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The "principlely feasible" Lianhua Qing plague, the relevant data on the mechanism are not better than the "Western medicine" of the folding halberd, and its actual effectiveness remains to be seen.
Written by | Ling Jun
Source | "Medical Community" public account
Since last week, the four words "Yiling Pharmaceutical" have continued to appear on major social platforms. Since the outbreak of the new crown epidemic in 2020, Lianhua Qingpest has been recommended by the national plan for the treatment of new crown pneumonia for the sixth time.
However, the effect of Lianhua Qingpeng in the treatment and prevention of the new crown is now intensively questioned by many parties.
Last night (April 20), Yiling Pharmaceutical responded to social hotspots from the perspective of efficacy and safety, and in the statement, Yiling Pharmaceutical responded: The effectiveness and safety of Lianhua Qing plague in the treatment of patients with mild and moderate COVID-19 are still in progress.
The questions from all walks of life about Lianhua Qingpeng and the response of Yiling Pharmaceutical industry have focused on the evidence level of the "effectiveness" of the treatment of the new crown. So, what did Lianhua Qingpeng do on the evidence-based road of the new crown curative effect? What else needs to be done to truly achieve the "self-justifying effect"?
Lianhua Qing plague proves prevention and
Papers on the efficacy of treatment have been questioned
Lianhua Qingpeng is not without attempts to embark on the path of "evidence-based medicine".
In response to the recent controversy, Yiling Pharmaceutical responded as early as April 18. According to the "Southern Plus" news client, Yiling Pharmaceutical said:
A number of authoritative scientific research institutions in China have carried out a series of basic and clinical research on the fight against new crown pneumonia in LianhuaQing plague, forming a chain of evidence for the prevention and treatment of new crown pneumonia "cell-animal-preventive drug-clinical treatment".
In terms of "preventive drugs", according to the 4th to 9th editions of the national "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia", Lianhua Qingpi is not recommended for the prevention of new crown, but The "hometown" of Ling Pharmaceutical, Hebei Province, has obviously taken this step first. According to the "Hebei Province Novel Coronavirus Pneumonia Traditional Chinese Medicine Prevention and Control Plan (Trial Sixth Edition)", Lianhua Qing plague capsules/granules can be used to prevent the new crown and need to be taken continuously for 7 to 10 days.
Yiling Pharmaceutical believes that this recommendation is based on scientific clinical evidence. "The results of the study confirmed that the positive rate of nucleic acid detection in the intervention group of Lianhua Qingxiao was 0.27%, which was significantly lower than the positive rate of 1.14% in the control group (with statistical significance), and the preventive application of Lianhua Qingpeng in close contact groups could reduce the positive infection rate of new crown pneumonia by 76%."
The above conclusions were published in the Evidence-Based Complementary and Alternative Medicine ,1976 people infected with COVID-19 and were enrolled in close and sub-contact patients, and the treatment group (1101 cases) and control groups (875 cases) were observed for 14 days.
Regarding this study, immunologist Shang Zhou posted an article on the public account "Intellectuals" yesterday to comment:
The small sample size used, especially among the contacts studied was very low (only 1.14% in the control group), resulting in too few POSITIVE cases and reducing the effectiveness and credibility of the statistics;
The grouping of the samples was not random, and whether or not to receive treatment for Lianhua Qingpeng in this study depended on the isolation points, some of which used Lianhua Qingpeng and some of which did not. The grouping itself may bring in a number of factors that affect the outcome, which are further amplified in the case of small sample sizes.
In the evidence section of "clinical treatment", the most famous is a study published in Phytomedicine by top experts such as Zhong Nanshan, Li Lanjuan, zhang Boli and other top experts in May 2020.
The study enrolled a total of 284 patients, and the results showed that the symptom recovery rate of patients taking Lianhua Qing plague capsules was 91.5% in 14 days, and the median time for symptom recovery was 7 days. The corresponding data of patients who did not take Lianhua Qing plague were 82.4% and 10 days.
Although the results show that Lianhua Qingpeng capsule has a certain efficacy for patients with new crown, its flaws at the design level have not allowed Lianhua Qingxiao to get rid of the controversy. The lack of strict "random control + double blindness" means that patients know what they are taking and therefore cannot rule out the effects of a "placebo effect". In addition, the sample size is too small, which has also been criticized by the doubters.
