Drug Design, Development and Therapy最新文献

Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with chronic inflammation. Current clinical management is confronted with multiple challenges, such as suboptimal drug bioavailability, insufficient joint targeting, and poor patient compliance, which critically limit therapeutic efficacy. Dissolving microneedles (DMNs) can overcome the limitations of traditional treatments through minimally invasive transdermal delivery, improve efficacy and reduce toxicity and side effects, offering an innovative solution for RA treatment. This article reviews the advantages of DMNs for RA, analyzes the advantages and limitations of their preparation methods, the physicochemical properties of DMN matrix materials and the application progress in RA treatment. The synergistic strategies of DMNs with nano-delivery systems, cell membrane bionics, stimulus response delivery systems and phototherapy are further discussed. This multi-technology integration solution solves the problems of poor targeting, low bioavailability, high toxic side effects, and poor patient compliance in RA treatment through the advantages of physical targeting, intelligent controlled release and portable drug delivery. Finally, combined with the patent landscape and clinical research progress, the existing challenges and future development prospects of DMNs in RA treatment are analyzed, hoping to provide theoretical basis and technical breakthrough direction for RA treatment.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally, creating an urgent need to elucidate its pathogenesis and develop effective therapeutic strategies.

Methods: In this study, we established obese mouse models using distinct dietary patterns. We then employed 16S rRNA sequencing and metabolomics to profile gut microbiota composition and identify differential metabolites in serum and intestinal contents. Using Limited proteolysis mass spectrometry, co-immunoprecipitation mass spectrometry and luciferase reporter assays were used to identify the downstream molecular mechanisms.

Results: Our findings revealed that the abundance of hippuric acid (HA) was significantly decreased in the serum and gut of obese C57BL/6 mice, and it positively correlated with the abundance of Akkermansia and Alistipes. Notably, HA supplementation effectively reduced body weight and alleviated hepatic lipid accumulation in obese mice. Mechanistically, we found that HA directly binds to UDP-glucose dehydrogenase (UGDH), enhancing its interaction with forkhead box protein K1 (FOXK1) in the cytoplasm, thereby preventing FOXK1 nuclear translocation. This event suppresses Cd36 transcription and mitigates hepatic lipid accumulation. Furthermore, silencing Ugdh attenuated the inhibitory effect of HA on FOXK1-mediated regulation of Cd36 transcription.

Conclusion: We demonstrate a novel mechanism for regulating hepatic lipid metabolism through HA/UGDH/FOXK1/CD36 pathway. This study provides evidence supporting the potential of HA as a therapeutic metabolite for MASLD. Moreover, these results are derived from preclinical murine models, and further clinical studies are warranted to validate the efficacy of HA.

Propose: Oxidative stress and immune dysfunction are closely associated with the onset and progression of vitiligo. Therefore, simultaneously regulating these two key pathological processes to achieve synergistic therapy is a practically feasible strategy. Based on this rationale, we previously developed a topical ointment co-loaded with antioxidant simvastatin and immunosuppressant tofacitinib, and evaluated its therapeutic potential for vitiligo. However, the lack of a bioanalytical method for simultaneous in vivo quantification of the two drugs has hindered further pharmacodynamic and pharmacokinetic studies of the formulation. The present study aimed to establish and validate an HPLC-MS/MS method for simultaneous determination of their in vivo concentrations, to support pharmacokinetic investigations of the ointment in rats.

Methods: Chromatographic separation was performed on a ZORBAX Eclipse C₁₈ column (50.0 × 3.5 mm, 1.7 μm) using a gradient elution program. The mobile phase comprised phase A (20 mM ammonium acetate aqueous solution) and phase B (acetonitrile), with a constant flow rate of 0.4 mL/min. The method was fully validated in strict accordance with the bioanalytical method validation guidelines specified in the Chinese Pharmacopoeia, including evaluations of specificity, calibration curve and linear range, lower limit of quantification, carryover effect, precision, recovery, matrix effect, stability, and dilution integrity.

Results: The results demonstrated that the method met all validation criteria and was suitable for pharmacokinetic studies. Pharmacokinetic data showed that, compared with oral gavage, the 24 h bioavailability of tofacitinib and simvastatin after topical administration was only 7.1% and 5.2%, respectively. This low systemic exposure indicated that the ointment formulation could effectively reduce the potential toxicity caused by excessive drug absorption into the circulation.

