Drug Design, Development and Therapy最新文献

Objective:  To compare the effects of remifentanil-propofol versus propofol alone on anesthesia outcomes in patients undergoing surgery for severe traumatic brain injury (TBI).

Methods:  In this single-center, retrospective cohort study, we analyzed the data of 113 consecutive severe TBI (GCS <9) patients who underwent emergency neurosurgery. Patients were allocated into two groups based on the anesthesia maintenance regimen: the control group (n=56) received a continuous infusion of propofol alone, while the observation group (n=57) received a combination of remifentanil and propofol. The groups were well-matched at baseline. We compared anesthesia recovery times, hemodynamic parameters (SpO₂, MAP, HR) at various time points, postoperative pain (VAS) and agitation (RSAS) scores, levels of inflammatory (TNF-α, IL-6) and neurological damage (S-100β, NSE) biomarkers, and 3-month neurological outcomes using the Glasgow Outcome Scale (GOS).

Results:  Compared to the control group, the observation group demonstrated significantly shorter extubation time (13.54 ± 3.23 vs 24.79 ± 5.71 min, P < 0.001) and awakening time (8.72 ± 2.43 vs 17.21 ± 3.96 min, P < 0.001). The remifentanil-propofol regimen was associated with superior intraoperative hemodynamic stability for MAP and HR (Group and Interaction effects, P < 0.05). At 24 hours postoperatively, the observation group also exhibited lower VAS and RSAS scores (both P < 0.05), as well as reduced elevations in TNF-α, IL-6, S-100β, and NSE levels (all P < 0.05). Critically, a significantly higher proportion of patients in the observation group achieved a "Good Recovery" on the GOS at 3 months (54.39% vs 25.00%, P = 0.001).

Conclusion:  For severe TBI surgery, remifentanil-propofol is associated with faster emergence, better hemodynamic control, reduced pain/agitation, attenuated neuro-inflammation, and improved long-term recovery versus propofol alone, suggesting significant clinical benefits. Prospective studies are warranted for confirmation.

Background: Diabetes mellitus (DM) is associated with vascular endothelial dysfunction, which may impair perioperative responsiveness to vasoactive drugs such as nitroglycerin.

Objective: This study aimed to assess vasodilatory dysfunction in diabetic patients using high-resolution ultrasound, compare their nitroglycerin response with non-diabetics during anesthesia emergence, and evaluate how endothelial impairment affects nitroglycerin-mediated vasodilation to guide personalized dosing.

Methods: This prospective cohort study compared 40 non-diabetic (Group A) and 40 diabetic patients (Group B). Preoperative brachial artery ultrasound assessed flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID). Following extubation, the total nitroglycerin dose required to restore blood pressure to baseline was recorded as the primary endpoint. Secondary endpoints comprised FMD and NID values, ED₅₀/ED₉₀ of nitroglycerin, and perioperative hemodynamic changes.

Results: Compared with Group A, the nitroglycerin dose was significantly higher in Group B (48.47±5.11 µg vs 39.74±4.15 µg; mean difference: 8.73 µg, 95% CI: 6.82-10.64; P<0.001). Group B showed significantly lower FMD (3.68±1.70% vs 8.45±1.77%; mean difference: -4.77%, 95% CI: -5.65 to -3.89; P<0.001) and NID (5.07±2.63% vs 9.15±2.99%; mean difference: -4.08%, 95% CI: -5.27 to -2.89; P<0.001). Both FMD and NID correlated negatively with nitroglycerin dose (r=-0.653 and r=-0.610, respectively; both P<0.001). Diabetic patients required higher effective doses (ED₅₀: 0.292[0.268-0.316] vs 0.272[0.250-0.294]µg/kg/min; ED₉₀: 0.329[0.302-0.356] vs 0.312[0.288-0.336] µg/kg/min). Multivariate analysis identified higher HbA1c and lower FMD/NID as independent predictors of increased nitroglycerin requirement.

