【作者】 王芳；

【导师】 罗洋；

【作者基本信息】 天津中医药大学 ， 中医内科学（专业学位）， 2025， 硕士

【摘要】 目的:1.本研究旨在评估扶正解毒祛瘀方治疗气虚血瘀型肺癌癌因性疲乏(Cancer Related Fatigue,CRF)的临床疗效及安全性。2.本研究基于网络药理学方法,初步揭示扶正解毒祛瘀方治疗肺癌CRF的潜在作用机制,旨在为CRF的临床治疗提供新的理论依据和治疗策略。方法:1.本研究选取2022年12月至2024年6月期间于天津中医药大学第二附属医院肿瘤科住院治疗的80例患者作为研究对象,所有入选病例均符合标准。按照随机数字表法将80例研究对象分为两组,每组40例,对照组以对症治疗为主,治疗组配合扶正解毒祛瘀方汤剂口服治疗,观察治疗4周后的临床疗效及安全性。分别记录治疗前后两组患者的疲乏量表(PFS)评分、中医证候积分、卡氏(KPS)评分、QLQ-C30生活质量评分以及生命体征、血常规、心电图及肝肾功能等安全性指标的变化情况。采用SPSS 27.0统计学软件对两组治疗前后的临床数据进行对比分析,运用Graph Pad Prism工具完成数据图表绘制。2.本研究综合运用TCMSP、Uni Prot、Pub Chem,Swiss Target Prediction、Swiss ADME及HERB等多个数据库,系统筛选并补充扶正解毒祛瘀方的药物活性成分及其潜在作用靶点,并借助Cytoscape3.10软件构建药物-成分-靶点相互作用网络图,通过整合OMIM、Genecards和DRUGBANK等数据库资源,全面收集肺癌CRF相关疾病靶点,利用Venny在线工具,对药物作用靶点与疾病相关靶标进行共表达分析,获取两者的交集靶点,采用STRING数据库进行蛋白互作网络分析,构建PPI网络图,运用Metascape数据库对疾病与药物相互作用的核心靶点进行KEGG通路及GO功能层面的富集解析,并将分析结果进行可视化,总结扶正解毒祛瘀方治疗肺癌CRF的关键作用靶点和重要信号通路。结果:1.临床观察此次研究中每组共纳入40例研究对象,对照组有2例和治疗组有1例患者因自身原因未完成全部研究,不再将此3例患者数据纳入研究进行统计学分析,故对照组有38例患者,治疗组有39例患者完成全部研究,结果如下:(1)基线对比:两组患者在性别、年龄、肺癌分期、病理类型及基础疾病方面对比均无显著差异(P>0.05),对治疗前两组患者的PFS评分、中医证候积分、卡氏(KPS)评分、EORTC QLQ-C30生活质量评分、血常规以及肝肾功能等资料进行对比,差异无显著性(P>0.05),可以进行比较。(2)疲乏量表(PFS)评分:研究结果显示,两组患者的PFS评分均呈下降趋势,对照组除身体疲劳维度评分(P>0.05)外,其他维度评分和PFS总分均显著低于治疗前水平(P<0.05),治疗组各个维度的评分和PFS总分均显著低于治疗前水平(P<0.05)。组间比较分析显示,治疗组在PFS评分改善方面效果明显优于对照组(P<0.05)。(3)中医证候积分:对照组治疗前后各项中医证候积分变化无统计学差异(P>0.05),治疗组患者除少气懒言和面色或口唇青紫症状在治疗后未明显改善外(P>0.05),其余证候均明显改善(P<0.05),且治疗组改善肢体倦怠乏力、疼痛、活动后易疲劳以及咳嗽咳痰症状的效果优于对照组(P<0.05),治疗后,两组患者的中医证候总积分均显著下降(P<0.05),且治疗组中医证候总积分下降较对照组明显(P<0.05),治疗组治疗肺癌CRF总有效率较对照组高(69.23%>42.11%),差异具有显著性(P<0.05)。(4)KPS评分:对照组的KPS评分在治疗后虽有一定提高,但未达到统计学显著水平(P>0.05);而治疗组患者的KPS评分提升具有显著性(P<0.05)。组间比较分析显示,治疗组在改善患者体力状况和提升KPS评分方面效果优于对照组(P<0.05)。(5)QLQ-C30生活质量评分:在功能领域,对照组治疗后的躯体评分和情绪评分较治疗前明显升高(P<0.05),治疗组治疗后的躯体评分、情绪评分、认知评分和社会评分较治疗前明显升高(P<0.05),且治疗组提升躯体、认知和社会功能的效果较对照组更优(P<0.05);在主要症状领域,治疗组可显著改善患者的乏力、恶心呕吐和疼痛的症状(P<0.05),而对照组改善恶心呕吐效果不明显(P>0.05),且治疗组改善乏力和疼痛效果优于对照组(P<0.05);在单项症状领域中,两组患者治疗后各单项症状评分较前均下降,但对照组治疗前后的单项症状评分变化无统计学意义(P>0.05),治疗组治疗后气短、食欲减退和便秘的症状评分较治疗前降低(P<0.05),且治疗组改善气短、食欲减退和便秘的效果较对照组更优(P<0.05);治疗后,两组患者的总体生活质量评分均较前提高,其中治疗组的改善达到统计学显著性水平(P<0.05),且其改善效果显著优于对照组(P<0.05)。(6)安全性指标:两组患者治疗前后安全性指标均无明显异常,均未发生不良反应事件。2.网络药理学结果基于网络药理学方法,筛选出槲皮素、β-谷甾醇、叶黄素及羟基苯甲酸等是扶正解毒祛瘀方发挥作用的主要活性成分,这些成分可能通过调控AKT1、EGFR和STAT3等靶点,发挥治疗肺癌CRF的作用,基于Metascape数据库,对筛选出的交集靶点进行了基因功能注释分析,包括基因本体论(GO)功能富集和京都基因与基因组百科全书(KEGG)通路富集研究,得到扶正解毒祛瘀方可能通过参与对氮化合物的反应以及对细胞因子刺激的反应等生物过程,作用于MAPK和JAK-STAT信号通路发挥治疗肺癌CRF的作用。结论:1.扶正解毒祛瘀方联合常规治疗能改善肺癌CRF患者的疲劳状态,改善患者气虚血瘀证候的相关表现,提升患者生活质量,安全性好,效果优于常规对症支持治疗。2.扶正解毒祛瘀方的多种有效成分槲皮素、β-谷甾醇、叶黄素以及羟基苯甲酸等作用于AKT1、EGFR以及STAT3等多个靶点,进而调控MAPK和JAK-STAT等信号通路对肺癌CRF起到治疗作用,阐释了扶正解毒祛瘀方治疗肺癌CRF的作用机制,为临床治疗提供理论支撑以及为进一步研究提供数据依据。更多还原

【Abstract】 Objective:1.The purpose of this trial was to evaluate the clinical efficacy and safety of Fu Zheng detoxification and blood stasis expulsion prescription for the treatment of lung cancer-related fatigue(CRF)with qi deficiency and blood stasis type.2.Based on a network pharmacological approach,this study initially demonstrates the potential mechanism of action of the Fu Zheng detoxification and stasis elimination prescription for the treatment of CRF in lung cancer,with the aim of providing a new theoretical basis and therapeutic strategy for the clinical treatment of CRF.Methods:1.Eighty patients who were hospitalized at the Oncology Department of the Second Affiliated Hospital of Tianjin Traditional Chinese Medicine University between December2022 and June 2024 were chosen for this research,and all included patients matched the criterion.Following the method of randomised number tables,eighty patients were separated into two groups,with forty patients in each group.The patients in the controlled group were mainly managed by symptomatic treatment,and the patients in the treated group were managed by the combination of oral treatment with Fu Zheng detoxification and blood stasis expulsion prescription,and the clinical efficacy and safety of the patients were observed after four weeks of treatment.The Changes of Progression-Free Survival Score,Traditional Chinese Medicine Syndrome Score,Karnofsky