Drug Design, Development and Therapy最新文献

Purpose: Canagliflozin (Ca), a sodium-glucose cotransporter 2 (SGLT2) inhibitor traditionally used for type 2 diabetes, has shown potential in the treatment of lymphangiomatosis (the pulmonary lesion phenotype of TSC). However, its effects on Tsc2 ^-/- cells, a key feature of tuberous sclerosis complex (TSC), have not been previously explored. This preclinical study aimed to investigate Ca's inhibitory mechanisms on Tsc2 ^-/- cell proliferation and its therapeutic potential in TSC-related lesions.

Methods: The effects of Ca on Tsc2 ^-/- cells were evaluated using in vitro cellular assays, including proliferation, cell cycle, and mitochondrial function analyses, as well as proteomics. In vivo, a mouse xenograft model was employed to assess tumor growth inhibition and safety profile. Comparative studies with other SGLT2 inhibitors were conducted to identify compound-specific mechanisms.

Results: Ca significantly inhibited Tsc2 ^-/- cell proliferation in a dose-dependent manner, inducing G1 phase cell cycle arrest and impairing mitochondrial function, as evidenced by reduced membrane potential and ATP production. Proteomic analysis revealed mitochondrial protein alterations, and Ca-induced ROS accumulation promoted apoptosis. In vivo, Ca (100 mg/kg/day) effectively suppressed tumor growth without significant adverse effects. Notably, Ca's effects were unique compared to other SGLT2 inhibitors, indicating mechanisms independent of SGLT2 inhibition.

Conclusion: Ca inhibits Tsc2 ^-/- cell proliferation through dual mechanisms of cell cycle arrest and mitochondrial impairment, demonstrating significant therapeutic potential for TSC-related lesions. These findings highlight Ca as a promising alternative to current mTOR inhibitors, warranting further investigation into its molecular targets and clinical applications.

Background: Fiberoptic bronchoscopy (FB) under sedation can provoke patient discomfort, cough, and hemodynamic fluctuations. This study evaluated the efficacy and safety of dexmedetomidine nasal spray as a premedication compared to intranasal normal saline and lidocaine.

Methods: A total of 90 patients scheduled for FB under sedation were randomly assigned to three groups. Group D (dexmedetomidine), Group C (control, normal saline), and Group L (lidocaine) received pre-induction nasal sprays via the same metered-dose aerosolization device. At 10 min post-spray, all patients received standard monitored anesthesia care (MAC) with preserved spontaneous ventilation (respiratory rate, RR ≥10 breaths/min; peripheral oxygen saturation, SpO₂ ≥95%). Outcomes included hemodynamic parameters (heart rate, HR; mean arterial pressure, MAP) measured at specific time points (T₁-T₈), Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores, cough severity and adverse events.

Results: Group D demonstrated better overall performance. Hemodynamically, HR in Group D was lower than Group C at T₃ and T₅, and lower than Group L at T₅. MAP in Group D was lower than both control groups from T₃-T₆. Recovery time in Group D was shorter than in both Group C and Group L. Group D also exhibited superior MOAA/S scores (lower at T₁, but higher at T₆-T₈), higher bronchoscopist satisfaction, and a lower incidence of both moderate-to-severe cough and postoperative nausea and vomiting (PONV) compared to the other groups. Respiratory rates were comparable, with Group D showing a higher RR than Group C at T₆.

Conclusion: Premedication with dexmedetomidine nasal spray in patients undergoing FB under sedation was associated with more effective suppression of procedure-induced cough, better hemodynamic stability, a lower incidence of PONV, and a faster recovery profile compared to both intranasal saline and lidocaine, without increasing respiratory depression. Consequently, dexmedetomidine nasal spray can effectively and safely enhance patient comfort and safety, and optimize the procedural conditions for the bronchoscopists.

The escalating global burden of an aging population and the rising incidence of secondary traumatic injuries have precipitated a mounting worldwide demand for bone grafts. However, autologous bone transplantation-the prevailing clinical "gold standard"-remains insufficient to meet this growing clinical need. Notably, rapid advancements in bone tissue engineering (BTE) have yielded diverse bone graft substitutes designed to recapitulate the three essential characteristics of bone tissue: osteoconductivity, osteoinductivity, and osteogenic potential. Within this domain, core scaffolds functioning as carriers for bioactive agents represent a highly promising strategy for treating bone defects. This review focuses on the design and fabrication of optimal xenogeneic bone scaffolds. It systematically examines commonly loaded bioactive components, including bone morphogenetic proteins (BMPs), platelet-rich plasma (PRP), natural products, active ingredients derived from traditional Chinese medicine ingredients (TCMs), and exosomes. The advantages and limitations inherent to these agents are critically analyzed. Furthermore, the review addresses current challenges and explores future research directions in bone scaffold engineering. By advancing multimodal strategies for modulating the delivery of bioactive agents, we aim to provide more effective therapeutic solutions for patients with critical bone defects.

