Safety Research in Traditional Chinese Medicine: Methods, Applications, and Outlook

Traditional Chinese medicine (TCM) is a medical system that has collected and summarized abundant clinical experience over its long history of more than 2000 years. However, the frequent occurrence of TCM-induced adverse reactions has hindered the modernization and internationalization of TCM, while attracting increasing attention from around the world. Unlike chemical drugs and biological agents, the difficulties involved in research on the toxicity and safety of TCM mainly include the complexity of its components and the unpredictability of drug–body interactions. Much of TCM, which has overall therapeutic effects, has the typical mechanisms of multiple components, multiple pathways, and multiple targets. While considering the gradualness and unpredictability of TCM toxicity, the ambiguity of toxicants and safe dosage, and individual differences during long-term TCM administration, we have systematically established key techniques for the toxicity assessment of TCM. These techniques mainly include TCM toxicity discovery in an early phase, based on a combination of drug toxicology genomics and metabolomics;methods to identify dose–toxicity relationships in TCM;and integrated techniques for the exploration of TCM interactions, such as fast-screening tests based on drug-metabolizing enzymes and receptor pathways. In particular, we have developed a new technical system for TCM safety evaluation using molecular toxicology, which has been validated well in research on TCM compatibility contraindication, quality control, and allergen discovery. The application of this key technical platform is introduced here in detail. This application includes model organisms, toxicant biomarkers, a magnetic suspension technique, and the application of network toxicology and computational toxicology in research on the toxicity of Fructus toosendan, Semen cassiae, Polygonum multiflorum, and Fructus psoraleae.

A holistic strategy for quality and safety control of traditional Chinese medicines by the “iVarious” standard system

An effective quality control system is the key to ensuring the quality, safety and efficacy of traditional Chinese medicines(TCMs). However, the current quality standard research lacks top-level design and systematic design,mostly based on specific technologies or evaluation methods. To resolve the challenges and questions of quality control of TCMs, a brand-new quality standard system, named "iVarious", was proposed. The system comprises eight elements in a modular format. Meaning of every element was specifically illustrated via corresponding research instances. Furthermore, frankincense study was taken as an example for demonstrating standards and research process, based on the "i Various" system. This system highlighted a holistic strategy for effectiveness,security, integrity and systematization of quality and safety control standards of TCMs. The establishment of"i Various" integrates multi-disciplinary technologies and progressive methods, basis elements and key points of standard construction. The system provides a novel idea and technological demonstration for regulation establishment of TCMs quality standards.

A Re-understanding on the Safety Matters of Chinese Herbal Medicine

Traditional Chinese medicine (TCM) plays a very important role in Chinese people ’ s health-keeping, enjoying an position of the same significance with Western medicine and drugs. Entering into the 21 century, and due to the swift and drastic development in economy and elevation in living quality, the public have come to pay much more

Effectiveness and safety of seven oral Chinese patent medicines as adjuvant therapy for cancer-related anemia: A systematic review and network meta-analysis of randomized controlled trials

Objective:To evaluate the effectiveness and safety of seven oral Chinese patent medicines(CPMs)as adjuvant therapy for cancer-related anemia(CRA)by network meta-analysis(NMA).Methods:A literature search to obtain randomized controlled trials(RCTs)of seven oral CPMs in the adjuvant treatment of CRA was conducted in multiple databases from the inception to April 2022.The RevMan5.3 and R 4.1.1 software were used for NMA.Results:We ultimately included 29 RCTs with 2140 patients.Traditional meta-analysis showed that Fufang E'jiao syrup(FFEJS),Shengxuebao mixture(SXBM),Shengxuening tablets(SXNT),Jianpi Shengxue granules(JPSXG),and Yixuesheng capsule(YXSC)combined with basic Western treatment(BWT)could improve the hemoglobin(HGB)level.JPSXG combined with BWT could improve the red blood cell(RBC).FFEJS combined with BWT improved the Karnofsky performance status(KPS).NMA showed that FFEJS,JPSXG,SXBM,and SXNT plus BWT improved HGB better than Shengxue tablets(SXT)plus BWT,with top three ranking results being JPSXG plus BWT>SXNT plus BWT>FFEJS plus BWT.FFEJS plus BWT,JPSXG plus BWT,SXBM plus BWT,SXNT plus BWT,and SXT plus BWT improved RBC better than BWT,with top three ranking results being SXNT plus BWT>JPSXG plus BWT>FFEJS plus BWT.In terms of the KPS score,compared with SXT plus BWT,FFEJS,JPSXG,SXBM,SXNT,and Yizhong Shengxue capsule(YZSXC)plus BWT had higher KPS,with top three ranking results being SXBM plus BWT>JPSXG plus BWT>FFEJS plus BWT.Conclusions:Our NMA demonstrated that seven oral CPMs used as adjuvant treatment of CRA had a definite clinical effect.JPSXG not only increases the levels of HGB and RBC to enhance the clinical effect but also improves patients'quality of life.More accurate conclusions need to be verified by more high-quality RCTs.