Cardio-oncology represents an emerging interdisciplinary discipline focusing on optimizing oncologic efficacy while mitigating treatment-related cardiovascular complications. The advent of novel anticancer agents such as targeted therapies, immune checkpoint inhibitors, and endocrine therapies has transformed cancer care, significantly improving survival rates. Nevertheless, prolonged patient survivorship has unmasked clinically significant cardiovascular sequelae, termed cancer therapy-related cardiovascular toxicity (CTR-CVT), which manifests as acute manifestations during therapy and delayed presentations persisting years post-treatment. This dual-onset toxicity profile necessitates rigorous longitudinal cardiovascular risk stratification integrating comprehensive pre-therapeutic assessment, multi-modal imaging, and biomarker-guided surveillance to detect subclinical dysfunction, prevent premature treatment cessation, and reduce cancer recurrence and mortality risks. Future research priorities include further elucidating pathophysiological mechanisms of CTR-CVT, developing cardio-protective strategies, implementing personalized therapeutic protocols, and reducing disparities in care to advance cardio-oncology and improve patient outcomes. This review synthesizes the development of CTR-CVT, existing evidence-based CTR-CVT risk surveillance approaches, and emerging innovative early-warning strategies, and the future development prospects.

Purpose: To compare the efficacy and safety of intravitreal conbercept monotherapy versus conbercept combined with dexamethasone implant in eyes with macular edema (ME).

Methods: Patients diagnosed with ME secondary to diabetic retinopathy or retinal vein occlusion were enrolled and randomized 1:1 to the combined or monotherapy group. In initial 12 weeks, the combined group received 1 loading dose of conbercept concomitantly with dexamethasone implant (DEX), while the monotherapy group received 3 monthly loading doses of conbercept. Following initial phases, all patients received intravitreal injections of conbercept on demand, assessed every 4 weeks over a 48-week follow-up period. The primary outcome measure was changes in best-corrected visual acuity (BCVA). Secondary outcome measures encompassed changes in optical coherence tomography (OCT) biomarkers and the total number of injections administered. Clinical safety was evaluated based on the incidence and severity of adverse events.

Results: 70 patients (70 eyes) were randomized to monotherapy (n=36) or combination therapy (n=34). Mean (SD) baseline BCVA and CMT were 44.60 (7.34) letters and 555.55 (150.87) μm in monotherapy group; 37.61 (13.47) letters and 581.80 (145.87) μm in combined group. The combined group showed greater BCVA improvement by week 8 and CMT reduction at weeks 4 and 8, and OCT biomarkers also improved more substantially during the first 12 weeks. The combination therapy required significantly fewer injections (P < 0.001) overall but a higher incidence of ocular hypertension. Outcomes of BCVA and CMT correlated with Hard Exudate (HE).

Conclusion: Conbercept combined with DEX is an efficient and safe treatment for ME by providing accelerated visual and anatomical improvements in short term and maintaining similar long-term efficacy with fewer injections compared to conbercept monotherapy. OCT biomarkers display prognostic value. HE is associated with poor visual prognosis.

Purpose: This trial aims to compare the effects of intraoperative low-dose dexmedetomidine combined with esketamine versus esketamine alone on postpartum depressive and esketamine-related neuropsychiatric adverse events in cesarean delivery.

Patients and methods: In this randomized controlled trial, 134 parturients scheduled for cesarean delivery under combined spinal-epidural anesthesia were enrolled. Following umbilical cord clamping, patients were randomly allocated to receive either 0.25 mg/kg esketamine combined with 0.5 μg/kg dexmedetomidine (Group DE, n=67) or 0.25 mg/kg esketamine alone (Group E, n=67). The study assessed Edinburgh Postnatal Depression Scale (EPDS) scores on postpartum days 7 and 42, the incidence of esketamine-related neuropsychiatric adverse events, maternal satisfaction, postoperative pain scores, and other adverse events.

Results: On postpartum day 7, the Group DE exhibited significantly lower EPDS scores than the Group E (median [IQR]: 3.00 [2.00-4.00] vs 4.00 [3.00-5.00]; P < 0.001). This between-group difference was no longer significant at the 42-day follow-up. The overall incidence of neuropsychiatric adverse events was significantly reduced in the Group DE [22 (32.84%) vs 39 (58.21%), P =0.003], with notably fewer cases of dizziness (19.40% vs 35.82%, P =0.034) and headache (8.96% vs 23.88%, P =0.020). Additionally, the Group DE had lower rates of nausea (8.96% vs 23.88%, P =0.020) and tachycardia (20.90% vs 47.76%, P =0.001), and higher maternal satisfaction scores [10.00 (9.00-10.00) vs 9.00 (9.00-10.00), P =0.005].

Conclusion: Combined low-dose dexmedetomidine and esketamine during cesarean section provides a short-term improvement in early postpartum depressive symptoms, reduces intraoperative neuropsychiatric adverse events, and enhances maternal satisfaction, with a favorable maternal and neonatal safety profile.