Aim: Aim to compare the effects of rivaroxaban and warfarin on rapid renal function decline.

Methods: 8842 patients from the Tianjin Health and Medical Data Platform, with a 2.3 years median follow-up (interquartile range,1.5-3.4), were assigned to either the warfarin group (n = 3913) or rivaroxaban group (n = 4929). Logistic models, inverse probability of treatment weighting(IPTW), and propensity score-matched (PSM) analyses were employed to compare the risk of rapid renal function decline associated with rivaroxaban versus warfarin. The multivariable fractional polynomial interaction(MFPI) was used to investigate interactions between continuous variables and the adverse outcome. Restricted cubic splines(RCS) were applied to assess the relationship between the prognostic nutritional index (PNI) score and the adverse outcome.

Results: Rivaroxaban was associated with an increased risk of rapid renal function decline compared with warfarin in both the univariate (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.14-1.36; P < 0.001) and multivariate (OR, 1.17; 95% CI, 1.07-1.29; P = 0.001) logistic models. Similar trends were observed in the IPTW (OR, 1.16; 95% CI, 1.09-1.33; P < 0.001), PSM model (OR, 1.21; 95% CI, 1.09-1.33; P < 0.001), and all subgroup analyses. In the MFPI analysis, the adverse outcome was significantly alleviated with an increasing PNI score (threshold at PNI score of 50, P = 0.039). A linear negative relationship (P for nonlinearity = 0.221) between the PNI score and rapid renal function decline was observed in patients receiving rivaroxaban.

Conclusion: Rivaroxaban was associated with a higher risk of rapid renal function decline than warfarin. Enhanced nutritional support may help mitigate this adverse outcome.

Purpose: This study aimed to develop a population pharmacokinetic (PopPK) model in elderly Chinese patient with NVAF, characterize the pharmacokinetic variability, identify relevant covariates affecting rivaroxaban disposition, and explore the exposure-response relationship.

Patients and methods: A prospective observational study was conducted with rivaroxaban plasma samples collected and analyzed. A PopPK model was developed using the nonlinear mixed-effects modeling approach. Monte Carlo simulations were employed to explore the correlation between significant covariates and estimated drug exposure. AUC_24,ss derived from the PopPK analysis, was computed to evaluate exposure-response relationships.

Results: Ninety-three elderly Chinese NVAF patients contributed 256 plasma concentrations were well described by a one-compartment PopPK model. Creatinine clearance (CrCL) and concomitant use of amiodarone were identified as significantly influencing clearance (CL). The simulation results revealed the following: (1) For patients with normal or mildly impaired renal function (CrCL ≥50 mL/min), both a 20 mg once-daily dosage without amiodarone and a 10 mg with amiodarone were acceptable; (2) For those with moderate to severe renal impairment (CrCL 15-49 mL/min), a 10 mg once-daily dosage was appropriate regardless of amiodarone coadministration; (3) Although a 15 mg once-daily dosage was generally suitable from the pharmacokinetic standpoint, concomitant use of amiodarone significantly increased bleeding risk in patients (RR = 8.00, p = 0.039); (4) AUC_24,ss was significantly decreased in patients with thromboembolic events compared to those without such events (p < 0.0001), with 2840 ng·h/mL identified as the optimal cut-off value (p = 0.023).

Conclusion: For elderly Chinese NVAF patients, a reduced-dose rivaroxaban regimen, specifically 10 mg once daily with amiodarone, is recommended for all patients regardless of renal function, whereas 15 mg once daily is a more optimal option for those not taking amiodarone. Based on the risk-benefit assessment, maintaining AUC_24,ss above 2840 ng·h/mL does not yield additional clinical benefit.

Purpose: Evaluation of the effectiveness of local dexmedetomidine and ropivacaine administration prior to epidural puncture in reducing breakthrough pain during labor analgesia.

Methods: A total of 267 parturients were enrolled in this study and allocated to three groups: Group C (n=86) received 0 µg/kg (control), Group D1 (n=87) received 0.4 µg/kg, and Group D2 (n=92) received 0.6 µg/kg. Dexmedetomidine combined with 0.5% ropivacaine (3 mL) was applied locally at the epidural puncture site. The primary outcome was the incidence of breakthrough pain during labor. The secondary outcomes included visual analog scale (VAS) score at the puncture site on days 3, 7, and 42 postpartum; the Edinburgh Postnatal Depression Scale (EPDS) score and Pittsburgh Sleep Quality Index score at prenatal, 7-day postpartum, and 42-day postpartum. In addition, the Apgar scores and umbilical artery blood gas status at 1 and 5 minute and the need for neonatal ward admission were also collected.

