Drug Design, Development and Therapy最新文献

Purpose: This study compares the analgesic effects of the Thoracoscopic Direct-view Thoracic Paravertebral Nerve Block (DTPVB) with those of the Ultrasound-guided Thoracic Paravertebral Nerve Block (UTPVB), providing a clinical reference.

Patients and methods: Sixty-eight patients undergoing three-port video-assisted thoracic surgery (VATS) with general anesthesia were randomly assigned to either the DTPVB group (Group D, n = 34) or the UTPVB group (Group U, n = 34). Both groups received a 10 mL injection of 0.75% ropivacaine at the T4 and T7 interspaces. Primary outcomes were cumulative sufentanil equivalents from the start of lung manipulation to 24 hours postoperatively, with group differences assessed against a non-inferiority margin of 5 μg (Δ). Secondary outcomes include postoperative pain scores, analgesic consumption, patient satisfaction, adverse effects, and other related indicators.

Results: The cumulative use of sufentanil equivalents from the start of lung manipulation to 24 hours postoperatively was 35.0 ± 6.1 μg in Group D and 33.2 ± 5.6 μg in Group U, with no significant difference (P = 0.217). The difference in cumulative sufentanil equivalents (Group D minus Group U) was 1.8 (95% CI -1.07, 4.65), within the non-inferiority margin of 5 (Δ). Postoperative pain scores, analgesic consumption, adverse effects, and complications were similar were similar between groups. However, DTPVB was associated with lower anxiety and higher satisfaction (P<0.001). At 15 minutes post-block, ropivacaine plasma concentrations were higher in Group D (P=0.024).

Conclusion: DTPVB, via transmural pleural puncture, was non-inferior to UTPVB in analgesic efficacy from the beginning of the manipulation of the lungs in operation to 24h postoperatively. DTPVB provides a good alternative, especially for patients who are anxious before surgery, have difficulty cooperating with UTPVB, or in cases where UTPVB puncture fails. However, when using high concentrations of ropivacaine, greater vigilance for toxicity is required.

Aim: The aim of this study was to compare the efficacy and safety of fixed-dose combination (FDC) of pioglitazone and metformin supplemented with dapagliflozin (test group) with those of basal insulin supplemented with metformin (control group) in patients with inadequately controlled type 2 diabetes mellitus (T2DM).

Methods: This 16-week, prospective, randomized, open-label study enrolled patients aged 18-75 years with glycated hemoglobin (HbA1c) levels between ≥ 8% and ≤ 11%. The primary endpoint was the proportion of patients who achieved HbA1c < 7% at week 16 without hypoglycemia or weight gain. The secondary endpoints included blood glucose, lipid profile, body weight, body mass index, inflammatory markers, bone Gla-protein, liver enzymes, and patient satisfaction.

Results: Among the full analysis set of 147 participants, no significant difference was observed in the primary endpoint between the test group and the control group. However, the test group had a higher percentage of patients who achieved HbA1c <7% at week 16 without hypoglycemia and experienced a weight loss of ≥3% (31.51% vs 13.51%, P=0.009). Patients in the test group whose BMI≥24 kg/m² also achieved a substantial achievement rate (36.73% vs 15.79%, P=0.014). The test group also exhibited a greater reduction in body weight and improvements in 2-hour postprandial glucose level, systolic blood pressure, and lipid profile. Notably, combination therapy did not increase the risk of hypoglycemia or weight gain. Patients in the test group were more satisfied than those in the control group with continuing to accept pioglitazone/metformin FDC combined with dapagliflozin.

Conclusion: In the absence of contraindications, pioglitazone/metformin FDC supplemented with dapagliflozin may serve as a safe and effective alternative to basal insulin combined with metformin for rectifying inadequate glucose control, as the former enables metabolic improvements without compromising safety.

Chinese clinical trial registry number: CHiCTR2000036076. https://www.chictr.org.cn/showproj.html?proj=58825.

Purpose: Bile acids promote the progression of colon adenocarcinoma (COAD), and ursodeoxycholic acid (UDCA) is a key drug in promoting bile acid excretion, but its role in COAD unclear. Our study aims to investigate the relationship between COAD and bile acid metabolism and to assess the feasibility of UDCA for the treatment of COAD.

