Drug Design, Development and Therapy最新文献

Background: Despite advances in pharmacological interventions for rheumatoid arthritis (RA), a subset of patients continues to experience disease activity, highlighting the need for adjunctive therapeutic strategies.

Objective: To assess the therapeutic efficacy of paroxetine when administered as adjuvant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA).

Methods: In this randomized, double-blind, clinical trial, one hundred patients were randomized in 1:1 ratio to receive either csDMARDs including methotrexate plus placebo (control group) or paroxetine (paroxetine group). The primary endpoint was the change in Disease Activity Score using 28 joint counts (DAS-28) [Tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP), visual analogue scale (VAS)] at three months. Secondary endpoints included multidimensional health assessment questionnaire [morning stiffness (MS), pain, fatigue, physical functioning (PF)].

Results: After treatment, both groups demonstrated significant within-group improvements in TJC, SJC, VAS, and DAS-28, with superior improvements observed in the paroxetine group (p = 0.016, 0.0006, 0.03, and 0.005, respectively). CRP showed no significant change in the control group (p = 0.933). Paroxetine group showed significant reductions in MS, pain, and fatigue (p = 0.024, 0.03, and 0.006, respectively) compared with the control group, while PF were significant within groups but not between groups (p = 0.208). Adverse events were comparable, except for a higher incidence of decreased libido in the paroxetine group.

Conclusion: Adjunctive paroxetine significantly improved clinical and patient-reported outcomes in mild and moderate RA patients and was generally well tolerated, supporting its potential as an effective adjunctive therapy. The relatively small single-center sample, the exclusion of severe RA patients, the short disease duration, the low seropositivity, absence of mental health assessment, the possibility of overlapping with secondary pain mechanisms (eg, central sensitization or early fibromyalgia features) may limit the generalizability of the findings to broader and more diverse patient populations.

Trial registration identifier: NCT06231745.

Purpose: Remimazolam is an ultrashort-acting benzodiazepine, which has been indicated to be effective in endoscopic surgery and general anaesthesia. Research on its use in outpatient dental procedures remains limited. This triple-blinded randomized clinical trial was designed to determine whether the quality of postoperative recovery is better with continuous intravenous remimazolam administration compared with midazolam administration for impacted wisdom tooth extraction in patients with dental anxiety.

Patients and methods: This study was a randomized, parallel triple-blinded, superiority trial conducted between 30 April 2022 and 24 June 2024. Participants aged ≥18 years who exhibited dental anxiety and who were eligible for impacted wisdom tooth extraction in an outpatient setting were included in this study. Participants were randomly assigned at a 1:1 ratio to receive either a continuous intravenous infusion of remimazolam or midazolam. The primary outcome was the time to recover full alertness. The secondary outcome was postoperative anterograde amnesia.

Results: A total of 150 participants were randomized in this study, with 75 patients assigned to the remimazolam group and 75 patients assigned to the midazolam group. The time to complete alertness was significantly shorter in the remimazolam group than in the midazolam group (3.0 ± 3.6 min vs 4.7 ± 5.2 min, mean difference, -1.9 min; 95% CI, -3.3min to -0.4 min; P = 0.013). The odds of immediate and delayed anterograde amnesia were much reduced with remimazolam administration compared with midazolam administration (immediate: 0.14, 95% CI, 0.05 to 0.34, delayed: 0.07, 95% CI, 0.03 to 0.15, both P < 0.001).

Conclusion: For patients with dental anxiety, remimazolam offers not only faster recovery, but also a much better restoration of memory function compared with midazolam.

Trial registration: https://clinicaltrials.gov/study/NCT05350085.

Background: Perioperative lung injury significantly affects the outcome of abdominal surgery. Research has shown that both dexmedetomidine and butorphanol can provide some perioperative lung protection. This study evaluated the protective effects of dexmedetomidine or metoprolol on lung function during laparoscopic resection of colorectal cancer and the potential synergistic effects of their combined use.

