Drug Design, Development and Therapy最新文献

Background: Postoperative sleep disturbance (POSD) is prevalent following breast cancer surgery, impairing postoperative recovery. However, effective interventions and underlying mechanisms remain unclear. This study aims to evaluate whether intravenous subanesthetic esketamine improves postoperative sleep quality and its association with electroencephalogram (EEG) frequency band changes in breast cancer patients.

Methods: In this randomized, double-blind, placebo-controlled trial, patients undergoing breast cancer surgery received either intravenous esketamine (0.2 mg/kg induction, 0.4 mg/kg/h maintenance) or placebo during anesthesia. Both groups received intraoperative EEG monitoring. The primary outcome was POSD incidence at 24 hours assessed by the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included PSQI scores at 72 hours, Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores, Visual Analog Scale (VAS) pain scores, and intraoperative EEG parameters.

Results: POSD incidence was significantly reduced in the esketamine group compared with the control group (27.3% [16/58] vs 51.7% [30/58]; odds ratio, 0.36; 95% CI, 0.16-0.77; P = 0.014). Moreover, the esketamine group demonstrated significantly lower PSQI scores at both 24 hours (median [IQR], 2 [1-5] vs 4 [4-8]; P < 0.001) and 72 hours (1 [0-2.5] vs 3.5 [2.75-5]; P < 0.001). The esketamine group exhibited significantly higher intraoperative gamma-band relative power spectral density (mean [SD], 0.74 [0.25] vs 0.52 [0.18]; P < 0.001), which was independently associated with reduced POSD risk in multivariate analysis (odds ratio, 0.63; 95% CI, 0.40-0.97; P = 0.039).

Conclusion: Subanesthetic esketamine significantly reduced the incidence of POSD and lowered PSQI scores. Importantly, esketamine was associated with enhanced intraoperative gamma-band EEG activity, which was independently associated with reduced POSD risk, suggesting that modulation of specific cortical oscillations may underlie its sleep-enhancing effects.

Trial registration: Chinese Clinical Trial Registry Identifier: ChiCTR2400092257.

Purpose: Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) affects up to 44% of patients and markedly impairs recovery and quality of life. Although regional anesthesia is integral to multimodal analgesia, its preventive effect on CPSP remains limited. Esketamine, a potent N-methyl-D-aspartate receptor antagonist with analgesic and neuroprotective properties, may enhance local anesthetic efficacy and reduce the development of chronic pain.

Patients and methods: In this prospective, randomized, double-blind trial, 367 patients undergoing unilateral TKA under general anesthesia with peripheral nerve blocks were allocated to three groups: CTRL (normal saline), ROP (0.5% ropivacaine), and ESK (0.5% ropivacaine plus esketamine 0.2 mg/kg) for genicular nerve and IPACK blocks. The primary outcome was the incidence of CPSP (Numerical Rating Scale ≥ 4) at 6 months. Secondary outcomes included opioid consumption, NRS pain scores, Timed Up and Go (TUG) test, walking distance, Quality of Recovery-15 (QoR-15) scores, and adverse events.

Results: At 6 months, the incidence of CPSP was significantly lower in the ESK group (4.9%) than in the ROP (17.9%) and CTRL (27.0%) groups. Esketamine significantly reduced overall pain burden (AUC = 559.3 ± 59.0 vs 641.9 ± 55.8 and 679.2 ± 58.5; P < 0.0001). It also lowered 24-hour opioid consumption, with patients in the ESK group requiring less morphine equivalent (26.8 ± 11.5 mg) compared with the ROP (29.7 ± 11.8 mg) and CTRL (34.8 ± 11.9 mg) groups (P < 0.001). Functional recovery improved, with shorter TUG times, longer walking distance, and higher QoR-15 scores. No serious adverse events or psychomimetic reactions were reported.

Conclusion: Esketamine as an adjuvant to ropivacaine in genicular and IPACK blocks significantly reduced CPSP incidence and improved early functional recovery after TKA without increasing adverse effects. Perineural esketamine may represent a safe and effective strategy to prevent pain chronification.

