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Objective. To identify and quantify the active phenolic components in Lonicerae japonicae flos (LJF) for fever treatment and their mechanism of action using network pharmacology and molecular docking. Methods. Based on qualitative analysis of LJF, 194 phenolics were obtained, including 81 phenolic acids and 113 flavonoids. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to identify potential targets for these components to interact with fever. Molecular docking with microsomal PGE2 synthase-1, EP1, EP2, EP3, and EP4 targets was used to determine antipyretic components. The antipyretic efficacy of the main components was verified by in vivo experiments. Finally, high-performance liquid chromatography-tandem mass spectrometry was used to quantify the main antipyretic components of LJF. Results. Phenolics in LJF may prevent and treat fever by participating in calcium signaling, regulating TRP channels, and cAMP signaling. Luteolin-7-O-glucoside, apigenin-7-O-glucoside, 3,5-O-dicaffeoylquinic acid, luteolin, and other components have a good docking effect with PGE2 synthase-1 and its four subtypes. 3,5-O-dicaffeoylquinic acid, luteolin-7-O-glucoside, and apigenin-7-O-glucoside have good antipyretic effects in a yeast-induced pyrexia model. The content of these antipyretic components varies with the developmental period of LJF. Phenolic acids are the main components that distinguish the different developmental periods of LJF. Conclusion. The potential antipyretic components and molecular mechanisms of phenolics provide a basis for the traditional medicinal effects and future development and utilization of LJF. [ABSTRACT FROM AUTHOR]

Background There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. Methods This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II–IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). Results Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00–18 198.00) from baseline, while LVEF increased by 5.00 (–0.25 to 9.25) from baseline after SV treatment. Conclusions PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF. [ABSTRACT FROM AUTHOR]

SY-007 is an interfering peptide designed to disrupt the cell death signaling of phosphatase and tensin homolog deleted on chromosome ten (PTEN) nuclear translocation during ischemic stroke. Preclinical studies indicated that rats treated with 1.5 mg/kg SY-007 in the middle cerebral artery occlusion (MACO) model had significantly reduced stroke lesion size even when administered 6 h after the stroke onset. The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of ascending doses of SY-007 administered intravenously in healthy Chinese subjects. A total of 78 healthy Chinese subjects were enrolled in the single ascending dose study (1–60 mg) and received a 15-min intravenous infusion SY-007 or placebo. Plasma concentrations of SY-007 were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were determined using non-compartmental and compartment analyses. A model based on target-mediated drug disposition was applied. Model evaluation was performed through visual predictive checks and bootstrap analysis. Across doses of 1–60 mg, SY-007 was well tolerated. All adverse events (AEs) were mild or moderate in intensity, and all resolved without intervention. After infusion, SY-007 plasma concentrations decreased quickly with the mean terminal half-life was shorter than 0.78 h. The area under the concentration-time curve increased with a greater than dose-dependent manner from 1 to 30 mg and resulted in a dose-dependent increased from 30 to 60 mg. The nonlinear phenomenon was well described by a simplified target-mediated drug disposition (TMDD) model. Intravenous dosing of SY-007 appears to be safe up to a dose of 60 mg. Nonlinear pharmacokinetics was observed across the evaluated doses and TMDD might be the primary reason. The effective dose of SY-007 for neuroprotective effect in patients with ischemic stroke is expected to be 10–30 mg and was recommended for the later multiple ascending dose study of SY-007. Clinicaltrials.gov: NCT04111523. [Display omitted] [ABSTRACT FROM AUTHOR]