Methods: A 6-month randomized double-blind placebo-controlled trial with a 2*2 factorial design was conducted at the Affiliated Hospital of Xuzhou Medical University. 176 patients undergoing laparoscopic colorectal cancer resection were randomized into four groups: control (C), dexmedetomidine (D), butorphanol (B), and combination dexmedetomidine + butorphanol (DB). The primary outcome was the arterial-alveolar oxygen partial pressure ratio (a/A ratio) at the end of the administration period (T1). Secondary outcomes included other lung function indices, incidence of postoperative pulmonary complications (PPCs) and other complications, the 15-item Recovery Quality Score (QoR-15) scores, and postoperative inflammatory marker levels.

Results: Factorial analysis revealed significant main effects for Group D on the arterial alveolar oxygen partial pressure ratio (a/A ratio) at T1 (F=18.739, P < 0.001, η²=0.098), and Group B (F=19.048, P < 0.001, η²=0.1), with a significant a significant interaction effect between Group D and Group B (F=6.690, P=0.011, η²=0.037). Administration of dexmedetomidine reduced the alveolar-arterial oxygen pressure difference (A-aDO₂), intrapulmonary shunt rate (Qs/Qt), and dead space to tidal volume ratio (Vd/Vt) compared to the control. Butorphanol lowered A-aDO₂, decreased pulmonary complications on postoperative day 3, reduced postoperative nausea and vomiting, and improved recovery quality. The combination therapy further reduced Vd/Vt, decreased pulmonary complications on postoperative days 1 and 3, and lowered postoperative IL-6 levels.

Conclusion: Dexmedetomidine combined with butorphanol enhances lung function in laparoscopic surgery patients by improving gas exchange, boosting ventilation efficiency, reducing inflammation, and decreasing postoperative pulmonary complications.

Purpose: Propofol and remimazolam monotherapy have their own limitations for general anesthesia in elderly patients. Optimizing anesthesia protocols is essential to enhance recovery and postoperative outcomes. This study aimed to evaluate the effects of combined sub-anesthetic doses of remimazolam and propofol on anesthesia recovery and sleep quality in this population.

Patients and methods: This single-center, single-blind, prospective, randomized controlled trial enrolled 92 patients aged 65-80 years scheduled for elective laparoscopic colorectal cancer surgery. Patients were randomly allocated to either group P (propofol alone, 4-12 mg/kg/h) or group PR (propofol 2-4 mg/kg/h combined with remimazolam 0.3 mg/kg/h). The primary outcome was awakening time. The secondary outcomes included sedation scores, intraoperative hemodynamics, postoperative Pittsburgh Sleep Quality Index (PSQI) scores, Visual Analogue Scale (VAS) scores, Quality of Recovery-15 (QoR-15) scores, and the incidence of adverse events.

Results: Awakening time was significantly reduced in group PR compared with group P (14.8 ± 4.8 min vs 18.9 ± 5.1 min, P < 0.001). Group PR showed higher QoR-15 scores at 24 h postoperatively (129 [124.3-133] vs 121.5 [118-128], P = 0.002), a lower incidence of sleep disturbances on postoperative days 1 and 3 (P < 0.001), and more stable intraoperative hemodynamics with a lower incidence of hypotension (19.6% vs 54.4%, P < 0.001). No significant differences were observed in VAS scores or other adverse events.

Conclusion: Anesthesia maintenance using a sub-anesthetic dose of remimazolam combined with propofol was associated with shorter awakening time and improved postoperative recovery quality. This combination may represent a promising anesthetic strategy, but further research with objective sleep monitoring is warranted to confirm these findings.

Background: Posaconazole is widely used for antifungal prophylaxis in patients with hematologic malignancies. However, interindividual pharmacokinetic variability may lead to subtherapeutic exposure and treatment failure. Real-world data on the pharmacokinetics of posaconazole tablets and infusion in East Asian populations remain limited. This study aims to evaluate the plasma concentration of posaconazole and risk factors for subtherapeutic exposure in Taiwanese patients.