Background: Postoperative delirium (POD) is a common complication in elderly patients. Since ephedrine and phenylephrine have different effects on cerebral perfusion and oxygenation, this randomized controlled trial aimed to compare the impact of these two drugs on the incidence of POD in elderly patients undergoing total hip or knee arthroplasty under general anesthesia.

Patients and methods: A total of 142 elderly patients, aged 65 to 80 years, who underwent elective surgery for total hip or knee arthroplasty were randomly assigned to either the ephedrine group (Group E) or the phenylephrine group (Group P). POD was evaluated using the 3-minute Diagnostic Confusion Assessment Method (3D-CAM). The primary outcome was the incidence of POD within three days after surgery, while secondary outcomes included the subtypes of delirium, intraoperative hemodynamic changes, intraoperative analgesic consumption, and the occurrence of intraoperative and postoperative adverse events.

Results: Delirium occurred in 5 out of 65 cases (7.7%) in Group E and in 15 out of 67 cases (22.4%) in Group P (relative risk [RR], 0.344; 95% confidence interval [CI], 0.132 to 0.891; p = 0.019). Compared to Group P, Group E exhibited a significantly lower incidence of intraoperative bradycardia (RR, 0.241; 95% CI, 0.114 to 0.508; p < 0.001). However, Group E also demonstrated a significantly higher consumption of intraoperative opioids (median difference [MD], 23.0; 95% CI, 2.0 to 25.0 mg; p = 0.020). Notably, despite the higher intraoperative opioid consumption in Group E, there was no statistically significant difference in postoperative pain scores between the two groups (p > 0.05). Additionally, there were no statistically significant differences between the two groups in other indicators, including intraoperative hemodynamic changes and the incidence of postoperative nausea and vomiting (p > 0.05).

Conclusion: In conclusion, among elderly patients undergoing hip or knee arthroplasty, the use of ephedrine to correct intraoperative hypotension was associated with a reduced incidence of POD within three days compared to phenylephrine. However, the absence of cerebral oxygen saturation monitoring and the limited follow-up period of only three days for POD assessment represent significant limitations. These factors should be carefully considered when interpreting our results.

Aim: Tigulixostat is a promising selective xanthine oxidase inhibitor under clinical development for the treatment of hyperuricemia. The aim of this study was to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of tigulixostat, along with its primary active metabolite, GD-MET-1, following single oral administration in healthy Chinese subjects.

Methods: A single center, open-label, dose-escalation study was conducted in healthy Chinese subjects who received single oral doses of tigulixostat ranging from 25 to 300 mg. Serial blood and urine samples were collected for PK and PD analysis. Safety was monitored throughout the study.

Results: Thirty subjects were enrolled, with six subjects per dose group. Tigulixostat exhibited dose-proportional increases in both maximum plasma concentration (C_max) and area under the concentration-time curve from time zero to infinity (AUC_0-inf), with coefficient of variation (CV%) for C_max ranging from 18.1% to 44.9% and for AUC_0-inf from 20.4% to 66.9%. The 24-hour mean serum uric acid decreased by 12.8% to 28.8% from baseline on Day 1, with greater reductions at higher doses. GD-MET-1 exposure increased with dose, with AUC_0-inf representing ~4.2-7.9% of parent exposure. Variability for GD-MET-1 was moderate (C_max CV%: 30.7%-43.5%; AUC_0-inf CV%: 24.8-38.9%). Tigulixostat demonstrated approximately dose-proportional PK, whereas GD-MET-1 showed less consistent proportionality, particularly for C_max. No serious adverse events occurred, and all treatment-emergent adverse events were mild in severity.

Conclusion: These findings demonstrate that tigulixostat exhibits approximately dose-proportional PK, with linear elimination and predictable exposure across the 25-300 mg range. A dose-dependent reduction in serum uric acid was observed up to 200 mg, with a plateau effect at 300 mg. The PK profile of GD-MET-1 indicated lower systemic exposure and less consistent dose proportionality compared with the parent compound, suggesting a supportive rather than dominant role in PD activity. The favorable safety and tolerability profile reinforces tigulixostat's potential as a novel therapeutic agent for the management of hyperuricemia.

Purpose: The West Nile Virus (WNV) remains a global health problem, necessitating the identification of effective antiviral strategies. This study aimed to identify potential druggable targets for WNV and assess the repurposing of three FDA-approved antivirals - remdesivir, rilpivirine, and doravirine - through comprehensive in silico evaluations.

