Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial
2021
Jun Liu | Dan-Dan Li | Wei Dong | Yu-Qi Liu | Yang Wu | Da-Xuan Tang | Fu-Chun Zhang | Meng Qiu | Qi Hua | Jing-Yu He | Jun Li | Bai Du | Ting-Hai Du | Lin-Lin Niu | Xue-Jun Jiang | Bo Cui | Jiang-Bin Chen | Yang-Gan Wang | Hai-Rong Wang | Qin Yu | Jing He | Yi-Lin Mao | Xiao-Fang Bin | Yue Deng | Yu-Dan Tian | Qing-Hua Han | Da-Jin Liu | Li-Qin Duan | Ming-Jun Zhao | Cui-Ying Zhang | Hai-Ying Dai | Ze-Hua Li | Ying Xiao | You-Zhi Hu | Xiao-Yu Huang | Kun Xing | Xin Jiang | Chao-Feng Liu | Jing An | Feng-Chun Li | Tao Tao | Jin-Fa Jiang | Ying Yang | Yao-Rong Dong | Lei Zhang | Guang Fu | Ying Li | Shu-Wei Huang | Li-Ping Dou | Lan-Jun Sun | Ying-Qiang Zhao | Jie Li | Yun Xia | Jun Liu | Fan Liu | Wen-Jin He | Ying Li | Jian-Cong Tan | Yang Lin | Ya-Bin Zhou | Jian-Fei Yang | Guo-Qing Ma | Hui-Jun Chen | He-Ping Liu | Zong-Wu Liu | Jian-Xiong Liu | Xiao-Jia Luo | Xiao-Hong Bin | Ya-Nan Yu | Hai-Xia Dang | Bing Li | Fei Teng | Wang-Min Qiao | Xiao-Long Zhu | Bing-Wei Chen | Qi-Guang Chen | Chun-Ti Shen | Yong-Yan Wang | Yun-Dai Chen | Zhong Wang
Abstract It’s a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86–19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82–20.82%, P = 0.0001 and 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 vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r 2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).
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