Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.

Study on time effect of residual pressure and bearing characteristics of jacked pile in saturated silt foundation.

The history of stress in soil mass and pile surface roughness significantly impacts the time effect of residual pressure at the pile end and bearing characteristics of the jacked pile. In this study, the impacts of soil over-consolidation ratio and pile surface roughness on the time effect of residual pressure and bearing characteristics of jacked pile end in saturated silt foundation are explored. Through the independently developed model test device for the vertical bearing characteristics of jacked pile, the driving of jacked pile with different pile surface roughness and static load tests at different resting phases are carried out on saturated silt foundations with different over-consolidation ratios. The model box is cylindrical in shape with a size of 40 cm × 48 cm (inner diameter × height) and is made of transparent tempered glass. The results show that: the increase in surface roughness of jacked pile in saturated silt foundation causes not only the increase in the pile side friction but also the increase in the pile end resistance during the static pressure sinking pile; the change laws on the residual pressure of pile end and limit friction resistance of pile side for jacked pile in saturated silt foundation vary with over-consolidation ratio of soil mass and the pile surface roughness.

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

[Study on oil-soluble components obtained from the fruit of Evoldia rutaecarpa].

OBJECTIVE: To extract and isolate the biologic-active components of the oil-soluble components obtained from the fruit of Evodia rutaecarpa. METHODS: Various chromatographic techniques were used to isolate and purifie the biologic-active components, the IR and NMR spectra were used to identify the structure of this compound from Evodia rutaecarpa, and the content and the chemical structure was calibrated with a standard mixture was by TLC. RESULTS: A crystal compound was isolated from the Evodia rutaecarpa of Rutaceae, and was elucidated as oleanolic acid. CONCLUSION: The main chemical constituents of oil-soluble components obtained from the fruit of Evodia rutaecarpa are terpenoid compounds, the content of oleanolic acid is 1.8%.