Patients and methods: Through molecular docking, molecular dynamics simulations (MDs), and Molecular Mechanics Generalized Born/Surface Area (MM-GBSA) free energy calculations, we assessed the stability, binding affinity, and thermodynamic profiles of the drug-protein complexes, focusing on the core protein, nonstructural protein NS3 serine protease, and two domains of nonstructural protein NS5: RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase).

Results: Doravirine showed the most favorable and stable interactions across multiple targets. Specifically, it exhibited strong and persistent binding within the C-terminal tunnel and N-terminal hydrophobic pocket of the core protein, as well as at the KDKE motif and SAH-binding site of the NS5 MTase domain. Triplicate MD simulations and residue-level fluctuation analyses further confirm doravirine's stability and consistent interaction patterns in all binding sites, highlighting its potential as a promising candidate for WNV inhibition with multitarget activity.

Conclusion: These findings provide in silico evidence supporting doravirine as a promising multitarget inhibitor of WNV, warranting further investigation for its repurposing for WNV treatment.

The precise structural differentiation of natural mono- and disaccharide isomers is fundamental for understanding carbohydrate bioactivity. However, this task remains challenging due to their minimal structural variances, high polarity, and lack of chromophores. This review traces the evolution of analytical technologies designed to overcome these hurdles. Early derivatization - GC-MS methods provided the foundation for isomer separation. Modern liquid chromatography-mass spectrometry (LC-MS), particularly with advanced chiral columns, now delivers high-resolution isomer profiling. Ion mobility spectrometry (IM-MS) further distinguishes conformers by their collision cross-section (CCS) values. Recent breakthroughs in non-derivatization strategies like UHPLC, coupled with the definitive structural validation offered by 2D-NMR, have revolutionized the field. We critically evaluate these methods' detection limits and throughput for practical applications in food chemistry, clinical glycomics, and pharmaceutical analysis. Looking forward, emerging directions such as AI-assisted spectral interpretation and integrated microfluidic systems promise to propel glycan analysis toward rapid, precise, and intelligent diagnostics. This review provides a practical roadmap for selecting and advancing analytical techniques for real-world isomer characterization.

Objective: This study aims to evaluate the predictive performance of the published population pharmacokinetic (PopPK) model of escitalopram in Chinese patients using an external validation method.

Methods: PubMed, Embase, and Web of Science databases were searched to identify PopPK models. Clinical data collected from Chinese patients treated with escitalopram were used to evaluate these models. The predictive performance of the models was evaluated using both prediction-based diagnostic methods and simulation-based diagnostic methods.

Results: Ten published PopPK models were included in the external validation. A total of 241 serum concentration samples were collected from 193 Chinese patient. Among all evaluated models, the Poweleit 2023 model exhibited the optimal predictive performance, with the PE of -2.14% and the RMSE of 22.27% at the individual level, and corresponding values of 14.13% and 104.19% at the population level, followed the model by Liu 2022. While the predictive performance of the other models was unsatisfactory.

Conclusion: Published PopPK models of escitalopram showed wide variations in predictive performance among our patient cohort. External models should be accurately evaluated before their application in clinical practice.

Knee osteoarthritis (KOA) is a degenerative condition of the joints marked by the gradual deterioration of cartilage, inflammation, and pain, impacting millions globally. Treatment approaches for KOA encompass both surgical and non-surgical methods aimed at alleviating symptoms and enhancing functionality rather than providing a cure. Recent research into the mechanisms of osteoarthritis (OA) has highlighted the significance of the knee joint's microenvironment in the success of drug delivery, particularly with intra-articular therapies. A notable approach involves intra-articular (IA) injections, which allow for the targeted administration of medications directly into the joint area. Nevertheless, traditional treatments often fall short in effectiveness due to the limited bioavailability of drugs within the joint, quick clearance rates, and potential systemic side effects. Consequently, innovative drug delivery systems (DDS) that focus on the knee joint's microenvironment have emerged as a viable method to enhance treatment efficacy and improve patient outcomes. Additionally, drug delivery systems utilizing nanotechnology have shown advantages such as precise targeting, minimized systemic toxicity, and extended therapeutic effects in treating diseases. Gaining insight into these interactions is crucial for developing optimized drug delivery systems that can improve treatment results for individuals with knee disorders. This article examines the latest developments in nanotechnology-based therapies for KOA and explores future directions for enhancing and refining treatment strategies for this condition.

