Jian Liu

Background: Uncoupling of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) axis and impaired cGMP synthesis are hallmarks of chronic kidney disease (CKD). While sGC has been a target of therapeutic interest for CKD, clinical progress has been limited. Methods: In this single center, phase 1 study (NCT07021157), the pharmacokinetics (PK), pharmacodynamics (PD), and safety of SK-08, a novel, oral sGC activator, were evaluated. Healthy participants were randomized to SK-08 or placebo in the single-ascending-dose phase; in the food-effect phase, SK-08 10 mg was administered under fasted and fed conditions. cGMP was the key PD biomarker, and exposure-response analyses were performed. Results: Between 18th March 2025–17th June 2025, 16 participants were randomized and received SK-08 5 mg ( n = 3), 7.5 mg ( n = 3), or 10 mg ( n = 6), or placebo ( n = 4). Adverse events (AEs) were mild/moderate and resolved spontaneously, those with an incidence > 10% were hypotension (4/12, 33.3%) and dizziness (2/12, 16.7%). A higher C _max was associated with an increased incidence of adverse drug reactions (ADRs) across all SK-08 doses. Under fasted conditions, the absorption and time to peak plasma concentration of SK-08 was fairly rapid (median T _max 2.5–5.0 h). Administration after a high-fat meal prolonged the median T _max by 0.7 h; C _max and AUC were decreased by ~ 10%. Mean cGMP maximum percentage change (E _max ) increased dose dependently, from 5.99% at 5 mg to 27.19% at 10 mg, with a median time to E _{max of} 2.75–6.00 h. Conclusions: SK-08 was well tolerated in healthy participants and induced dose-related sGC activation. A potential association between C _max levels and the incidence of ADRs, and no clinically meaningful impact of food, was observed. These findings guide the optimization of a controlled-release formulation to maximize the therapeutic potential of SK-08. Trial registration: Chinadrugtrials.org.cn (CTR20250337). Registered 20,250,126 Clinicaltrials.gov (NCT07021157). Registered 20,250,512.

Depression is highly comorbid with gastrointestinal dysfunction, yet antidepressant therapies are limited by suboptimal efficacy and frequent gastrointestinal adverse effects. Previous studies showed that total glycosides (TG) from the stems of Cistanche tubulosa could alleviate depression-like behaviors. However, the pharmacodynamics and mechanisms of TG against depression with gastrointestinal dysfunction symptoms remain unclear to date. Employing a restraint stress mouse model coupled with a multi-modal experimental approach, we demonstrated that TG administration significantly ameliorated stress-induced depressive-like behaviors. Concurrently, TG improved multi-segment gastrointestinal dysmotility, evidenced by shortened total gut transit time, restored colonic propulsion, and enhanced gastric emptying and intestinal transit rates. Meanwhile, TG preserved intestinal barrier integrity by mitigating epithelial damage and restoring tight junction proteins and MUC2 expression, while reducing pro-inflammatory cytokines in intestine, serum and central nervous system. Metabolomic analysis further identified arachidonic acid metabolism as the key altered pathway. Specifically, TG decreased the cecal levels of arachidonic acid and 20-hydroxy-leukotriene B4, and increased the level of dinoprost that were associated with ferroptosis. Correspondingly, TG were found to suppress intestinal oxidative stress, lipid peroxidation and Fe²⁺ accumulation, reverse chronic stress-induced ACSL4 upregulation and GPX4 downregulation, and its major constituents (e.g., echinacoside) showed strong binding affinity with ACSL4, which indicated that TG could suppress the intestinal ACSL4-mediated ferroptosis through regulating arachidonic acid metabolism. These findings position glycosides from C. tubulosa as a promising natural management for comorbid depression and gastrointestinal dysfunction via a novel gut-targeted mechanism.

Background: ASC10, an oral double prodrug of the antiviral ribonucleoside analog ASC10-A (also referred to as NHC), is currently in clinical trials for the treatment of COVID-19. Upon administration, ASC10 undergoes rapid biotransformation into the monoprodrug molnupiravir, which then swiftly converts to the active metabolite ASC10-A. Alternatively, ASC10 can directly transform into ASC10-A without forming molnupiravir as an intermediate. This study aimed to describe the population pharmacokinetics (popPK) of ASC10-A in healthy Chinese subjects and to inform clinical drug development. Methods: We performed popPK modeling for ASC10-A using data from a Phase I clinical trial involving 57 healthy subjects and 1634 observations. The M3 method was employed to handle data below the quantification limit (BQL), while the Laplacian algorithm was implemented for popPK modeling. The final model was evaluated through goodness-of-fit (GOF) plots, non-parametric bootstrap method, and visual predictive check (VPC). The model-based simulations were performed to generate concentration-time profiles for ASC-10 or NHC across different studies, evaluate the exposure levels of ASC10-A under an 800 mg twice-daily dosing regimen (consistent with the recommended dose of molnupiravir), and quantify the covariate effects on the pharmacokinetic parameters of ASC10-A. Results: The ASC10-A pharmacokinetics was described using a two-compartment model with first-order elimination and transit compartment absorption. Food intake and body weight were identified as influential variables on ASC10-A pharmacokinetics. The simulation results revealed that the ASC10-A exposure decreased with increasing body weight, and participants fasting could result in a higher peak concentration while retaining a similar exposure to those fed. The ASC10 dosing regimen of 800 mg every 12 hours could provide desirable exposure associated with clinical response. Conclusion: This study provides a comprehensive population pharmacokinetic profile of ASC10-A in healthy Chinese volunteers. These findings support the clinical development and identification of effective regimens for ASC10.

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.

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.

Purpose: Mammalian Target of rapamycin (mTOR) plays a central role in regulating cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly expressed in docetaxel-resistant prostate cells. However, the underlying molecular effects on prostate cells remain unclear. Methods: A docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to investigate the role of mTORC2 in docetaxel resistance. The lentivirus was transfected into cells to knock down the expression of Rictor, and cell viability was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze the cell cycle, and the changes in related signal cascades were assessed by immunohistochemistry (IHC) staining and Western blot. Results: Docetaxel showed the lowest IC₅₀ (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. Decreased Rictor expression resulted in a larger proportion of arrested cells in the G0/G1 phase in PC-3/DTX cells. The IC₅₀ values of the AZD8055 group were lower than in the Rapamycin group when treated with docetaxel again. Furthermore, a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the AZD8055 group compared to the Rapamycin group. The IHC results of the prostate cancer tissues from a CRPC patient revealed the over expression of Rictor only, while Raptor expression was unaffected. Conclusion: We investigated the role of mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify potential methods for clinical treatment. MTORC2 expression is essential for docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, reversing docetaxel resistance, may become a therapeutic option in the treatment of mCRPC patients.

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 HIS, LIS, EMR, and 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 V4.2.5 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.