Methods: This nested case-control study was conducted using data from the National Taiwan University Hospital database. The study cohort comprised adult patients with hematologic malignancies receiving delayed-release tablets or intravenous formulations of posaconazole and undergoing therapeutic drug monitoring. Factors associated with subtherapeutic posaconazole exposure (<0.7 μg/mL) were identified through multivariate logistic regression. Supratherapeutic concentration was defined as a level >1.83 μg/mL.

Results: Of a total of 221 patients, 24.9% and 24.0% exhibited subtherapeutic and supratherapeutic posaconazole concentrations, respectively. Multivariate logistic regression indicated that male sex (odds ratio [OR] = 2.31), diarrhea (OR = 2.18), and concurrent use of proton pump inhibitors (OR = 2.00) or prokinetic agents (OR = 2.17) were independently associated with subtherapeutic exposure to posaconazole.

Conclusion: Subtherapeutic and supratherapeutic exposures to posaconazole remain a concern despite standard dosing. Therapeutic drug monitoring and personalized risk assessment are essential for optimizing antifungal prophylaxis in patients with hematologic malignancies.

Purpose: The systemic inflammatory response triggered by video-assisted thoracic surgery (VATS) is associated with the risk of perioperative neurocognitive disorders (PND). Remimazolam, a newer benzodiazepine anesthetic, has unknown anti-inflammatory properties and uncertain effects on elderly patients. This study investigated the effects of remimazolam on postoperative inflammation and neurocognitive disorders in elderly patients undergoing VATS.

Patients and methods: Ninety-two patients aged 60 years or older scheduled for VATS were randomized to receive either remimazolam (induction: 0.25 mg/kg; maintenance: 0.5-1.5 mg/kg/h) or propofol (induction: 2 mg/kg; maintenance: 4-6 mg/kg/h). The primary outcome was the serum C-reactive protein concentration at 24 h postoperatively. Secondary outcomes included the incidence of PND, assessed using the 3-Minute Diagnostic Confusion Assessment Method and the Mini-Mental State Examination on postoperative days 1, 3, 5, and 7. Exploratory outcomes included inflammatory cells (leucocytes and neutrophil counts), cytokines (IL-6, TNF-α, S100β), stress markers, and the systemic inflammatory response index. Other measures comprised hemodynamic parameters, anesthesia parameters, and potential adverse events.

Results: All 92 patients completed the intention-to-treat analysis. At 24h postoperation, the remimazolam group showed significantly higher CRP, IL-6, leukocyte counts, neutrophil counts, and systemic inflammatory response index than the propofol group. No differences were found in TNF-α, S100β, or PND incidence (8.7% vs 6.5%). Stress marker levels were comparable between groups at all time points. Additionally, the remimazolam group demonstrated shorter anesthesia awakening time (P<0.001), with reduced incidence of hypotension (P <0.001) and injection pain (P = 0.015).

Conclusion: Although remimazolam is less effective than propofol in suppressing the early postoperative inflammatory response in elderly patients undergoing VATS, it did not increase the risk of PND or infection. It has significant advantages in hemodynamic stability, facilitates faster recovery, and reduces injection pain, establishing it as a preferred anesthetic option for geriatric VATS, though its inflammatory mechanisms require clarification.

Purpose: The Poikilospermum genus, which belongs to the Urticaceae family, has historically been used for medicinal purposes in Southeast Asia. However, its phytochemical potential and pharmacological mechanisms have not yet been adequately investigated. This review consolidates current data on the bioactive chemicals and therapeutic potential of Poikilospermum spp. with an emphasis on Poikilospermum suaveolens (Blume) Merr.

Methodology: A comprehensive search was performed using the PubMed, Scopus, Google Scholar, and Web of Science databases. This study examined publications from 2015 to 2025 that explored the phytochemical composition and pharmacological properties of Poikilospermum species. Terms such as "Poikilospermum", "inflammatory", "phytochemicals", "anticancer", "ethnobotany", "phytochemistry", "pharmacological", "antimicrobial", and "antioxidant".

