Guizhou Bailing Group Pharmaceutical Co., Ltd.

Sabia parviflora (SP, "xiao hua qing feng teng" in Chinese) was recorded as an important ethnic medicine to be used for treating viral hepatitis. The antiviral activity of four SP extracts and potent antiviral compounds evaluated with cathepsin L protease (Cat L PR) and HIV-1 protease (HIV-1 PR). UPLC-HRMS was used for identifying the bioactive components. In addition, the possible inhibitory mechanism of the identified compounds on viral protease was further discussed by molecular docking. As a result, four extracts of SP exhibited inhibitory activity of HIV-1 PR and Cat L PR with IC₅₀ range from 0.015 to 0.80 mg/mL. Meanwhile, six compounds inhibited HIV-1 PR with IC₅₀ range from 0.032 to 0.80 mg/mL. Moreover, procyanidin B2 had good affinity for HIV-1 PR and CatL PR protein, respectively. These findings suggest S. parviflora leaves can be used for treating HIV and procyanidin B2 may play a role in antiviral protease.

With increasing stress in daily life and work, subhealth conditions induced by "Shi-Re Shanghuo" syndrome was gradually universal. "Huanglian Jiedu Wan" (HLJDW) was the first new syndrome Chinese medicine approved for the treatment of "Shi-Re Shanghuo" with promising clinical efficacy. Preliminary small-sample clinical studies have identified some notable biomarkers (succinate, 4-hydroxynonenal, etc.). However, the correlation and underlying mechanism between these biomarkers of HLJDW intervention on "Shi-Re Shanghuo" syndrome remained ambiguous. Therefore, this study was designed as a randomized, double-blind, multicenter, placebo-controlled Phase II clinical trial, employing integrated analysis techniques such as non-targeted and targeted metabolomics, salivary microbiota, proteomics, parallel peaction monitoring, molecular docking and surface plasmon resonance (SPR). The results of the correlation analysis indicated that HLJDW could mediate the balance between inflammation and immunity through succinate produced via host and microbial source to intervene "Shi-Re Shanghuo" syndrome. Further through the HIF1α/MMP9 pathway, succinate regulated downstream arachidonic acid metabolism, particularly the lipid peroxidation product 4-hydroxynonenal. Finally, an animal model of recurrent oral ulcers induced by "Shi-Re Shang Huo" was established and HLJDW was used for intervention, key essential indicators (succinate, glutamine, 4-hydroxynonenal, arachidonic acid metabolism) essential in the potential pathway HIF1α/MMP9 discovered in clinical practice were validated. The results were found to be consistent with our clinical findings. Taken together, succinate was observed as an important signal that triggered immune responses, which might serve as a key regulatory metabolic switch or marker of "Shi-Re Shanghuo" syndrome treated with HLJDW.

Objective To analyze the tolerance and pharmacokinetics of Tefentai Tablets in healthy volunteers.Methods In this study, a randomized, double-blind method was used to study 26 healthy volunteers from Jan. to June2017, all patients were given 300 and 600 mg of Tefentanil, two doses of which were given single or multiple times, once a day for multiple times, 7 days in a row, in which the drug elution cycle was 2 wk.The pharmacokinetic parameters(the highest blood concentration [C_(max)], the lowest blood concentration [Cmin], the average blood concentration[Cavg], the curve area of blood concentration over a period of time [AUC_(0-t)], the infinite curve area of blood concentration[AUC_(0-∞)] and accumulation index) were measured by high performance liquid chromatog. at different time points.Pharmacokinetic parameters, high performance liquid chromatog. characteristics and related adverse reactions were analyzed.Results The peak time(T_(max)) was(1.02±0.13) h, and the half-life(t1/2) was(3.08±0.09) h after taking different doses of Tifentai Tablets for many times in healthy volunteers.The T_(max) of M8 was(3.05 ±0.07) h and t1/2 was(9.56±0.67) h; The T_(max)of M9 was(4.11±0.15) h and T1/2 was(6.17±0.21) h.At the dosage of 300 mg, there were no significant differences in C_(max), Cmin, Cavg, AUC_(0-t), AUC_(0-∞)and accumulation index between multiple and single administration of Tifental(P>0.05).AUC_(0-t)and AUC_(0-∞)in multiple administration of metabolite N-benzoyl-O-(dimethylaminoethyl)-L-tyrosine(M8) and metabolite N-benzoyl-L-tyrosine-o-(N-oxidation-dimethylaminoethyl)-L-tyrosine(M9) were significantly higher than those of single administration(P<0.05).C_(max)of M9 multiple administration was higher than that of single administration, the difference was statistically significant(P<0.05).At the dosage of 600 mg, C_(max) in Tifental of multiple administration was higher than that of single administration, the difference was statistically significant(P<0.05).There were no significant differences in Cmin, Cavg, AUC_(0-t), AUC_(0-∞), accumulation index between multiple and single administration of Tifental(P>0.05).C_(max)and AUC_(0-t)in multiple administration of M8 and M9 were significantly higher than that of single administration, the differences were statistically significant(P<0.05).The AUC_(0-∞)of M9 multiple administration was higher than that of single administration, the difference was statistically significant(P<0.05).At the dose of 600 mg, repeated administration increased C_(max) of Tifental, but had no significant effect on AUC_(0-∞)of its exposure.The C_(max)of metabolites M8 and M9 increased, and the exposure of AUC_(0-∞)increased.After several times of oral administration(doses of 300 and 600 mg) of Tifentai Tablets to healthy volunteers, a case of adverse event with foreign body sensation occurred in one volunteer at the dose of 600 mg, which was determined to be unrelated to the drug, and no volunteer withdrew from the trial due to adverse event.Conclusion Tifentai Tablets 600 mg dose not show obvious accumulation effect and high safety, in order to obtain better antiviral effect, it is suggested that the daily reference dose be 600 mg.