Performance Status Score,Quality of Life Questionnaire Core 30 Score and safety indicators such as vital signs,blood count,electrocardiogram and liver and kidney function were recorded before and after treatment in both groups respectively.SPSS 27.0 statistical analysis software was used for comparing and analysing clinical data before and after the treatment of the two groups,and Graph Pad Prism was used to draw the data.2.This study comprehensively used several databases such as TCMSP,Uni Prot,Pub Chem,Swiss Target Prediction,Swiss ADME and HERB.This study comprehensively utilized TCMSP,Uni Prot,Pub Chem,Swiss Target Prediction,Swiss ADME,HERB and other databases to systematically screen and supplement the active ingredients of Fuzheng Detoxification and Expulsion of Blood Stasis Formula and their potential targets,and constructed a drug-ingredient-target interaction network diagram with the help of Cytoscape 3.10 software,and comprehensively collected the CRF-related disease targets of lung cancer by integrating the resources of databases such as OMIM,Genecards,and DRUGBANK,and utilized the Venny Online mapping platform,the intersection analysis of drug targets and disease-related targets was performed to obtain the intersection targets of diseases and drugs,and the STRING database was used to analyze the protein interaction network and construct the PPI network map.Metascape database was further used to perform KEGG pathway and GO function enrichment analysis on the key targets of disease and drug,and the analysis results were visualized to summarize the key action targets and important signaling pathways of Fuzheng detoxification and elimination of stasis formula for the treatment of CRF in lung cancer.Results:1.Clinical observationIn this study,each group had a total of 40 participants.Two patients in the controlled group and one patient in the treated group failed to finish the treatment for their own reasons and the data from these three patients were not included in the study for statistical analysis,so thirty-eight patients in the controlled group and thirty-nine patients in the treated group finished the trial and the findings are as follows:(1)Comparison between baseline conditions:there were no significant differences between the two groups of patients in terms of sex,age,lung cancer stage,pathological type and underlying disease(P>0.05).There were no significant differences between the two groups in the pre-treatment fatigue scale(PFS)score,TCM evidence score,KPS score,EORTC QLQ-C30 quality of life score,blood routine,liver and kidney function(P>0.05).(2)Fatigue scale(PFS)score:The results of the study showed that PFS scores of patients in both groups demonstrated a downward trend,with the scores of all dimensions and total PFS scores in the control group being significantly lower than pre-treatment levels(P<0.05),with the exception of the physical fatigue dimension(P>0.05).The scores of all dimensions and total PFS scores in the treated group were significantly lower than pre-treatment levels(P<0.05).Comparative analysis between two groups showed that the treated group was significantly better than the controlled group in terms of improvement in PFS scores(P<0.05).(3)Traditional Chinese Medicine(TCM)Syndrome Score:In the control group,there was no statistically significant difference between the changes in TCM scores before and after therapy(P>0.05).Patients with rhinorrhea significantly improved all symptoms(P<0.05),except symptoms of low qi and slurred speech and facial or lip bruising,which did not significantly improve after treatment(P>0.05).The arm treatment group was more effective than the control group in improving symptoms of limb fatigue and tiredness,pain,mild fatigue after activities and mucus cough(P<0.05).After the two groups were treated,total Chinese medicine symptom scores decreased significantly(P<0.05),and the treatment group’s reduction in total Chinese medicine symptom scores was more apparent than the control group(P<0.05).The overall efficacy of the treatment group was higher than that of the control group(69.23%>42.11%),and the difference was significant(P<0.05).