Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.

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).

[Effect of meliae toosendan fructus on nerves system and its mechanism].

OBJECTIVE: To study the effect of the ethanol extract of stir-bake to yellowish Meliae Toosendan Fructus on nerve system and its mechanism. METHODS: The effect of the ethanol extract on sensory nerve was carried out through ache models induced by hot board method and radiant heat stimulation method in mice. The thermalgesia liminal value was investigated. The effect of the ethanol extract on the A-delta fiber and C fiber was measured by electrical stimulation procedure. Motor nerve conduction velocity (NCV) was measured by indirect detection method in vivo. The pathology changes of the motor nerve were observed by transmission electron microscope and the silver stain test. RESULTS: The ethanol extract of Meliae Toosendan Fructus could increase the thermalgesia liminal value of mice and reduce the conduction velocity of motor nerves. Meanwhile, pathology results showed the changes of the fiber of motor nerve, including demyelination and the number of Schwann cells dropping. CONCLUSION: The ethanol extract of stir-bake to yellowish Meliae Toosendan Fructus can reduce the pain sensitivity of mice and slow down NCV, which may be related to decreasing of the number of Schwann cells.

[Compared studies on the effect and toxicity of extractions of Fructus Meliae Toosendan in mice].

OBJECTIVE: To evaluate the effect and acute toxicity of different extraction of Fructus Meliae Toosendan. METHODS: Samples were extracted from Fructus Meliae Toosendan using petroleum ether (I), ethyl acetate (II), 80% alcohol (III) or water (IV). Mices writhing response were induce by ip 0.9% acetic acid and foot ache were induced by sc formaldehyde. Mices feet or ears were smeated by sccarrageenin or dimethylbenzene. And the effects of these samples were evaluated on these models. RESULTS: The sample II 40 g/kg significantly decreased the writhing response induced by acetic acid and relieved mice foot pain induced by formaldehyde, inhibited the swelling of mice ear induced by dimethylbenzene. It markedly decreased the body weight and increased the index of testes in mice. The sample III 20 g/kg inhibited foot swelling induced by carrageenin and ear swelling induced by dimethylbenzene in mice. The sample I significantly relieved the foot pain induced by formaldehyde, increased the indexes of testis and adrenal gland in mice. The sample IV had no action on pain or inflammatory in mice. The LD50 of the sample II was 82.85 g/kg. And ig the sample I 133.2 g/kg, sample III 122.0 g/kg or sample IV 52.0 g/kg could not induce mice to death. CONCLUSION: The sample II has anti-inflammatory and antalgic action. But it also has serious acute toxicity. These results show that the efficacious component of Fructus Meilae Toosendan may exist in the ethyl acetate extraction, The toxicity and efficacious component may be the same material.