In its response on April 18, Yiling Pharmaceutical said:
Due to the urgency of the outbreak in early 2020 and the need for timely treatment of patients, no double-blind trials were conducted, i.e. both the investigator and the subject knew the true dosing situation. In addition, for humanitarian reasons, the study did not have a placebo-controlled trial.
In the face of doubts, Yiling Pharmaceutical said that the follow-up Lianhua Qingpeng would conduct a double-blind, prospective randomized controlled trial to fully evaluate the efficacy of Lianhua Qingxiao capsules in a larger patient population.
Treatment of the new crown,
What other clinical trials have been done in Lianhua Qingpi?
An unnamed former director of pharmacy told the "medical community", and do not discuss whether Chinese medicine needs to use the "Western medicine system" for efficacy demonstration, traditional Chinese medicine is usually dialectical individualized medicine, pay attention to "looking and asking", and the current Lianhua Qingpeng recommended treatment of the new crown is closer to the "Western medicine" drug use, so it has to be proved according to the theoretical system of modern medicine.
Since the outbreak of the new crown epidemic, a total of 11 trials related to the prevention and treatment of new crown have been registered in China, of which 5 were registered after February 11, 2022 and 6 were registered between February 1, 2020 and April 20, 2021, but 2 of the latter are still in the state of material supplementation.
The four studies registered between 1 February 2020 and 20 April 2021 (see table below), including the two mentioned above published in the Journal of Evidence-Based Complementary and Alternative Medicine and Botanical Medicine, have a common feature: the study size is small and none of them use randomized double-blind controlled studies.
It is worth noting that In ling pharmaceuticals responded last night, it was mentioned that even the international multi-center clinical research of Huaqing plague has been carried out in many countries. The "medical community" did check the relevant information on the website of the "China Clinical Trial Registration Center", the registration time is February 11, 2022, and the collection of research subjects is currently shown to be "not yet started".
According to the registration information, the study involved 5 countries in China, Cambodia, Thailand, Vietnam and Singapore, and plans to recruit 860 subjects. According to a recent report by the Singapore media, the Singapore Science and Health Authority confirmed:
The trial in Singapore, initiated by Chung Hwa Hospital, assessed whether Lianhua Qingpeng Capsules could provide adjuvant therapy for home-based adults recovering from vaccination and mild symptoms on the basis of existing Western medicines, and to see if it could help the antigen test results to turn from yang to yin faster. It is currently in the recruitment phase with the expectation of reaching 300 people.
That is to say, the current clinical trials on the "Lianhua Qing Plague" are indeed advancing, but they are in the early stages and there are no definite results.
Searched on the US ClinicalTrials.gov platform with keywords, there were only two trial records related to Lianhua Qingpest after the new crown epidemic, one of which was cooperated by the Singapore Ministry of Health, but it was withdrawn in August 2020 because it was impossible to find a suitable research center principal investigator.
The other was released on February 4, 2022, but it is only a Phase I human pharmacokinetics, safety and tolerability study of Lianhua Qingpeng capsules, which is in the recruitment stage.
How far is "feasible in principle" and "clear in efficacy"?
It is not difficult to see from the above that the clinical evidence for the effectiveness of Lianhua Qing plague is not sufficient, so how can we get the conclusion that the drug can effectively treat the new crown and publicize it? According to the previous response of Yiling Pharmaceutical, 35 experimental and clinical research papers related to Lianhua Qing plague have been published (15 published abroad).
The "medical community" once again searched the database Web of Science with "lianhuaqingwen" as the keyword, excluded meta-analysis and review, and obtained 13 research papers with a high correlation with the treatment of new crown, 6 related to the clinical treatment effect, and the other 7 were mechanistic studies.
Among the 13 articles, most of the journals with relatively high impact factors show the mechanism of action of Lianhua Qing plague antiviral and anti-inflammatory. Purely from the institutional level, it can fight the new crown virus is not without evidence.