Investigation of Heavy Metal Contents in Traditional Chinese Herbal Medicine Peristrophe roxburghiana Collected from Northwest of Guangxi

Objective] This study was conducted to evaluate the product quality and safety of Peristrophe roxburghiana_ col ected from different places in Hechi City, northwest of Gunagxi, so as to provide basic data for further development and uti-lization of the characteristic plant resource P. roxburghiana. [Method] Contents of 9 kinds of heavy metals including Cd, Mn, Pb, Zn and Cu in the herb were deter-mined by the method of wet digestion-flame atomic absorption spectrophotometry and atomic fluorescence spectrometry, respectively. [Results] Heavy metal contents of Cd, Mn, Pb, Fe, Cu, Zn, As, Hg and Se were 1.62-17.25, 8.93-142.53, 4.37-18.43, 103.7-242.81, 2.55-5.35, 85.40-146.30, 0.07-0.54, 0.00-0.08 and 0.00-0.47 mg/kg, respectively. According to the national food safety standards and Green Trade Standards of lmporting ＆amp; Exporting Medicinal plants ＆amp; Preparations, the heavy metal contents of the P. roxburghiana_samples col ected from different coun-ties in Hechi City exceeded standards or at the critical values. Among which, Cd, Pb and Zn contents of the samples are seriously higher than the standards. [Con-clusion] Therefore, the impact of soil heavy metal pol ution on the safety of edible plants in the northwest of Guangxi should be highly concerned.

Reflections on the Toxicity and Safety of Traditional Chinese Medicine Combined with the Cases of Nephrotoxicity and Hepatotoxicity

This paper analyzes the relationship between toxicity and safety of traditional Chinese medicine(TCM)based on the cases of current nephrotoxicity and hepatotoxicity,and summarizes the literature on hepatotoxicity and nephrotoxicity.It is found that the main reasons for the toxic reaction of TCM are own factors of drugs,irregular administration of medicine and individual difference.However,as long as the"quality"and"quantity"of TCM are guaranteed,the toxicity of TCM can be controlled within the safety range.

The efficacy and safety of anti-humidification traditional Chinese medicine in the treatment of viral pneumonia: A meta-analysis

Objective A meta-analysis was used to evaluate the efficacy and safety of traditional Chinese medicine(TCM)for dispelling dampness in the treatment of viral pneumonia.Methods The databases of CNKI,CBM,WanFang data,VIP,EMBASE,PubMed,and Cochrane library were searched,and the clinical trials of dispelling dampness TCM in the treatment of viral pneumonia were selected.The retrieval period is from the establishment of the database to December 2022.Stata 17.0 software was used to perform meta-analysis,and review manager 5.3 software was used to assess the risk of bias.Overall efficacy was evaluated by OR,and improvement in major clinical symptoms were evaluated by RR.Results A total of 20 randomized controlled trials were included,with a total of 2136 patients,including 1180 patients in the experimental group and 956 patients in the control group.Meta-analysis showed that TCM for dispelling dampness could significantly improve the efficacy of viral pneumonia patients[OR=2.652,95%CI=(2.187,3.217),Z=9.908,P<0.05];The child with abnormal lung X-rays returned to normal after treatment[RR=4.23,95%CI=(2.42,7.42),Z=5.04,P<0.05];In addition,patients had fewer adverse reactions to dispelling dampness TCM,and the safety of the trial was good.Conclusion This Meta-analysis further clarified the efficacy of TCM for dispelling dampness in the treatment of viral pneumonia by combining clinical data and has suggestive significance for the treatment of novel coronavirus pneumonia.