(4)KPS scores:The findings of the research showed that the KPS indices of patients in the control group were higher after therapy than before therapy and the difference was not statistically significant(P>0.05),while the KPS indices of patients in the treatment group were higher after therapy,and the difference was significant(P<0.05).The KPS indices of the patients in the arm group were higher than those in the control group and the improvement in the physical condition of the patients was better than that of the control group(P<0.05).(5)QLQ-C30 quality of life scores:In the domain of functioning,the somatic score and emotional score of the control group were significantly higher after treatment than before treatment(P<0.05),and the somatic score,emotional score,cognitive score and social score of the treatment group were significantly higher after treatment than before treatment(P<0.05),and the treatment group was more effective than the control group in improving somatic,cognitive and social functioning(P<0.05);in the domain of core symptoms,the treatment group was able to significantly improve patients’symptoms of fatigue,nausea and vomiting and pain(P<0.05),while the control group did not show an improvement in nausea and vomiting(P>0.05),and the treatment group showed a better improvement in fatigue and pain than the control group(P<0.05);in the domain of individual symptoms,the individual symptom scores of the control group and the treatment group decreased after treatment compared to before,and the difference between the control group was not statistically significant(P>0.05).Respiratory failure,appetite loss and constipation symptom scores decreased in the treatment group after treatment compared with before treatment(P<0.05),and the effect of improvement in respiratory failure,appetite loss and constipation in the treatment group was better than control group(P<0.05).After treatment,overall quality of life scores improved for patients in both groups,with a significant improvement in the treatment group(P<0.05)and a greater effect of the treatment group than the control group(P<0.05).(6)Safety data:there were no apparent abnormalities in the patients’safety data before or after treatment.2.Network pharmacology resultsBased on a network pharmacological approach,quercetin,β-citosterol,lutein and hydroxybenzoic acid were screened as the main active ingredients in the mechanism of action of the Fuzheng detoxification and hemostasis elimination formula.These components may play a role in the treatment of CRF in lung cancer by regulating targets such as AKT1,EGFR and STAT3.Using the Metascape database,screened cross-targets were analyzed by GO function enrichment and KEGG pathway enrichment.It discovered that Fuzheng Detoxification and Stasis Elimination Formula may work on the MAPK and JAK-STAT signaling pathways to have a role in the treatment of CRF in lung cancer by participating in biological processes such as response to nitrogen compounds and response to cytokine stimulation.Conclusion:1.The combination of Fu Zheng Detoxification and Expulsion of Blood Stasis Prescription with conventional treatment can improve the fatigue status of CRF patients,improve symptoms and manifestations of qi deficiency and blood stasis,and improve the quality of life of patients,with a good safety profile,which is more effective than the conventional symptomatic supportive treatment.2.Quercetin,β-sitosterol,luteolin,and hydroxybenzoic acid,which are the components of Fuzheng Detoxification and Expulsion of Blood Stasis Formula,can act on multiple targets,including AKT1,EGFR,and STAT3,and thus regulate MAPK and JAK-STAT signaling pathways,and regulate the function of MAPK and JAK-STAT.The mechanism of CRF treatment by Fuzheng formula is explained,which provides theoretical support for clinical treatment and data basis for further research.更多还原