| Objective 1.1 To carry out systematic reviews on the published RCTs of Traditional Chinese Medicine(TCM)for treatment of common cold,and to evaluate the efficacy and safety of TCM for treatment of common cold in a larger scope and more accurately,and provide evidence-based medical evidence for clinical practice and research.1.2 Currently,the systematic review of RCTs for the treatment of common cold by TCM is characterized by small sample size,low methodological quality,and unreasonable design.Most of these RCTs do not reflect the unique prescription system of TCM as a complex intervention in the treatment of common cold.The purpose of this study is to design a reasonable TCM efficacy verification test based on the characteristics of common cold.A randomized,double-blind,placebo-controlled,multi-center clinical trial conducts to evaluate the efficacy and safety of Ganduqing granule in the treatment of common cold.1.3 As a traditional Chinese medicine compound,Ganduqing granule has the characteristics of synergy of multiple ingredients,multiple pathways and multiple targets,and its mechanism of treatment for common colds is still unclear.In this study,network pharmacology was used to explore the potential molecular mechanism of Ganduqing in the treatment of common cold at the molecular level,and provide reference for further animal and cell experiments to verify the mechanism of action.Methods 2.1 Chinese Herbal Medicines for The Treatment of Common Cold: A Systematic Review of Randomized Controlled Trials We searched seven main databases for randomized clinical trials(RCTs)on Chinese herbal medicines(CHMs)for common cold from their inception to December 2019.Two researchers extracted the data independently using a self-developed and standard data extraction form.Disagreements were resolved by discussion and consensus with another team member.The methodological quality of RCTs was assessed using the Cochrane risk of bias tool.Review Manager 5.3 software was used for data synthesis and analysis.Quantitative synthesis would be done if clinical heterogeneity is low.I2 test was used to judge the heterogeneity of meta-analysis.I2 value>50% or more was considered as an indication of substantial heterogeneity.If heterogeneity existed in the pooled studies,the data were analyzed using a random-effect model.Otherwise,a fixedeffect model would be used.The primary outcome measures included the cure rate at 5 days and the time to symptom resolution/resolution rate.The secondary outcome measures included improvement in symptoms of the common cold(symptom effectiveness,TCM syndrome score),temperature recovery,and adverse events.Publication bias was evaluated by the SAS software and Egger linear regression method.2.2 Efficacy and Safety of Ganduqing Granules for Treating the Common Cold with Qi Deficiency Syndrome: A Multicenter,Randomized,Double-blind,Placebo-Controlled Trial This is a multicenter,randomized,double-blind,placebo-controlled clinical trial.This study was conducted on patients with common cold with the syndrome of qi deficiency.The study has been registered in the Chinese clinical trial registry with the registration number Chi CTR-1900026714.In this study,strict inclusion and exclusion criteria were established,and R software was used to generate group random sequences.The 120 eligible participants were divided into groups in a 1:1 ratio,and the random sequence was hidden in an opaque sealed envelope.Both groups received Ganduqing granule and the placebo for 5 days.To evaluate the clinical efficacy and safety of Ganduqing in the treatment of common cold,all symptom disappearance rates,symptom improvement,TCM syndrome score,and adverse events were used as evaluation indexes.2.3 Molecular Mechanism of Ganduqing for Common Cold Based on Network Pharmacology The active components of Ganduqing were screened by Traditional Chinese Medicine Systems Pharmacology Database(TCMSP).Common cold targets were predicted and screened by Genecard database platform;"drug-active ingredient-disease-targets" networks were built by Cytoscape software,and protein interaction networks were built by String database platform.Finally,Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed by using Bioconductor platform and R language.Results 3.1 Chinese Herbal Medicines for The Treatment of Common Cold: A Systematic Review of Randomized Controlled Trials In the part of the systematic review,29 RCTs with 4196 