Study and Countermeasures on Safety Control of Traditional Chinese Medicines Industry Chain

I'm very grateful to Chinese Pharmaceutical Association and DIA for their elaborate organization,so that we are able to participate in the Sino-Europe Symposium.Yesterday and today,several professors have talked about various aspects.It is true that the effectiveness of traditional Chinese medicine is important,and safety is equally important.For this reason,our laboratory works on the effective test,and at the same time,since 2001,we have been focusing on the safety of traditional Chinese medicines,especially the research on exogenous pollution.Today,I would like to share with you some of the quality control of the whole industry chain of traditional Chinese medicine and some of our thoughts.

International expert consensus on clinical application of traditional Chinese medicine formula granules

Guided by the theory of traditional Chinese medicine(TCM),TCM formula granules are made through the optimal process of extraction,concentration,drying,and granulation by combining modern new preparation technologies and pharmaceutical technologies.TCM formula granules are stable,safe,convenient,and effective.Compared with TCM decoction pieces,TCM formula granules can achieve the full process control of its industry chain from field to workshop and standardize the management of the origin of medicinal materials,processing of decoction pieces,processing technology,quality inspection,sales,and products distribution.TCM formula granules can partially replace Chinese patent medicines.Only available for around 800 common varieties of TCM,TCM formula granules cannot replace decoction pieces for many types which are not commonly used in clinical practice.A large number of formula granules are used in clinical and animal studies so that investigators no longer need to extract and control the quality of TCM decoction pieces.How to improve the production process,establish the quality standard,perfect the regulatory system,and expand the clinical application are the problems we need to solve as soon as possible for the better development of formula granules.

Translational Chinese Medicine: A Way for Development of Traditional Chinese Medicine

Translational Chinese medicine is one of the latest developing fields in traditional Chinese medicine. In this paper, we discuss the “3 w” namely, “what is”, “why to advance”, “how to carry out” and the significance of translational Chinese medicine. To overcome the innate drawbacks of traditional Chinese medicine (TCM), the basic theory of TCM had better be refreshed. The safety and efficacy of classic formulae and therapy experience of TCM should be evaluated based on strict quality control and reaffirmed with evidence based medicine. The significance of translational Chinese medicine is to transform Chinese medicine into a balanced, personalized medicine with sound safety, good efficacy and strict quality control.

Status and Development Trend of Evaluation of Post-Marketing Traditional Chinese Medicines in China

Evaluation of traditional Chinese medicines after the market has achieved fruitful results after years of development.The real-world research concept has been first proposed by Chief Researcher Xie Yanming in 2010 and to 2020 with the approval of the National Medical Products Administration to use real-world evidence to support drug development and review in 2020.Real-world data application and transformation continue to cause heated discussions in the industry.Real-world research concepts have been added new motivation into the evaluation of Chinese medicines after they are marketed.The development of the Chinese patent medicine industry is facing unprecedented opportunities and challenges.

Comparative Evaluation of Antitumor Chinese Patent Medicine Injections Based on Evidence-Based Medicine and Markov Model

Objective: The objective of this study was to explore the safety, efficacy, economy, and other aspects of frequently-used antitumor Chinese patent medicine injections through a comprehensive evaluation of evidence-based medical research to provide scientific information and decision-making basis for drug selection, rational drug use, public awareness of safe drug use, and medical insurance. Materials and Methods: The names of five frequently used antitumor Chinese patent medicine injections were used as search terms, including the compound Sophora flavescens injection, Kangai injection, Aidi injection, Kanglaite injection, and Brucea javanica oil emulsion injection. Relevant evidence-based medical research was extracted from the databases. A descriptive evaluation was conducted, and the Markov model was used for the cost-benefit analysis. Finally, the above injections are ranked by comprehensive scores using the multi-criteria decision analysis and Delphi method. Results: The five injections had their own advantages in enhancing the effectiveness of anti-tumor treatments, improving the quality of life for cancer patients, and reducing the incidence of adverse reactions. From the perspective of economy and other attributes, compound S. flavescens was superior to B. javanica oil, Aidi, Kangai, and Kanglaite. After a comprehensive evaluation of the above five injections, the compound S. flavescens injection received the highest score. Conclusions: Compound S. flavescens, Kangai, Aidi, B. javanica oil, and Kanglaite have their own advantages in effectiveness and no significant difference in safety. Compound S. flavescens injection has the highest comprehensive score. Clinical attention should be paid to monitoring the initial stage of medication and special groups.