Methods: Firstly, biological targets closely related to COAD were identified: Based on the cancer genome atlas (TCGA) database, the core genes of COAD were obtained by differential expression analysis and weighted gene-coexpression network analysis (WGCNA), and subjected to gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Secondly, finding a drug by target, after identifying UDCA as a candidate drug, the feasibility of UDCA in treating COAD was verified in reverse: Using databases to collect potential targets for COAD and UDCA, and the intersecting genes were the potential targets for UDCA to exert anti-tumor effects. Then Autodock was used for molecular docking to analyze the interaction between UDCA and core target proteins. Finally, experimental validation was performed: MTT assay, wound healing, transwell migration, and angiogenesis assays were used to detect the effects of UDCA on cell proliferation, migration, invasion, and neovascularization.

Results: 2064 differential genes were screened from TCGA. WGCNA obtained the module most relevant to CRC, containing 493 genes. KEGG analysis found that overlapping genes were mainly concentrated in bile acid metabolic pathways. A total of 26 UDCA anti-tumor targets were obtained in database, and 5 core targets were selected by STRING database and Cytoscape software: TNF, CYP27B1, MDM2, MMP2, CASP3. Molecular docking results showed that UDCA had good binding activity with the core targets. In vitro experiment showed UDCA effectively inhibited the proliferation, migration, invasion and neovascularization in colon cancer cells.

Conclusion: The antitumor activity of ursodeoxycholic acid may be related to cell apoptosis, proliferation, migration and vascular neogenesis.

Background: This study seeks to identify research trends and hotspots concerning tyrosine kinase inhibitors (TKIs) for the treatment of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) through a comprehensive bibliometric analysis.

Methods: Publications on TKIs and EGFR-mutated NSCLC from 2006 to 2024 were analyzed using VOSviewer, CiteSpace, and R-bibliometrix to visualize collaboration, keyword co-occurrences, and research trends.

Results: A total of 962 articles were analyzed, authored by 7,458 researchers from 5,401 institutions across 208 countries. Wu Yi-Long was identified as the most prolific author, contributing 30 publications. AstraZeneca emerged as the industrial leader with 103 articles, while the New England Journal of Medicine was recognized as the primary journal with the highest total link strength. Keyword co-occurrence analysis revealed significant research topics including "gefitinib", "chemotherapy", "open label", and "erlotinib." Moreover, keyword burst analysis indicated notable periods of increased research focus on topics such as "osimertinib" and "liquid biopsy", suggesting emerging trends and current hotspots in the treatment of EGFR-mutated NSCLC.

Conclusion: This analysis highlights research trends on TKIs for EGFR-mutated NSCLC, emphasizing the importance of targeted therapies like gefitinib and osimertinib for future research and clinical practice enhancement.

Background: Temozolomide (TMZ) is a first-line chemotherapeutic agent for gliomas. However, its efficacy is limited by drug resistance. Platycodin D (PD) exhibits notable anti-glioma activity The objective of this study was to investigate the potential of PD to augment glioma sensitivity to TMZ and the underlying mechanisms.

Methods: Cell viability and proliferation were assessed using CCK-8 and clonogenic assays, respectively, while flow cytometry was used to detect apoptosis. Cell migration and invasion were assessed using Transwell assays. Western blotting and immunohistochemistry analyses were performed to determine protein expression levels. A xenograft glioma model was established to investigate the in vivo effects of PD.

Results: PD augmented glioma cell sensitivity to TMZ, as evidenced by heightened inhibition of cell growth, colony formation, migration, and invasion, accompanied by elevated apoptosis. Treatment with PD or a combination of PD and TMZ robustly suppressed the expression of active β-catenin and c-Myc, which was reversed by the β-catenin activator, SKL2001. In vivo experiments demonstrated that PD amplified the anti-glioma efficacy of TMZ, resulting in diminished Ki67 expression and substantially reduced expression of active β-catenin and c-Myc in the tumor tissue.

