Effect of food on the pharmacokinetics and safety profiles of a new PARP inhibitor fuzuloparib capsules in healthy volunteers.

PURPOSE: This study assessed effect of food on pharmacokinetics (PK) and safety of fuzuloparib capsules. METHODS: A randomized, open-label, two-cycle, two-sequence, crossover clinical trial was conducted. 20 subjects were randomly assigned to 2 groups at a 1:1 ratio. The first group subjects were orally administered 150 mg fuzuloparib capsules under fasting condition in first dosing cycle. The same dose of fuzuloparib capsules were taken under postprandial state after a 7-day washout period. The second group was reversed. 3 ml whole blood was collected at each blood collection point until 72 h post dose. PK parameters were calculated. Furthermore, safety assessment was performed. RESULTS: The time to maximum concentration (Tmax) was prolonged to 3 h and maximum concentration (Cmax) decreased by 18.6% on high-fat diets. 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for Cmax, area under the concentration-time curve from time zero to time t (AUC0-t), and area under the concentration-time curve extrapolated to infinity (AUC0-∞) after high-fat meal were 71.6-92.6%, 81.7-102.7% and 81.6-102.5%, respectively. All treatment-emergent adverse events (TEAEs) were grade 1; No serious adverse events (SAEs), serious unexpected suspected adverse reaction (SUSAR) or deaths were reported. CONCLUSION: Food decreased the absorption rate and slowed time to peak exposure of fuzuloparib capsules, without impact on absorption extent. Dosing with food was found to be safe for fuzuloparib capsules in this study. CLINICAL TRIAL REGISTRATION: This study was registered with chinadrugtrials.org.cn (identifier: CTR20221498).

LC-MS/MS method for quick detection of vonoprazan fumarate in human plasma: Development, validation and its application to a bioequivalence study.

A liquid chromatography-tandem mass spectrometry method with vonoprazan fumarate-d4 as a stable isotope-labeled internal standard was developed and validated aiming at quantification of vonoprazan fumarate in human plasma for a bioequivalence study. Chromatographic separation was achieved by acetonitrile one-step protein precipitation using a gradient elution of 0.1% formic acid aqueous solution and acetonitrile with a run time of 3.65 min. Detection was carried out on a tandem mass spectrometer in multiple reaction monitoring mode via a positive electrospray ionization interface. The multiple reaction monitoring mode of precursor-product ion transitions for vonoprazan fumarate and vonoprazan fumarate-d4 were m/z 346.0 → 315.1 and 350.0 → 316.0, respectively. The linear range was 0.150-60.000 ng/ml. This method was fully validated with acceptable results in terms of selectivity, carryover, lower limit of quantification, calibration curve, accuracy, precision, dilution effect, matrix effect, stability, recovery and incurred sample reanalysis. A successful application of this method was realized in the bioequivalence study of vonoprazan fumarate tablet (20 mg) among healthy Chinese volunteers.

Age-related pharmacokinetics differences were observed between young and elderly populations of a novel PDE5 inhibitor, youkenafil, and its metabolite M459.

PURPOSE: Youkenafil is a novel oral selective PDE5 inhibitor for treating Erectile Dysfunction. This investigation assessed pharmacokinetics (PK), safety, and tolerability of youkenafil and its main metabolite (M459) after taking 100 mg youkenafil hydrochloride tablets in elderly and young subjects. METHODS: This Phase I, single-center, open-label, parallel-group, single-dose study was conducted on 24 individuals (12 elders and 12 youngsters). Each subject received a single oral 100 mg youkenafil hydrochloride tablets. Blood samples were collected before medication and up to 48 h after medication for PK analysis. Safety and tolerability were also assessed, including treatment-emergent adverse events (TEAEs), laboratory tests, 12-lead ECG, vital sign inspections, color vision examinations, and physical examinations. RESULTS: Plasma concentrations of youkenafil and M459 were quantified. PK parameters were determined by non-compartmental analysis. Median Tmax of elderly and young groups were both 0.733 h. However, Cmax, AUC0-t, and AUC0-∞ of youkenafil were separately 16.8 %, 37.2 %, and 37.5 % higher in elders and t1/2 of youkenafil was 2.1 h longer in elders. More great differences were observed for M459. T1/2 values were 4.05 h longer in elders, with Cmax, AUC0-t and AUC0-∞ 73.7 %, 81.1 %, and 81.4 % higher in elders. Two (8.3 %) elderly subjects reported TEAEs (all grade Ⅰ in severity) and both recovered without any treatment. No serious adverse reactions (SAEs) or serious unexpected suspected adverse reactions (SUSARs) occurred in this study. CONCLUSIONS: This was the first PK research of youkenafil and M459 in elderly men. PK parameters differences between youkenafil and M459 were comparable between elderly and young groups. Moreover, safety and tolerability of youkenafil were favorable in both groups.