Results: The investigation revealed various bioactive components such as flavonoids, tannins, alkaloids, and terpenoids, which contribute to the antibacterial, anti-inflammatory, and antioxidant capabilities of Poikilospermum. Initial data indicated possible anticancer properties of P. suaveolens; however, additional research is required to validate these effects and elucidate the underlying pathways.

Conclusion: Poikilospermum species, particularly P. suaveolens, is a promising source of bioactives; priority next steps include standardized in vivo studies, toxicity assessment, and targeted mechanistic work. Subsequent studies should focus on clinical trials and more in-depth inquiries into the mechanisms of action of identified substances.

Xenin, a 25-amino acid peptide hormone predominantly secreted by intestinal K cells, demonstrates evolutionary conservation with neuropeptides such as xenopsin and neurotensin. Functionally, it engages neurotensin receptor 1 (NTSR1) to regulate appetite via hypothalamic signaling pathways and modulates glucose homeostasis through synergistic interactions with incretin hormones. Preclinical studies highlight its dual role in suppressing appetite and enhancing pancreatic β-cell survival, while a single pilot human study suggests xenin-25 may delay gastric emptying and attenuate postprandial glucose excursions; however, these data await independent confirmation. Native xenin, however, is constrained by rapid proteolytic degradation and limited bioavailability. Advances in peptide engineering, including C-terminal truncation, site-directed amino acid substitution, and lipidation, have generated analogues that exhibit prolonged metabolic activity in rodent models, with plasma half-life extended from minutes to hours. In murine models of metabolic dysfunction, these derivatives enhance insulin secretion, improve glycaemic profiles and restore incretin responsiveness. Furthermore, multi-agonist peptides combining xenin with other gastrointestinal hormones show synergistic potential in preclinical studies, concurrently augmenting insulin secretion and reducing energy intake, though their clinical relevance remains to be validated in human trials. Despite promising preclinical outcomes, challenges persist in translating xenin-based therapies to clinical practice, including incomplete mechanistic insights into receptor cross-talk and species-specific variations in gastrointestinal responses. This review uniquely integrates the preclinical landscape of xenin biology, peptide-engineering principles, and emerging multi-agonist design, identifying knowledge gaps critical for future translation. We conclude that xenin-based therapeutics are a promising yet early-stage strategy whose efficacy and safety in human metabolic diseases remain to be established through rigorous pharmacokinetic profiling and phased clinical trials.

Pyrazoline benzenesulfonamide derivatives represent a distinctive class of heterocyclic compounds that synergistically combine the pharmacological versatility of the pyrazoline scaffold with the enzyme-inhibitory prowess of benzenesulfonamide moieties. These hybrids have emerged as promising candidates in anticancer drug discovery. This review systematically examines various synthetic strategies employed to prepare these derivatives, including classical Claisen-Schmidt condensation as well as modern ultrasound- and microwave-assisted protocols. These methods facilitate efficient structural diversification, incorporating a wide range of heterocyclic and aromatic substituents such as morpholine, pyrazole, benzodioxole, tetrazole, and ferrocene. Biological evaluations, integrating both in vitro cytotoxicity assays and in silico molecular docking studies, were analyzed to elucidate the anticancer potential and mechanistic insights of these compounds, particularly their selective inhibition of tumor-associated enzymes such as matrix metalloproteinases (MMP-2, MMP-9), carbonic anhydrase isoforms (hCA IX, hCA XII), and cyclooxygenase-2 (COX-2). The results reveal that several derivatives exhibit potent antiproliferative activity across multiple cancer cell lines, including lung (A549), breast (MCF-7), cervical (HeLa), colon (COLO 205), and oral squamous carcinoma, demonstrating significant tumor selectivity and low toxicity toward normal cells. Structure-activity relationship analyses further underscore the critical influence of electronic substituents and their positioning on aromatic rings in modulating both efficacy and selectivity. These findings highlight the therapeutic potential of pyrazoline benzenesulfonamide derivatives and support the continued optimization of synthetic strategies and mechanistic studies to facilitate their development as effective anticancer agents capable of overcoming clinical challenges such as drug resistance and adverse side effects.