Efficacy and safety of Traditional Chinese Medicine for the treatment of acquired immunodeficiency syndrome:a systematic review

OBJECTIVE:To systematically review the efficacy and safety ofTraditional Chinese Medicine(TCM)interventions,compared with control interventions(placebo or conventional Western medical therapy),in the treatment of acquired immunodeficiency syndrome(AIDS).METHODS:Electronic databases including PubMed,the Cochrane Library,China National Knowledge Infrastructure(CNKI),and Wanfang Data were searched to identify relevant randomized controlled trials(RCTs)published as of May 2012.Studies were selected according to the specified inclusion and exclusion criteria and then subjected to methodological quality assessment,data extraction,and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions.RESULTS:Twelve RCTs involving 881 patients with AIDS were included.Methodological quality assessment showed that two were high-quality,two were moderate-quality,and eight were low-quality.Meta-analysis showed that TCM interventions were associated with significantly reduced plasma viral load compared with placebo[odds ratio OR=2.46,95%confidence interval CI(1.02,5.94);P=0.04].However,the reductions in plasma viral load significantly favored conventional Western medical therapy alone over integrated traditional Chinese and Western medical therapy[OR=0.16,95%CI(0.05,0.55);P=0.004].Patients receiving TCM interventions had significantly higher CD4+T lymphocyte counts compared with those on placebo[OR=2.54,95%CI(1.40,4.60);P=0.002].In addition,TCM interventions were significantly more likely to have improved clinical symptoms[OR=2.82,95%CI(1.85,4.31);P<0.00001].TCM interventions conferred a similar risk of adverse events(AEs)compared with control interventions[OR=1.87,95%CI(0.58,6.01);P=0.29].CONCLUSION:Current evidence suggests that TCM interventions are significantly more effective than placebo in reducing plasma viral load and increasing CD4+T lymphocyte count in patients with AIDS.When compared with conventional Western medical therapy,TCM interventions were significantly less effective in reducing plasma viral load,although they were associated with a higher percentage of patients with improved symptoms.Patients receiving TCM interventions did not seem to be at an increased risk of AEs.

To Establish A Body of Evidence on Safety for Postmarketing Chinese Medicine：A New Research Paradigm

The issue of safety evaluation on postmarketing Chinese medicines has become a hot topic in China’s mainland recently. Researchers and decision-makers can obtain a variety of evidence resources about safety in order to evaluate the safety profile for postmarketing Chinese medicines. A registry study on ten Chinese medicine injections for postmarketing surveillance has come to the end. From such a study observing more than 300,000 patients for more than 4 years, a theoretical research question emerges, that is, how to identify and evaluate safety evidence systematically. We put forward a brand new research paradigm on the theory level, which is to establish a body of evidence on safety evaluation for postmarketing Chinese medicine. Therefore, multiple information sources were explored and extracted from preclinical experiments for toxicity, postmarketing clinical trials for efficacy and safety evaluation, registry study for surveillance, retrospective data analysis from hospital information system and spontaneous response system, and case reports and systematic review from literature. Greater efforts for this idea and cooperation with experts in this field both in China and abroad are urgently needed.

Scientific understanding of toxicity and safety of Chinese medicines

Traditional Chinese medicine is a treasure of traditional culture and medicine which should be inherited and developed. How to cor- rectly understand the toxicity of Chinese materia medica （CMM） is an important guarantee for safe drug use. The history of the applica- tion and research of the toxicity of CMM has been long, and the Chi- nese medicine community ,has never stopped exploring the issues related to the safety of CMM.