Results: The incidence of breakthrough pain episodes was markedly lower in the Group D1 (23 of 87 [26.4%] vs 43 of 86 [50.0%]; odds ratio [OR], 0.395; 95% confidence interval [CI], 0.190-0.675; p = 0.002) and Group D2 (21 of 92 [22.8%] vs 43 of 86 [50.0%]; OR, 0.296; 95% CI, 0.155-0.564; p < 0.001) than in the Group C. Postpartum analysis revealed significantly lower VAS scores for puncture site pain in Groups D1 and D2 than in Group C at the 3-days postpartum (p < 0.001). Parturients in Group D2 demonstrated a significant reduction in EPDS scores compared to Group C at postpartum day 7.

Conclusion: Administering local infiltration of 0.4 µg/kg or 0.6 µg/kg dexmedetomidine prior to epidural puncture in parturients undergoing elective labor analgesia has been shown to be effective in decreasing the incidence of breakthrough pain during labor analgesia.

Trial registration: The trial has been registered in the Chinese Clinical Trials Registry (ChiCTR2400083244) https://www.chictr.org.cn/showproj.html?proj=227790.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder. Emodin (EMD), which is derived from multiple Chinese medicinal herbs, has been reported to possess anti-inflammatory, anti-ferroptosis, and neuroprotective effects. However, the mechanisms underlying the regulation of PD-related ferroptosis remain unclear.

Objective: To investigate whether EMD protects dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced models of PD and to elucidate its underlying mechanisms.

Methods: Potential EMD targets were predicted using SEA and Swiss databases. The PD targets were identified using the OMIM and GeneCards databases. Overlapping genes were introduced to construct protein-protein interactions (PPI) and perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Molecular docking was used to ascertain the possibility of the binding of EMD to p53 and TfR1. The stability of EMD-p53 complex was validated by using molecular dynamics simulations using the YASARA. To validate these mechanisms, we used an MPTP-induced mouse model to investigate the beneficial effects of EMD. Motor function was assessed using the open field and rotarod tests. Malondialdehyde (MDA) and iron contents in the midbrain were determined. SH-SY5Y cells were subjected with 1-methyl-4-phenyl-pyridinium (MPP⁺) or ferroptosis inducer. Ferroptosis signaling, iron metabolism, and mitochondrial superoxide levels were investigated using Western blotting, qPCR, immunofluorescence, and flow cytometry.

Results: Enrichment analysis revealed that the shared targets of the PD and EMD gene sets were involved in iron metabolism, with TP53 being the most connected protein in the PPI network. Molecular docking analysis suggested that EMD formed a stable complex with p53 or TfR1. Molecular Dynamics Simulation further confirmed that the interactions between EMD and p53 remained stable over time. In vivo studies demonstrated the beneficial effects of EMD in an MPTP mouse model of PD. This action was achieved by inhibiting p53 expression and mitigating ferroptosis signaling in the substantia nigra (SN). EMD similarly attenuated cell injury and ferroptosis in SH-SY5Y cells by inhibiting p53-ferroptosis signaling. In contrast, pharmacological enhancement of p53 nullified these effects in the MPP⁺-treated SH-SY5Y cells.

Conclusion: These preliminary results indicate that EMD could exert neuroprotective effects against MPTP-induced toxicity, possibly via modulating p53-ferroptosis signaling.

Purpose: To evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effects of single and multiple oral doses of ABP-671, a novel URAT1 inhibitor, in healthy and hyperuricemic subjects.

Patients and methods: This placebo-controlled study of ABP-671 was conducted in the United States, and contained three parts: a. single ascending dose (SAD); b. multiple ascending dose (MAD); c. food effect. The study doses of SAD part, 0.1, 0.5, and 1.0 mg, and placebo oral solutions were investigated in healthy volunteers. In the MAD study, hyperuricemic but otherwise healthy subjects received 0.2, 0.5, or 1.0 mg/d of ABP-671 or placebo oral solutions for 10 days. In the food effect study, healthy subjects received 1.0 mg ABP-671 tablet in the fasted or fed state in a crossover design.

Results: A total of 24, 27, and 12 subjects were enrolled, with 5, 9, and 5 treatment-emergent adverse events (TEAEs) observed in the SAD, MAD, and food effect studies, respectively. There were no serious adverse events (SAEs) or TEAEs leading to discontinuation or death. In the SAD and MAD studies, the peak plasma concentration and areas under the curves increased with the increasing drug doses. The serum uric acid (sUA) levels started decreasing 3 hours after ABP-671 administration, and the percentage changes from baseline for sUA increased with the increasing drug doses. Fasting or postprandial state did not affect the PK of ABP-671.

Conclusion: Single or multiple oral doses of ABP-671 are well tolerated at doses 0.1, 0.5 and 1.0 mg for the SAD, 0.2, 0.5, and 1.0 mg/d for the MAD, and 1.0 mg for the food effect study. A proportional relationship between dose and exposure was observed. ABP-671 reduced the sUA levels with a rapid (3 hours) onset and in a dose responsive manner.