Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.
СтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Liu Jun, Li Dan-Dan, Dong Wei, Liu Yu-Qi, Wu Yang, Tang Da-Xuan, Zhang Fu-Chun, Qiu Meng, Hua Qi, He Jing-Yu, Li Jun, Du Bai, Du Ting-Hai, Niu Lin-Lin, Jiang Xue-Jun, Cui Bo, Chen Jiang-Bin, Wang Yang-Gan, Wang Hai-Rong, Yu Qin, He Jing, Mao Yi-Lin, Bin Xiao-Fang, Deng Yue, Tian Yu-Dan, Han Qing-Hua, Liu Da-Jin, Duan Li-Qin, Zhao Ming-Jun, Zhang Cui-Ying, Dai Hai-Ying, Li Ze-Hua, Xiao Ying, Hu You-Zhi, Huang Xiao-Yu, Xing Kun, Jiang Xin, Liu Chao-Feng, An Jing, Li Feng-Chun, Tao Tao, Jiang Jin-Fa, Yang Ying, Dong Yao-Rong, Zhang Lei, Fu Guang, Li Ying, Huang Shu-Wei, Dou Li-Ping, Sun Lan-Jun, Zhao Ying-Qiang, Li Jie, Xia Yun, Liu Jun, Liu Fan, He Wen-Jin, Li Ying, Tan Jian-Cong, Lin Yang, Zhou Ya-Bin, Yang Jian-Fei, Ma Guo-Qing, Chen Hui-Jun, Liu He-Ping, Liu Zong-Wu, Liu Jian-Xiong, Luo Xiao-Jia, Bin Xiao-Hong, Yu Ya-Nan, Dang Hai-Xia, Li Bing, Teng Fei, Qiao Wang-Min, Zhu Xiao-Long, Chen Bing-Wei, Chen Qi-Guang, Shen Chun-Ti, Wang Yong-Yan, Chen Yun-Dai, Wang Zhong
Аннотация
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 (r2: 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).