The highest impact factor is the Top journal Officia Pharmaceutica Sinica B (impact factor 11.61) of the Chinese Academy of Sciences, a paper published in 2021 suggests through the molecular docking model that the active ingredients metabolized in lianhua qing plague can block the binding of the new coronavirus spike protein and human ACE2 receptor to varying degrees, which provides a theoretical basis for lianhua qing plague to prevent new crown.
A paper published in february 2021 in the Comprehensive Medical Journal of Medical Sciences (impact factor 3.7) showed that the targets of the active ingredients in Lianhuaqing plague are highly enriched in immune response-related and inflammation-related pathways. In addition, four key ingredients: quercetin, luteolin, hancalian and kaempferol and the new crown virus 3CL protease, which are also targets of the new crown drug Paxlovid, show high affinity.
Other test results include:
Rhubarb inhibits the over-release of inflammatory mediators, thereby improving lung damage;
Patchouli improves diarrhea and improves host defenses in the gastrointestinal tract;
Rhodiola rosea can improve lung damage by inhibiting oxidative stress and apoptosis, eliminating inflammation in the lungs.....
However, a researcher in the medicinal chemistry laboratory of a third-class hospital in Jiangsu Province told the "medical community" that these mechanism studies have always been the focus of research on the active ingredients of traditional Chinese medicine, which are valuable but belong to basic work, and there is still a long way to go from the real evaluation of clinical efficacy.
"Taking anti-tumor 'Western medicine' as an example, the active compounds in the laboratory have been proved to work mechanically, and there are not a few molecular docking models, cell experiments and animal experiments that show good results at the same time, but in the end, they can pass the clinical trial layer by layer, and it is rare to be listed and used in patients."
In fact, in the face of the constantly mutating new crown virus, even targeted research and development of vaccines have successively experienced a sharp decline in infection protection, many therapeutic drugs have also been folded, "in principle may work" lianhua qing plague, the mechanism of the relevant data is not better than the "Western medicine" of the fold, how effective it is to be seen.
In terms of real-world studies, the quality of published targeted trials is generally not high, and most of them are retrospective or case studies. Even in 2015, it entered the US FDA's Phase II clinical trial, and for 391 cases of influenza enrollment, the latest progress only came from the response of Yiling Pharmaceutical on the investor platform at the end of 2020:
The US FDA Phase II clinical trial study of Lianhua Qing plague capsules is currently in the stage of statistical analysis.
A Chinese-American scholar who has been responsible for the establishment, evaluation, and management of scientific projects at the National Institutes of Health (NIH), based on his experience in participating in/chairing hundreds of preclinical and clinical Phase I.-IV. projects, told the "medical community":
In the United States, if a drug is to be recognized, it must at least do phase I to III clinical trials. At present, the clinical trial of Lianhua Qing plague treatment of new crown is stuck in phase I, only in the pharmacokinetic, safety and tolerability exploration stage; even the clinical trial for the treatment of influenza is only in phase II, which means that it is still in the conceptual demonstration stage of efficacy and safety, and the sample size is small.
"From the perspective of empirical medicine, Lianhua Qing plague may have an effect on the treatment of new crown, but in order to be a globally recognized treatment of new crown drugs, it is also necessary to carry out global multi-center clinical trials with sufficiently large sample size and scientific design."
Based on the existing research, Lianhua Qingpeng still has a long way to go to complete the "self-evident efficacy" of new crown pneumonia.
bibliography:
[1] Efficacy and safety of Lianhuaqingwen capsules,a repurposed Chinese herb,in patients with coronavirus disease 2019:A multicenter,prospective,randomized controlled trial，https://www.sciencedirect.com/science/article/pii/S0944711320300738
[2] A meta-analysis for LianhuaQingwen on the treatment of Coronavirus disease 2019(COVID-19)，https://www.sciencedirect.com/science/article/pii/S0965229921000959
[3] Efficacy and Safety of Lianhuaqingwen Capsules for the Prevention of Coronavirus Disease 2019:A Prospective Open-Label Controlled Trial，https://www.hindawi.com/journals/ecam/2021/7962630/
[4] Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening，https://www.sciencedirect.com/science/article/pii/S2211383520307358
5:A network pharmacology based approach for predicting active ingredients and potential mechanism of Lianhuaqingwen capsule in treating COVID-19，https://www.medsci.org/v18p1866.htm
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