Purpose: Gastric ulcer (GU) is a prevalent digestive system disease, yet effective treatment methods remain limited. D-mannose, a monosaccharide isolated from Bletilla striata polysaccharides, has been demonstrated to exhibit significant antioxidant potential in previous studies. Prior investigations have not addressed the therapeutic implications of this compound in preventing alcohol-induced gastric epithelial disruptions. This scientific inquiry is designed to investigate the gastroprotective attributes and antioxidant activity of D-mannose in mitigating alcohol-related gastric ulceration.

Methods: An ethanol-induced GU mouse model was established using absolute ethanol. The protective effects and antioxidant activity of different doses of D-mannose (40%, 20% w/v) on gastric tissues were evaluated through morphological observation, pathological staining, and biochemical analysis. Complementarily, computational methodologies encompassing network pharmacological analysis and molecular interaction modeling were utilized to anticipate potential therapeutic mechanisms of D-mannose in gastric ulcer management, subsequently validated through comprehensive experimental investigations in biological systems.

Results: D-mannose significantly reduced the ulcer index and pathological scores in gastric tissues, alleviating the damage induced by absolute ethanol. D-mannose markedly increased the activity of antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), while reducing the production of reactive oxygen species (ROS) and malondialdehyde (MDA), thereby enhancing the antioxidant capacity of gastric tissues. Bioinformatics predictions identified HSP90 as the key target for the therapeutic effect of D-mannose on GU. Molecular biology experiments confirmed that D-mannose significantly activated the expression of HSP90 and the downstream Nrf2/HO-1 pathway-related genes and proteins. Similarly, in vitro experiments demonstrated that D-mannose activated key genes and proteins in the HSP90/Nrf2/HO-1 pathway, counteracting oxidative stress damage to gastric epithelial cells induced by absolute ethanol.

Conclusion: D-mannose enhances the antioxidant capacity of gastric tissues by activating key molecules in the HSP90/Nrf2/HO-1 pathway, thereby exerting a protective effect on the stomach.

Background: High-altitude pulmonary edema (HAPE) is a severe and potentially fatal complication without effective and safe measures. 7-hydroxyethyl chrysin (7-HEC) is a derivative of chrysin and exhibits excellent anti-hypoxia activities. The objective of this study was to investigate the protective effect and mechanism of 7-HEC against HAPE.

Methods: The HAPE rat model was established using a hypobaric hypoxic cabin. The lung water content (LWC) and pulmonary microvascular permeability were measured, and the pathological changes of lung tissue were assessed by HE staining. The arterial blood gas indexes and routine blood indexes were measured. The levels of oxidative stress, inflammatory, energy metabolism and endothelial function markers in lung tissue or serum were quantified by commercial kits. qRT-PCR and Western blotting were employed to analyze the expressions of inflammatory and permeability associated genes and proteins. Network pharmacology and molecular docking were performed to reveal the pivotal targets of 7-HEC against HAPE and underlying mechanisms.

Results: 7-HEC treatment reduced the LWC, attenuated pulmonary microvascular hyperpermeability, and improved lung tissue pathology in HAPE rats. Moreover, 7-HEC treatment normalized HAPE-induced changes in arterial blood gas and routine blood parameters. In addition, 7-HEC treatment significantly inhibited oxidative stress and inflammation, suppressed the energy metabolism dysfunction, and maintained the endothelial function. PI3K/AKT signaling pathway was identified as the core pathway for 7-HEC against HAPE by the results of network pharmacology analysis, molecular docking and Western blotting. Furthermore, LY294002, a selective PI3K/AKT inhibitor, significantly attenuated the protective effects of 7-HEC against HAPE.

Conclusion: These findings indicate that 7-HEC may mitigate HAPE by activating the PI3K/AKT signaling pathway and could serve as an effective agent for preventing HAPE.