Conclusion: This prospective cohort study demonstrated that impaired vascular endothelial function in diabetic patients significantly reduced sensitivity to nitroglycerin perioperatively. This was manifested by the requirement for higher nitroglycerin doses to achieve target baseline blood pressure levels during hemodynamic management following extubation. These findings suggest that preoperative vascular ultrasound may provide an individualized nitroglycerin dosing framework for diabetic patients.

One of the most common malignant tumors in women worldwide is breast cancer, which affects even more than one-third of all female tumor patients. Patient outcomes and effective therapeutic strategies are frequently determined by molecular subtypes in breast cancer. However, the underlying epigenetic characteristics that could further divide breast cancer patients into groups and affect their outcomes could be the reason for the differences in therapeutic response. It is true that there have been recent findings about the role of epigenetic abnormalities in cancer, and that therapeutics targeting particular epigenetic pathways have been developed. Phytochemicals function as gene regulators in a variety of cancers and are crucial to the pathophysiology of many human cancers, including breast cancer. Preclinical studies have revealed that phytochemicals exhibit promising therapeutic efficacy against breast carcinoma by modulating several epigenetic alterations including DNA methylation, histone modifications, non-coding RNA and estrogen associated epigenetic changes. Nevertheless, despite promising in vitro and in vivo results, the clinical application of phytochemicals targeting epigenetic markers in breast cancer is limited. Further research is required to confirm their effectiveness and safety in clinical settings. Thus, this study provides a thorough summary of how epigenetic changes contribute to the development of breast cancer. This article also explores the potential benefits of phytochemicals, such as flavonoids, terpenoids, alkaloids, isothiocyanates, and quinones, in modulating these epigenetic markers in preclinical models of breast cancer.

Background: Minimal Change Disease (MCD) / Focal Segmental Glomerulosclerosis (FSGS) are leading causes of adult nephrotic syndrome. Roughly half of patients need long-term immunosuppression for steroid dependence or relapse, but traditional drugs carry substantial adverse effects. Rituximab (RTX) depletes CD20⁺ B cells and reduces anti-podocyte antibodies; pediatric data are encouraging, yet direct adult evidence-especially between treatment-naïve and relapsed patients-remains scarce.

Methods: This study enrolled 82 patients with MCD/FSGS diagnosed between 2020 and 2023, divided into the RTX group (24 patients, 9 treatment-naïve and 15 relapsed) and the glucocorticoid group (58 patients). The RTX group received standard-dose RTX (375 mg/m² weekly for 4 weeks), while the glucocorticoid group was treated with prednisone (1 mg/kg/day). Outcomes were compared using t-tests, χ²/Fisher, logistic regression, and Kaplan-Meier analyses.

Results: The overall remission rates were 100% in the RTX group and 98.3% in the glucocorticoid group (P=0.876), but the RTX group had a significantly higher eGFR at the last follow-up (124.25 vs 109.00 mL/min/1.73 m², P=0.019). A statistically significant intergroup difference was also observed, with complete remission achieved in 89.5% of MCD patients versus 40% of FSGS patients (P< 0.05). In relapsed patients treated with RTX, prednisone dosage decreased from 34.0±15.7 mg/day to 7.7±7.8 mg/day (P< 0.001), annual relapse frequency dropped from 1.0 to 0 episodes/year (P=0.001), and 40% of patients completely discontinued glucocorticoids. The Complete Remission rate in treatment-naïve patients (88.9%) was higher than in relapsed patients (73.3%), but the difference was not statistically significant. No independent predictors of RTX efficacy were identified, and no severe infections or allergic reactions were observed.

Conclusion: RTX equals glucocorticoids in podocytopathy, cuts steroid use and relapse, improves long-term kidney survival, and is safe. Treatment-naïve patients may choose RTX upfront to avoid steroid side effects; relapsed patients can taper and stop steroids. However, due to the limited sample size, these results should be interpreted with caution. Larger trials must confirm its long-term efficacy and ESRD protection.

Purpose: This study aimed to evaluate the predictive value of initial trough concentration (C_min) of voriconazole (VCZ) and procalcitonin (PCT) in hepatotoxic adverse events.

