The aim of the present study was to establish a novel docetaxel‑resistant prostate cancer cell line and investigate its biological characteristics. The human prostate cell line, PC‑3, was exposed to docetaxel, the concentrations of which were increased in a stepwise manner in the medium to select the drug‑resistant cell line, PC‑3/DTX. The morphological features were observed using inverted microscopy. The growth curves of PC‑3 and PC‑3/DTX cells were drawn to calculate the doubling time. Flow cytometry was performed to determine cell‑cycle distribution. A 3‑(4,5‑dimethyl‑2‑thiazol)-2,5‑diphenyl‑2H tetrazolium bromide assay was performed to test the drug resistance of PC‑3 and PC‑3/DTX cells. Western blot analysis was conducted to determine the protein expression levels of the mammalian target of rapamycin (mTOR) signaling pathway, which may serve a role in regulating drug resistance in the two cell lines. PC‑3/DTX cells exhibited changes in morphology, proliferation rate, doubling time and cell‑cycle distributions, compared with PC‑3 cells. PC‑3/DTX cells were 10.9‑fold resistant to docetaxel in comparison with PC‑3 cells. The results showed that PC‑3/DTX cells overexpressed Rictor and p‑AKT(S473) proteins, which are specific subunits or downstream substrates of mTORC2. The new findings suggested that the mTORC2 signaling pathway may serve an important role in the regulation of docetaxel drug resistance of PC‑3 cells. In conclusion, PC‑3/DTX cells may be applied to study the resistance of anticancer drugs and to identify methods to overcome resistance.

Background: The process of initiating and completing clinical drug trials in hospital settings is highly complex, with numerous institutional, technical, and record-keeping barriers. In this study, we independently developed an integrated clinical trial management system (CTMS) designed to comprehensively optimize the process management of clinical trials. The CTMS includes system development methods, efficient integration with external business systems, terminology, and standardization protocols, as well as data security and privacy protection. Methods: The development process proceeded through four stages, including demand analysis and problem collection, system design, system development and testing, system trial operation, and training the whole hospital to operate the system. The integrated CTMS comprises three modules: project approval and review management, clinical trial operations management, and background management modules. These are divided into seven subsystems and 59 internal processes, realizing all the functions necessary to comprehensively perform the process management of clinical trials. Efficient data integration is realized through extract-transform-load, message queue, and remote procedure call services with external systems such as the hospital information system (HIS), laboratory information system (LIS), electronic medical record (EMR), and clinical data repository (CDR). Data security is ensured by adopting corresponding policies for data storage and data access. Privacy protection complies with laws and regulations and de-identifies sensitive patient information. Results: The integrated CTMS was successfully developed in September 2015 and updated to version 4.2.5 in March 2021. During this period, 1388 study projects were accepted, 43,051 electronic data stored, and 12,144 subjects recruited in the First Affiliated Hospital, Zhejiang University School of Medicine. Conclusion: The developed integrated CTMS realizes the data management of the entire clinical trials process, providing basic conditions for the efficient, high-quality, and standardized operation of clinical trials.

Considering the rise of new SARS-CoV-2 variants that have reduced the efficacy of COVID-19 vaccines, the development of new antiviral medications for the disease has become increasingly necessary. In this study, ASC10, a novel antiviral prodrug, was studied in a phase 1 trial in healthy Chinese participants. Part 1 involved 60 participants, receiving 50-800 mg ASC10 or placebo twice daily for 5.5 days. Part 2, with 12 participants, explored ASC10 dosing in the fed/fasting states. ASC10-A, the main pharmacologically active metabolite, rapidly appeared in plasma (T_max: 1.00-2.00 h) and decreased (t_1/2: 1.10-3.04 h) without accumulation. The C_max and area under the plasma concentration - time curve (AUC) of ASC10-A increased dose-dependently (50-800 mg BID) over 5.5 days, with no accumulation. The T_max was slightly delayed in the fed state; however, the C_max and AUC were similar between the fed and fasting states. Adverse events (AEs) were comparable (ASC10/placebo, 66.7%) and mostly mild (95%). ASC10 was demonstrated to be safe and well-tolerated and exhibited dose-proportional exposure and minimal food effects. www.clinicaltrials.gov identifier is NCT05523141.

Purpose: Tenofovir amibufenamide (TMF) is a novel nucleotide reverse transcriptase inhibitor. The aim of this study was to investigate the effect of food on the single-dose pharmacokinetic properties of TMF. Patients and Methods: In this open-label, randomized, crossover study, after an overnight fast, eligible subjects received a single 25 mg dose of TMF tablet, either under fasted conditions or following consumption of a high-fat, high-calorie meal, followed by a two-week washout period. Blood samples were collected until 144 h after administration. TMF and its metabolite, tenofovir (TFV), were analyzed using validated liquid chromatography-tandem mass spectrometry methods. The geometric mean ratio (GMR) and the corresponding 90% confidence interval (CI) values of AUC_0–t, AUC_0–∞, and C_max were acquired for analysis. The absence of an effect of food was indicated if the 90% CI values were within the predefined equivalence limits of 80%– 125%. Safety and tolerability were also assessed. Results: For TMF, adjusted GMR (90% CI) values for the fed versus fasted states were 150.28% (125.36%– 180.16%), 158.24% (130.42%– 192.00%), and 57.65% (45.68%– 72.76%) for AUC_0–t, AUC_0–∞, and C_max, respectively. For TFV, the GMR (90% CI) of C_max was 82.00% (74.30%– 90.49%) after administration under fed conditions, slightly outside the bioequivalence boundary of 80%– 125%, while the corresponding values for AUC_0–t and AUC_0–∞ were within range. The absorption of TMF was delayed by food, with median T_max values of 0.33 and 1.00 h in fasted and fed conditions, respectively. The adverse events observed in subjects were all mild. Conclusion: Our results demonstrated that TMF tablets were well-tolerated in healthy volunteers. When TMF tablets were taken with food, T_max was delayed and exposures of TMF and TFV were higher than under fasted conditions. The modest changes observed are not considered clinically relevant, so TMF can be taken with or without food. Plain Language Summary: Tenofovir amibufenamide (TMF) is the first innovative, oral anti-hepatitis B drug to be developed in China. To better understand the effect of food on TMF bioavailability, 25 mg of TMF was given with or without food randomly to twenty healthy volunteers. Plasma samples were collected up to 144 h after dosing to measure the concentrations of TMF and its metabolite, tenofovir (TFV). The rate of drug absorption was measured by determining the maximum plasma concentration of drug (C_max) and the time to C_max (T_max). The amount of drug absorbed was measured using the area under the plasma concentration-time curve (AUC). When subjects were fed, the AUC values for TMF and TFV were higher than when they fasted. The C_max values for TMF and TFV under fed conditions were lower compared with fasted conditions. The T_max of TMF was delayed when subjects were fed compared with fasted. The modest changes observed are not considered clinically relevant. The adverse events (AEs) occurring in volunteers were all mild. Our findings suggested that TMF can be taken with or without food.

Purpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug. Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC_0-t, AUC_0-∞), the peak plasma concentration (C_max), the time to achieve C_max (T_max), and the elimination half-life (t_1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs). Results: The values of t_1/2 and T_max for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of C_max, AUC_0–t, and AUC_0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events. Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.