Efficacy and safety of external application of Chinese herbal medicine trials

OBJECTIVE:To evaluate the clinical efficacy and safety of external application of Chinese herbal medicine(exCHM)for psoriasis vulgaris(PV).METHODS:Different search portals,including the China National Knowledge Infrastructure Database,China Science and Technology Journal Database,Wanfang,Sino Med,clinicaltrials,Pub Med,Cochrane Library,and Cochrane Central Register of Controlled Trials,were searched for randomized controlled trials(RCTs)that compared the ex-CHM intervention with other treatment protocols for PV,with available data as of November 25,2020.The Review Manager 5.3 software was used for analysis.RESULTS:Nineteen RCTs involving 1988 participants were included,of which twelve RCTs qualified for the Meta-analysis.The results showed that the addition of CHM bath to narrow-band ultraviolet B(NB-UVB)had a higher response rate[RR=1.29;95%CI(1.19,1.40);P<0.00001];lower psoriasis area severity index(PASI)[MD=-3.15;95%CI(-4.79,-1.52);P=0.0002],adverse reactions rate[RR=0.32;95%CI(0.15,0.66);P=0.002],and recurrence rate[RR=0.48;95%CI(0.30,0.79);P=0.004]than NB-UVB alone.The addition of CHM fumigation to NB-UVB also showed a higher response rate[RR=1.29;95%CI(1.11,1.49);P=0.0007]and lower adverse reactions rate[RR=0.44;95%CI(0.24,0.79);P=0.006].In addition,CHM bath could reduce the adverse reactions induced by 308 nm excimer laser and improve patients’quality of life better than phototherapy.CHM fumigation could improve the efficacy of calcipotriol ointment and reduce the adverse reactions.CHM fumigation combined with external washing plus acitretin showed better results than using acitretin alone.No statistical difference was observed between CHM external washing and calcipotriol ointment or CHM ointment and retinoic acids.CONCLUSIONS:Current evidence showed that CHM bath and fumigation appeared to be efficient and safe for PV treatment.However,no definite conclusion could be drawn due to the low quality of included studies and thus more well-designed studies are needed for further assessment.

Efficacy and safety of activating blood circulation and removing blood stasis of Traditional Chinese Medicine for managing renal fibrosis in patients with chronic kidney disease:a systematic review and Meta-analysis

OBJECTIVE:To evaluate the efficacy and safety of activating blood circulation and removing blood stasis in terms of Traditional Chinese Medicine(TCM) for managing renal fibrosis(RF) in patients with chronic kidney disease(CKD).METHODS:We searched randomized controlled trials(RCTs) from eight databases.RESULTS:Sixteen eligible studies with 1,356 participants were included in this study.Compared to treatment with Western Medicine(WM) alone,the combined treatment with activating blood circulation and removing blood stasis in terms of TCM(ARTCM) and WM to manage RF in patients with CKD significantly ameliorated type Ⅳ collagen(C-Ⅳ)(SMD:-2.17,95% CI:3.01 to-1.34),type Ⅲ procollagen(PC-Ⅲ)(SMD:-1.08,95% CI:-1.64 to-0.53),laminin(LN)(SMD:-1.28,95% CI:-1.65 to-0.90),transforming growth factor β 1(TGF-β1)(SMD:-0.65,95% CI:-1.18 to-0.12),serum creatinine(Scr)(SMD:-1.36,95% CI:-1.85 to-0.87),blood urea nitrogen(BUN)(MD:-1.51,95% CI:-2.59 to-0.43),and 24 h urine protein(24h Upro)(SMD:-1.23;95% CI:-1.96 to-0.50).The level of hyaluronic acid(HA) was similar in both types of treatment(SMD:-0.74,95% CI:-1.91 to 0.44).The subgroup analysis showed that the duration of 8 weeks might affect the concentration of C-Ⅳ,PC-Ⅲ,and LN(P < 0.05).The effectiveness of the longer duration to C-Ⅳ,PC-Ⅲ,and LN was not certain.However,the result should be interpreted in care.The safety of the treatment using ARTCM and WM could not be evaluated because a few studies had reported adverse effects.The results of the Meta-analysis were not stable enough.There was publication bias for the reports on Scr(P = 0.001),C-Ⅳ(P = 0.001),PC-Ⅲ(P = 0.026),and LN(P = 0.030) and no publication bias for the reports on BUN(P = 0.293).The quality of evidence varied from low to very low.CONCLUSIONS:The combined treatment using ARTCM and WM to manage RF in patients with CKD has some advantages over treatment with WM alone.High-quality RCTs need to be conducted for the strong support.