Patients and methods: A retrospective analysis was performed on clinical data from 170 patients administered VCZ at our institution between January 2021 and July 2025. Risk factors associated with VCZ-induced hepatotoxicity were identified through binary logistic regression analysis. The diagnostic performance of initial VCZ-C_min and PCT in predicting hepatotoxicity was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: The mean loading dose of VCZ was 9.48 mg/kg, with a maintenance dose of 6.62 mg/kg, and an average initial C_min of 5.58 mg/L. Hepatotoxicity was observed in 20.59% (35/170) of patients during the treatment period. Multivariate logistic regression analysis, adjusted for confounding factors including weight, maintenance dose, and proton pump inhibitors use, revealed that elevated initial VCZ-C_min and high PCT levels were significantly associated with hepatotoxicity. ROC curve analysis identified critical thresholds for hepatotoxicity risk: an initial VCZ-C_min of 5.035 mg/L (AUC=0.663, P=0.003) and a PCT level of 0.835 ng/mL (AUC=0.754, P<0.001), the predictive probability of their combination was 0.184 (AUC=0.744, P<0.001). After grouping according to the threshold level of PCT, there was a significant difference in the initial VCZ-C_min between patients with high PCT levels and those with low PCT levels (P=0.005).

Conclusion: VCZ-induced hepatotoxicity is the common adverse reaction, exhibiting significant associations with elevated initial VCZ-C_min and increased PCT levels. Both the initial VCZ-C_min and PCT levels are independent risk factors, and either alone or in combination can predict the occurrence of hepatotoxicity. Among these, PCT levels have the most significant predictive value.

miR-34, as an important class of microRNA, plays a dual regulatory role in host antiviral immunity and tumor suppression. Its unique mechanism targeting both viruses and tumors demonstrates significant potential for synergistic therapeutic applications. During viral infection, miR-34 enhances host immune responses by regulating interferon signaling pathways to target IRF3 phosphorylation and NF-κB activation, which leads to the viral replication suppression. In tumor prevention and treatment, miR-34 acts as a downstream effector of the p53 signaling pathway, inducing cell cycle arrest and apoptosis by inhibiting Cyclin D1 and promoting Bax expression, exhibiting the tumor-suppressive roles. Additionally, miR-34 plays a key role in the interactions between viruses and hosts, as well as tumors and the microenvironment, by balancing the expression of inflammatory factors (eg, IL-6, TNF-α). Although miR-34 has shown significant potential in preclinical studies, its clinical application still faces challenges such as low drug delivery efficiency, off-target effects, and safety concerns. Notably, miR-34 mimics have demonstrated potential in tumor trials to restore tumor suppressor functions, offering the promising and novel strategies for combined anti-viral and anti-tumor therapies. In the future, through multi-omics integration, the development of novel nano-delivery systems, and multicenter clinical trials, miR-34 is expected to become a crucial target for viral prevention and precision tumor therapy.

Objective: This randomized controlled study aimed to explore the safety and efficacy of a fentanyl-reduced regimen combining esketamine and remimazolam for bronchoscopy in elderly patients.

Methods: A total of 274 elderly patients (aged 65-85 years, ASA I-III) underwent bronchoscopy in our hospital from September 2024 to May 2025 were randomly divided into two groups: the study group (remimazolam 0.2 mg/kg + esketamine 0.3 mg/kg + fentanyl 0.5 ug/kg) and the control group (remimazolam 0.2 mg/kg + fentanyl 1.5 ug/kg). Remimazolam 0.05 mg/kg was added as needed to maintain sufficient sedation in both groups. The primary outcome was the incidence of procedure-related hypoxemia (SpO₂ < 90%). Secondary outcomes included the procedural success rate, recovery metrics (time to awakening, time to discharge, and quality of recovery score), satisfaction levels (patient and endoscopist scores), and adverse events (incidences of hypotension and hypertension, degree of salivation, and body movements like coughing or limb swings).