Study on Oil and Gas Amphiphilic Surfactants Promoting the Miscibility of CO2 and Crude Oil.

In order to cope with the global climate crisis, carbon capture, utilization, and storage are the key technologies to achieve carbon neutrality, and it is an elegant geological utilization method for the oil and gas industry to improve the recovery rate of crude oil by using CO2. However, in practical applications, the problem of low miscibility of CO2 and crude oil, resulting in low oil displacement efficiency, cannot be avoided. Thus, finding an appropriate method to increase the utilization rate of CO2 is a worth in-depth study. In light of this, this paper carries out the study on improving the CO2 flooding efficiency by using oil and gas amphiphilic surfactants. First of all, according to the molecular structure theory and the solubility experiment of surfactants in CO2, five kinds of surfactants and two kinds of additives with good performance of oil and gas were selected. Then, three experiments were conducted to explore the mechanism of the selected surfactants. The main mechanism of promoting the miscibility of CO2-crude oil is to reduce the interfacial tension of the oil and gas phases, followed by increasing the volume expansion of crude oil and reducing the viscosity of crude oil. Finally, through the slim tube displacement experiment, the oil displacement efficiency effect of adding the compound systems of SPO5/n-pentanol was simulated. The results show that the oil displacement efficiency is significantly higher than that of pure CO2 flooding, and the pressure of miscibility reduces at the same time. The selected reagents have a good effect of promoting miscibility. Therefore, this is an effective method to improve the geological utilization of CO2.

Pore Structure and Movable Fluid Characteristics of Typical Sedimentary Lithofacies in a Tight Conglomerate Reservoir, Mahu Depression, Northwest China.

The pore structure and movable fluid characteristics of tight conglomerate reservoirs are complex, which are greatly different from conventional reservoirs. The depositional mechanism is the fundamental factor controlling the physical properties of conglomerate reservoirs. However, there is a lack of systematic research on the pore structure and movable fluid characteristics of conglomerate reservoirs with typical sedimentary facies. This paper investigates the pore structure and movable fluid characteristics of conglomerate of different sedimentary facies based on various experiments. Casting thin sections, X-ray diffraction, scanning electron microscopy, high-pressure mercury injection, and nuclear magnetic resonance experiments were conducted on 32 conglomerates samples from the Mahu Sag, Junggar Basin, China. The quality classification method of tight conglomerate reservoirs is established. The results show that the conglomerate can be divided into three sedimentary facies; traction flow conglomerate (TFC) and pebbled sandstone (PSS) mainly develop intergranular pores and dissolved pores; and the pore diameter curves are mainly a double peak, single peak, and flat peak. Gravity flow conglomerate (GFC) mainly develops dissolved pores and interstitial micropores, and the pore diameter curve is mainly a single peak. PSS includes pebbled gritty sandstone (P(G)SS) and pebbled fine sandstone (P(F)SS). TFC and P(G)SS are favorable class I reservoirs, while GFC and P(F)SS are nonfavorable class II reservoirs. A new parameter, the ratio of the major axis to the minor axis of the pore outer ellipse (axial ratio), is proposed to quantitatively describe the compaction effect. The average axial ratios of the three lithofacies are 3.04, 3.98, and 8.78, respectively, indicating that the compaction is intensified and the pore structure becomes worse. By analyzing the correlation between pore structure parameters and permeability, it is found that the main controlling factors of permeability of GFC and TFC are sorting and connectivity, respectively, and the main flow radius is the most suitable parameter to describe permeability. A linear spectral decomposition method was used to establish a new quantitative calculation method of movable fluid saturation for different types of pores, and the results show that the movable fluid saturation of intergranular pores is the highest (average: 65.43%), and the movable fluid saturation of TFC and P(G)SS with more intergranular pores is the highest. Movable fluid saturation is inversely proportional to the content of I/S and the compaction rate and positively proportional to the content of quartz and feldspar and the cementation rate. The fluid mobility of water-wet samples is weaker. The research results provide theoretical support for the identification of favorable reservoirs and the cognition of a development mechanism.