the first two botanical drug products that were approved by the Food and Drug Administration （FDA） to market in the US in recent years. Additional herbal medicines, including Compound Danshen Dripping Pills （复方丹参滴丸）, Fuzheng Huayu Tablets （扶正化瘀片）, Xuezhikang Capsule （血脂康胶囊）, Guizhi Fuling Capsule （桂枝茯苓胶囊）, Kanglaite Capsule （康莱特胶囊） and Kanglaite Injection （康莱特注射液）, have filed the investigational new drug （IND） application to the FDA and are in phaseⅡ or phase Ⅲ clinical development. In order to gain better understanding of the process of botanical drug approval in the US, this article examines the aforementioned drugs by looking at their composition, indication, prior clinical experience and clinical development process, and summarizes key features that enabled IND filing and marketing approval by the FDA.