participants were included,including TCM control placebo,TCM control of antiviral drugs,antipyretic,analgesic and anti-inflammatory drugs,antimicrobial drugs or their combination treatment,and TCM control of expectorant and antispasmodic combined with TCM control of expectorant and antispasmodic alone.The overall methodological quality of the included studies was not high,among which 12(41.4%,12/29)studies reported the generation of random sequences,only four(13.8%,4/29)studies reported the random concealment,only four(13.8%,4/29)studies implemented blind method,among which three set up researcher and subject blind method,and one set up subject blind method.Seven studies(24.1%,7/29)reported a loss of follow-up after shedding,and only one of the other six studies carried out the intentional analysis,except one that had no loss of follow-up after shedding.Only one of the included studies(3.4%,1/29)was prospectively registered,and three of the other 28 studies reported different outcomes from those reported in the methods section.The results showed that compared with the placebo group,the high-dose group of Regan Tangjiang significantly increased the disappearance rate of symptoms of fever(RR:0.05,95%CI:[0.00,0.97]),sore throat(RR:0.15,REM,95%CI:[0.04,0.61],I2=54%),aversion wind(RR:0.11,FEM,95%CI:[0.02,0.62],I2=40%)and thirst(RR:0.27,FEM,95%CI:[0.13,0.59],I2=0%)after 5 days of treatment.The high-dose group had better efficacy than the low-dose group.The high dose of Yinqiao Jiedu tablets can shorten the time from the beginning of treatment to the disappearance of overall symptoms(h)(MD:-9,39,95%CI:[-11.83,-6.95]),and the high dose is more obvious.Kanggan can shorten the antipyretic time(h)(MD:-13.84,95%CI:[-23.41,-4.27]),and the effect is faster(h)(MD:-9,96,95%CI:[-17.63,-2.29]).Compared with ribavirin,Gegen decoction granules could shorten the course of the disease(h)(MD:-6.76,95%CI:[-8.91,-4.61])and have a faster effect(h)(MD:-1.20,95%CI:[-1.93,-0.47]).Jiawei Xiaochaihu decoction can significantly reduce the antipyretic time(h)(MD:-91.20,95%CI:[-95.73,-86.67])and the duration of symptoms such as runny nose(h)(MD:-60.96,95%CI:[-65.59,-56.33]),cough(h)(MD:-72.00,95%CI:[-77.52,-66.48])and nasal congestion(h)(MD:-91.92,95%CI:[-96.91,-86.93]).Compared with ribavirin combined with roxithromycin,Jiawei Yinqiao powder can shorten the duration of fever(h)(MD:-8.10,95%CI:[-12.59,-3.61])and have a faster effect(h)(MD:-1.67,95%CI:[-2.61,-0.73]).Compared with aminophenol xanamine granules of children,Ganmao granules of children can reduce the duration of pharyngeal pain(h)(MD:-7.20,95%CI:[-13.85,-0.55])and fever(h)(MD:-12.00,95%CI:[-19.20,-4.80]).Ganmao Qingre granules can reduce the duration of fever(h)(MD:-9.19,FEM,95%CI:[-12.77,-5.61],I2=0%),runny nose(h)(MD:-26.18,REM,95%CI:[-44.02,-8.35],I2=94%)and cough(h)(MD:-47.39,REM,95%CI:[-87.20,-7.59],I2=98%).Compared with ribavirin combined with aminophenol xanamine granules of children,Ganmao granules of children still had advantages in antipyretic time(h)(MD:-8.09,FEM,95%CI:[-12.30,-3.88],I2=0%).18 of the included studies reported safety outcomes,all of which showed no difference between TCM and western medicine(62.1%,18/29).The Egger linear regression method was used to test the publication bias and showed that there was no publication bias(t=0.08,P=0.937 和 t=1.57,P=0.1913).3.2 Efficacy and Safety of Ganduqing Granules for Treating the Common Cold with Qi Deficiency Syndrome: A Multicenter,Randomized,Double-blind,Placebo-Controlled Trial(1)Baseline condition: The baseline comparison of demographic characteristics,disease course,disease degree,syndrome score and syndrome frequency before treatment of the two groups of participants showed no statistical significance(P > 0.05)and was comparable.(2)Symptom remission rate: After 5 days of treatment,the overall symptom remission rate of the experimental group was 95%,and that of the control group was 72.41%.Compared with the two groups,the overall symptom remission rate of the experimental group was significantly better than the control group(P < 0.01).The overall symptom remission rate of common cold after 3 days of treatment was 95% in the experimental group and 62.07% in the control group.The overall symptom remission rate of the experimental group after 3 days of treatment was significantly better than control group(P<0.01).