Results: The study group had a lower incidence of hypoxemia (2.19% vs 9.49%, p = 0.010) and shorter awakening time (17.47 ± 3.10 vs.19.33 ± 3.78, p < 0.001), as well as a higher QoR-15 score (138.95 ± 2.41 vs 137.38 ± 2.70, p < 0.001) compared to the control group. The incidence of hypotension was significantly lower in the study group (0.73% vs 18.25%, p < 0.001). Although the study group exhibited a significantly higher degree of salivation (p < 0.001), no aspiration occurred. There were no significant differences in sedation success rate, discharge time, patient/endoscopist satisfaction, or incidence of agitation between the two groups.

Conclusion: The fentanyl-reduced regimen ensures sedation efficacy, and reduces adverse events like respiratory depression and hypotension, despite increasing salivation. It provides a safer anesthetic option for bronchoscopy in elderly patients.

Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus with complex pathophysiology. Conventional therapies often lead to poor healing and high recurrence. This mini-review highlights the promise of advanced natural therapeutics and delivery strategies for DFU management. We focus on bioactive natural compounds, such as ginsenosides, astragalus polysaccharides, and resveratrol, that target critical processes like hyperglycemia, vascular impairment, and oxidative stress by modulating key signaling pathways. To improve bioavailability, innovative delivery systems including nanotechnology and nitric oxide-releasing platforms have been developed, enabling sustained release and enhanced healing. Clinical evidence shows promising results, such as shortened healing time and improved ulcer closure rates, supports the translational potential of standardized natural formulations. Moving forward, priorities should focus on standardizing natural formulations, optimizing delivery, and conducting rigorous clinical trials. With continued innovation, natural therapeutics hold significant potential to improve wound healing, reduce amputations, and enhance the quality of life for DFU patients.

Purpose: To evaluate the association between perioperative dexmedetomidine exposure and one-year mortality risk following video-assisted thoracoscopic surgery (VATS).

Patients and methods: We conducted a multi-institutional retrospective cohort study using the TriNetX Research Network. Adult patients aged ≥18 years who underwent elective VATS between January 2010 and December 2024 were included in the study. Patients were categorized into dexmedetomidine or midazolam (control) groups based on perioperative medication exposure. Midazolam was selected as the active comparator as it represents a standard perioperative sedative with different pharmacological properties than dexmedetomidine. After applying the exclusion criteria, 1:1 propensity score matching was performed using demographic variables, comorbidities, and laboratory parameters. The primary outcome was all-cause mortality within one year; and the secondary outcome was overall major complications (composite of sepsis, acute respiratory failure, acute myocardial infarction, cerebral infarction, and acute kidney failure).

Results: After propensity matching, 6387 patients were included in each group with balanced baseline characteristics. Patients receiving dexmedetomidine had significantly lower one-year mortality compared to midazolam (4.1% vs 5.4%; hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.68-0.94; p=0.007). This mortality difference was observed during the later follow-up period (31-365 days: HR:0.80; p=0.008) rather than the early postoperative period (1-30 days: HR:0.89; p=0.695). No difference was observed in overall major complications between groups (12.7% each; HR 1.05; p=0.289). Sensitivity and subgroup analyses confirmed these findings.

Conclusion: Perioperative dexmedetomidine administration is associated with reduced one-year mortality following VATS compared to midazolam. The mortality benefit appears during the later follow-up period without differences in major complication rates. Future prospective randomized trials are needed to confirm these findings and determine optimal dosing strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, but there has long been a lack of effective therapeutic drugs. Thyroid hormone (TH) and its receptor THR-β play pivotal roles in hepatic metabolism, positioning THR-β as a promising therapeutic target for MASLD. Notably, Resmetirom, a selective THR-β agonist, gained FDA approval in 2024 for MASLD treatment, and several other THR-β agonists are currently undergoing preclinical or clinical studies. While these agents demonstrate effective in alleviating hepatic steatosis, inflammation, and fibrosis in MASLD, the disease heterogeneity and drugs' adverse reactions remain key challenges. Therefore, further research is necessary to comprehensively assess their clinical efficacy and safety. This review summarizes the mechanisms by which TH/THR-β influences MASLD and recent advances in THR-β-targeted pharmacotherapy, aiming to enhance understanding of its therapeutic potential and promote drug development and clinical applications.