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 (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).
Highlights
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
We found that 18.2% of patients became free of over 90% similarity among the batches used in this trial) is a polycomponent drug, which contains 5 main compounds including Danshensu sodium, protocatechualdehyde, p-coumaric acid, angina in the DHI group during the first 30 days, with continuous improvement to 34.59% thereafter at Day 90, which was significantly higher than the rosmarinci acid, salvianolic acid B (Supplementary Fig. S2), exacted from two kind of herbal medicine, Danshen and Honghua
No significant differences were found between the two groups regarding the proportion of status with favorable safety patients with normal electrocardiogram (ECG) recordings (Supple-From December 2012 through October 2016, we screened 1327 mentary Table S9), total cholesterol, high-density lipoprotein (HDL)
Summary
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. We found that 18.2% of patients became free of over 90% similarity among the batches used in this trial) is a polycomponent drug, which contains 5 main compounds including Danshensu sodium, protocatechualdehyde, p-coumaric acid, angina (i.e., had a SAQ-AF score of 100) in the DHI group during the first 30 days, with continuous improvement to 34.59% thereafter at Day 90, which was significantly higher than the rosmarinci acid, salvianolic acid B (Supplementary Fig. S2), exacted from two kind of herbal medicine, Danshen and Honghua It is widely used in China due to its safety and efficacy in treating cardiovascular diseases.[13,14] DHI was reported to have multiple pharmacological effects with multiple targets on CAD,[14] including proportion in the control group from Day 30 through Day 90 (P = 0.0219–0.0057) (Fig. 2f and Supplementary Table S5). The main compounds, as Danshensu sodium, and salvianolic acids were reported with polypharmacological effects against platelet aggregation and thrombus formation, promoting fibrin degradation, protecting against myocardial ischemia, and improving the microcirculation.[19,20]
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