Purpose: Vancomycin is frequently used to treat central nervous system (CNS) infections, yet its cerebrospinal fluid (CSF) penetration remains poorly characterized in patients with intracranial hemorrhage (ICH) requiring external ventricular drains (EVDs).

Methods: A prospective observational study was conducted on nine neurosurgical patients with ICH and EVDs receiving intravenous vancomycin. Plasma and CSF samples were collected at predefined time points and analyzed by validated assays. Noncompartmental analysis, regression modeling, and nonlinear mixed-effects pharmacokinetic (PK) modeling were performed.

Results: The AUC_CSF/plasma ratios ranged from 0.84% to 14.22%. CSF penetration correlated strongly with plasma-CSF concentration ratios at the end of infusion (Spearman r = 0.791; p = 0.004). Linear regression identified urine output (R² = 0.51, p = 0.014), WBC/total cell ratio (R² = 0.62, p = 0.007), and end-of-infusion concentration (R² = 0.45, p = 0.049) as significant predictors of AUC_CSF. A two-compartment model provided the best fit for vancomycin population PK, yielding clearance and volume of distribution estimates similar to previous reports, although no significant covariates for CSF penetration were identified.

Conclusion: To our knowledge, this is the first study reporting real-world data of vancomycin CSF penetration in Taiwanese neurosurgical patients. These findings provide a critical PK foundation for developing future model-informed precision dosing strategies and validating surrogate TDM markers in this neurocritical care population.

Background: Poor ovarian response (POR) is a serious problem that decreases the effectiveness of conventional ovarian stimulation. Its concern is elevated production of reactive oxygen species, causing DNA destruction and mitochondrial malfunction, which contributes to the decline in oocyte quality.

Objective of the study: This trial aimed to identify the impact of Coenzyme Q10 as an antioxidant on ovarian reserve markers and Intra-cytoplasmic sperm injection results in poor ovarian responders.

Methods: A prospective controlled study included 100 patients classified as poor ovarian responders according to the Bologna criteria. The patients were randomly allocated to two groups. Fifty participants in group A were administrated Coenzyme Q10 plus folic acid for one month prior to the ICSI cycle and through the ICSI cycle. Fifty patients in group B were administrated folic acid only for a similar duration. The primary outcome measured was the count of oocytes obtained. The chemical pregnancy rate was considered a secondary outcome.

Results: The baseline features were equivalent among the groups. CoQ10 markedly improved the oocyte count and peak E2 (p <0.001). Higher levels of antral follicle count at the start of the induction were observed in the treated group (p= 0.001). Endometrial thickness was greater in the CoQ10 group than in the control group (p=0.004). Significant differences were found in the count of embryos transferred and the percentage of women who underwent no embryo transfer (p=0.011). No substantial variations were detected in the gonadotropin doses, induction days, or progesterone levels among the two groups. The chemical and clinical pregnancy rates and completed cycles were equivalent between the two groups, with insignificant differences.

Conclusion: CoQ10 promotes ovarian response to conventional induction and has a beneficial effect on ovarian reserve and embryological measures in poor responders. Despite this, additional investigations are essential to determine its influence on pregnancy rates.

Clinical trial id: NCT06405204.

Anti-vascular endothelial growth factor (anti-VEGF) therapy is the cornerstone of care for neovascular age-related macular degeneration (nAMD), yet its effects on the inner retina are not widely studied. We conducted a narrative review, guided by the SANRA checklist, to map evidence on peripapillary retinal nerve fibre layer (pRNFL), macular RNFL, and ganglion cell-derived metrics (GCL/GCIPL/GCC) during anti-VEGF treatment. Major databases were searched from inception to 10 November 2025 for human studies reporting optical coherence tomography (OCT) measurements of inner-retinal structure during anti-VEGF treatment. Data were charted for study design, OCT device/segmentation, scan protocol, timing relative to injections, treatment regimen, fluid phenotype (intraretinal fluid [IRF], subretinal fluid [SRF], pigment epithelial detachment [PED]), follow-up interval, and magnitude of change (µm). Across cohorts and agents, global pRNFL thickness was largely stable over weeks to years, with short-term peri-injection fluctuations typically within device test-retest limits. In contrast, macular ganglion cell layers more often showed modest thinning over time, most consistently in eyes with baseline IRF; SRF-predominant disease showed less consistent inner-retinal change. Apparent between-agent differences were small and inconsistent; evidence specific to faricimab remains limited but generally reassuring for structural stability. Overall, most observed changes were often within OCT test-retest variability. In practice, clinicians should prioritise GCL/GCIPL monitoring where IRF is present, interpret small absolute changes against device repeatability, and avoid attributing trivial sectoral shifts to drug toxicity without corroboration.

Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.