Challenges in Research and Development of Traditional Chinese Medicines

This review is briefly to recall the history of research and development (R&D) of Chinese materia medica (CMM) and to discuss the challenges of Chinese traditional and herbal medicines (CTHM) facing the modern science and technology. The R&D of CTHM is thought to be an important pathway for new drug discovery. Since1949, about 140 approved new drugs have been developed, among which about 80 originated directly or indirectly from medicinal plants. CTHM has gained interest from the international medical, biomedical, and pharmaceutical institutions as a valuable source of potential medicines. For the modernization of CMM and innovative research of CTHM, there are following challenges to be faced: (1) to evaluate the efficacy, pharmacological properties, action mechanism, and active chemical constituents; (2) to develop new methodologies for the quality and safety of CTHM; (3) to apply new '-omics' techniques to accelerate drug discoveries developed from CTHM; and (4) to apply international practices including good agricultural practice, good manufacturing practice, good laboratory practice, and good clinical practice in the R&D of CTHM.

Safety issues and new rapid detection methods in traditional Chinese medicinal materials

The safety of traditional Chinese medicine(TCM) is a major strategic issue that involves human health. With the continuous improvement in disease prevention and treatment, the export of TCM and its related products has increased dramatically in China. However, the frequent safety issues of Chinese medicine have become the ‘bottleneck' impeding the modernization of TCM. It was proved that mycotoxins seriously affect TCM safety; the pesticide residues of TCM are a key problem in TCM international trade; adulterants have also been detected, which is related to market circulation. These three factors have greatly affected TCM safety. In this study, fast, highly effective, economically-feasible and accurate detection methods concerning TCM safety issues were reviewed, especially on the authenticity, mycotoxins and pesticide residues of medicinal materials.

Western medication plus Traditional Chinese Medicine preparations in patients with chronic heart failure:a prospective,single-blind,randomized,controlled,and multicenter clinical trial

OBJECTIVE: To assess the efficacy and safety in patients with chronic heart failure(CHF) of Western medication plus Traditional Chinese Medicine(TCM) preparations.METHODS: This prospective, single-blind, randomized, controlled, and multicenter clinical trial began on September 17, 2008, and was completed on June 25, 2011. A total of 340 inpatients, aged 40-79 years, with exacerbating CHF from 10 hospitals were enrolled and randomly allocated within 24 h of admission. The trial included three intervention periods. During hospitalization, the control group received western medication for CHF and the treatment group received Danhong injection with Shenfu injection or Shenmai injection. After discharge,all patients were treated with Qiliqiangxin capsules and Buyiqiangxin tablets or a placebo for 6 months. After the 6-month intervention, both groups received only continuous western medication. The primary endpoint was all-cause mortality.The efficacy assessments were as follows: B-type natriuretic peptide(BNP), Lee's HF score, the 6-minute walking test(6 MWT), left ventricular ejection fraction(LVEF), and the Minnesota Living with Heart Failure Questionnaire(MLHFQ). The safety assessments were as follows: blood and urine routine examination, hepatic and renal function, electrolytes in blood and adverse events.RESULTS: Compared with the control group, the treatment group showed a 30.99% reduction in all-cause mortality and an improved survival rate.The treatment group showed greater improvement in 6 MWT(P = 0.02) than the control group on discharge, after 12-month follow-up, there was a time-group interaction for MLHFQ(P = 0.03). Incidence rate of adverse events and other relevant safety indexes were not statistically significant between the two groups.CONCLUSION: Western medication plus TCM treatment can increase 6-minute walking distance(improve exercise tolerance) and quality of life with heart failure patients.