It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in thedfferentiated populations with complex diseases,as stable coronary heart disease...It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in thedfferentiated populations with complex diseases,as stable coronary heart disease.Here,in an adaptive,31-center,randomized,double-blind trial invoving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI),a kind of polyphamacological drug with high quality control,or placebo(0.9%saline),with 76-day following-up,we firstly confrmed that DHl couldincrease the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire(ASAQ-AF220)(12.78%at Day 30,95%confidence interval[C]5.86-19.71%,P=0.0003,13.82%at Day 6C0,95%CI 6.82-20.82%,P=0.0001and 8.95%at Day 90,95%CI 2.06-15.85%,P=0.01).We also found that there were no significant differences in new-onset major vascularevents(P=0.8502)and serious adverse events(P=0.9105)between DHl and placebo.After performing the RNA sequencing in 62 selectedpatients,we developed a systemic modular approach tp identfy differentilly expressed modules(DEMs)of DHI with the Z_(summay)valueless than 0 compared with the control group,calculated by weighted gene co-expression network analysis(WGCNA),and sketched out thebasic framework on a modular map with 25 functional modules targeted by DII.Furthermore,the effective therapeutic module(ETM),defined as the highest corelation value with the phenotype alteration(SAQ-AF,the change in SAQ-AF at Day 30 from baseline)calculatedby WGCNA,was identifed in the population with the best effect(ASAQ-AF240),which is related to anticoagulation and regulation ofcholesterol metabolism.We assessed the modular flexbility of this ETM using the global topological D value based on Euclidean distance,which is corelated with phenotype alteration(r^(2):0.8204,P=0.019)by linear regression.Our study identified the ant-angina therapeuticmodule in the effective population treated by the multi-target drug.Modular methods facilitate the discovery of network pharmacologicalmechanisms and the advancement of precision medicine.(ClinicalTrials.gov identifier:NCTO1681316).展开更多
基金funded by China National Science and Technology Major Project for"Significant New Drugs Development"(2011ZX09304-07)National Natural Science Foundation of China(81673833)China Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ0908029).
文摘It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in thedfferentiated populations with complex diseases,as stable coronary heart disease.Here,in an adaptive,31-center,randomized,double-blind trial invoving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI),a kind of polyphamacological drug with high quality control,or placebo(0.9%saline),with 76-day following-up,we firstly confrmed that DHl couldincrease the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire(ASAQ-AF220)(12.78%at Day 30,95%confidence interval[C]5.86-19.71%,P=0.0003,13.82%at Day 6C0,95%CI 6.82-20.82%,P=0.0001and 8.95%at Day 90,95%CI 2.06-15.85%,P=0.01).We also found that there were no significant differences in new-onset major vascularevents(P=0.8502)and serious adverse events(P=0.9105)between DHl and placebo.After performing the RNA sequencing in 62 selectedpatients,we developed a systemic modular approach tp identfy differentilly expressed modules(DEMs)of DHI with the Z_(summay)valueless than 0 compared with the control group,calculated by weighted gene co-expression network analysis(WGCNA),and sketched out thebasic framework on a modular map with 25 functional modules targeted by DII.Furthermore,the effective therapeutic module(ETM),defined as the highest corelation value with the phenotype alteration(SAQ-AF,the change in SAQ-AF at Day 30 from baseline)calculatedby WGCNA,was identifed in the population with the best effect(ASAQ-AF240),which is related to anticoagulation and regulation ofcholesterol metabolism.We assessed the modular flexbility of this ETM using the global topological D value based on Euclidean distance,which is corelated with phenotype alteration(r^(2):0.8204,P=0.019)by linear regression.Our study identified the ant-angina therapeuticmodule in the effective population treated by the multi-target drug.Modular methods facilitate the discovery of network pharmacologicalmechanisms and the advancement of precision medicine.(ClinicalTrials.gov identifier:NCTO1681316).