(3)TCM symptom score: After 5 days of treatment,the experimental group showed significant efficacy in improving the scores of main symptoms,secondary symptoms and total symptoms of common cold,which were better than the control group(P<0.01).After 5 days of treatment,Ganduqing group showed better improvement in the primary symptoms than the placebo group(P<0.01、P<0.05).There was no significant difference between the two groups in the improvement of fever,headache and limb pain(P > 0.05).(4)TCM Syndrome Effect: After 5 days of treatment,the total effective rate was 95% in the Ganduqing group and 65.5% in placebo group.The clinical efficacy of Ganduqing group was significantly better than placebo group(P < 0.01).(5)Safety evaluation: In this study,a total of five participants experienced adverse events,including two in the experimental group and three in the control group.The incidence of adverse events was 3.33% in the experimental group and 5.26% in control group(P>0.05).There was no significant difference in the incidence of adverse events between the two groups.(6)Immune function,inflammatory factors and oxidative stress indicators: After 5 days of treatment,CD3+,CD4+,and CD4+/ CD8+ were increased in the experimental group.Compared with the control group,there were statistical differences in the NK cell activation rate,CD3+,and CD4+ immune indexes in experimental group(*P < 0.05).Compared with the control group,the experimental group was only significantly better in inhibiting the change of IL-12 concentration(*P < 0.05),and the changes of TNF-α、IL-6、IL-8 concentrations were not significantly improved(P > 0.05).In experimental group,SOD activity,GSH-PX and CAT content of oxidative stress indexes all increased,while MDA content decreased,which was consistent with the body’s antioxidant process.The experimental group was significantly better in improving SOD activity and CAT than control group(*P < 0.05).3.3 Molecular Mechanism of Ganduqing for Common Cold Based on Network Pharmacology A total of 22 active components of Ganduqing were obtained through screening,among which 16 were active components of the active compounds of Astragalus membranaceus and 6 were active components of radix astragali.Finally,138 common targets of Ganduqing-common cold were obtained,mainly regulating PGR,NOS2,PTGS1,PTGS2,ESR2 and other target genes,and the core targets were related to immunity,inflammation and oxidative stress.147 GO enrichment biological processes and 149 relevant signaling pathways were obtained,involving the age-rage signaling pathway,fluid shear stress and atherosclerosis pathway,interleukin-17 signaling pathway,tumor necrosis factor signaling pathway and so on.Conclusion 4.1 TCM is effective in improving the symptoms and shortening the course of the common cold.Compared with western medicine alone or in combination,TCM has more advantages in improving the symptoms and shortening the course of treatment.Due to the small sample size and low methodological quality of RCTs included in this study,the relevant conclusions still need to be verified by more high-quality,large-sample RCTs.In addition,it is worth noting that most of the clinical trials included in this study fail to reflect the unique TCM formula system in the treatment of common cold.It is hoped that clinicians can design more reasonable TCM efficacy verification tests in the future according to the characteristics of TCM.4.2 With the obvious advantages of improving the symptoms of common cold,shortening the course of illness,and higher safety,Ganduqing is a safe and effective Chinese medicine compound for the treatment of common cold with qi-deficiency syndrome,which is worthy of clinical application.However,there is still a lack of relevant indicators to demonstrate the mechanism of action of Ganduqing in the treatment of common cold,and more clinical and basic research is needed to further explore,as to develop new treatment plans and drugs for the future.4.3 Ganduqing has the function of anti-inflammation,adjusting immunity,anti-virus and anti-oxidation.It exerts the anti-inductive effect of network pharmacology through multi-component,multi-target and multi-pathway.However,since Ganduqing is a Chinese herbal compound,this study still has certain limitations,which need further experimental verification from the cellular and molecular levels,to provide support for clinical and basic research on Ganduqing for the treatment of common cold. |
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