Conclusion: PD augmented glioma cell sensitivity to TMZ by modulating Wnt/β-catenin pathway. Our findings demonstrate the potential of PD as an innovative therapeutic agent to enhance glioma treatment, especially in TMZ-resistant gliomas.

Objective: To evaluate the effects of different ciprofol doses on hemodynamics in patients undergoing cardiac surgery.

Methods: 209 patients were randomly divided into four groups: 0.2 mg/kg etomidate group (group E, n = 50), 0.2 mg/kg, 0.3mg/kg, 0.4mg/kg ciprofol group (group A, n = 53, group B, n = 51, group C, n = 54). Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and bispectral index were recorded at the following time points: 5 minutes after entering the operating room (T₀); before anesthesia induction (T₁); immediately after induction (T₂); 1 minute and 2 minutes after induction (T₃~T₄); at intubation (T₅); 1 minute, 3 minutes, 5 minutes and 10 minutes after intubation (T₆~T₉); at skin incision (T₁₀). The incidence of hypotension and bradycardia and the doses of vasoactive drugs were recorded.

Results: Compared with T₀, HR, MAP, SV, CO all decreased to varying degrees after administration, and the decrease time in Group B and Group C were earlier than that in other two groups (P < 0.05). SVR increased slowly after T₄ in all groups, but there was no significant differences (P > 0.05). Compared with group E, the norepinephrine dose was significantly lower in groups A and B (both P < 0.05). Group C showed a greater decline in CO and SV than the other three groups from T₇ to T₁₀ (P < 0.05), while there was no significant difference between groups A and E in CO and groups A, B, and E in SV (P > 0.05). No significant differences were observed in MAP, SVR, and the incidences of hypotension and bradycardia among the four groups (P > 0.05).

Conclusion: 0.2 mg/kg ciprofol has the least impact on hemodynamics in patients undergoing cardiac surgery, and reduced norepinephrine use.

Background and aim: Postoperative sore throat is a common complication following endotracheal intubation, which can significantly affect patient comfort and recovery. The purpose of this study is that compares the efficacy of preoperative topical magnesium sulfate spraying with that of magnesium sulfate gargling aimed at preventing postoperative sore throat.

Patients and methods: 236 Participants were randomly allocated to either the magnesium sulfate spray group (Group A) or the magnesium sulfate gargle group (Group B), with 118 patients in each group. In Group A, during intubation under direct laryngoscopy, 15 mg/kg of magnesium sulfate was sprayed using a single-use otorhinolaryngology anesthesia sprayer onto the pharyngeal mucosa and posterior pharyngeal wall near the glottis. In Group B, gargling with 20 mg/kg of magnesium sulfate for 30 seconds 15 minutes before surgery. The primary outcome measure was the total incidence of postoperative sore throat within 48 hours, with a non-inferiority margin of 0.15.

Results: The upper limit of the 95% confidence interval (CI) for the difference in the total incidence of POST between Group A and Group B was below the non-inferiority margin (0.15) (non-inferiority P<0.001). The upper limits of the 95% CI for the differences in the incidence rates of POST between Group A and Group B at time points T1- T6 were all below the non-inferiority margin (all non-inferiority P<0.001). The total incidence of POST (P=0.046) and the incidence of POST at T2-T4 (all P<0.001) in group A were lower than those in group B. The analysis of the individual effects between groups indicated significant differences in POST NRS scores at T1 (P=0.034) and T2-T4 (all P<0.001).

Conclusion: The local spray of magnesium sulfate on the throat before surgery to prevent postoperative sore throat is not inferior to, and may even be superior to, gargling with magnesium sulfate.

Background: Non-alcoholic steatohepatitis (NASH), as a progressive form of Non-alcoholic fatty liver disease (NAFLD), poses a significant threat to human health as a prevalent and common condition, with a lack of safe and effective therapeutic options. However, the therapeutic effects and potential mechanisms of Lang Qing Ata (LQAtta) against NASH remain elusive.

Materials and methods: The components of LQAtta were identified using Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS). Subsequently, we employed network construction and analysis approaches within the field of network pharmacology. By integrating known databases and target prediction algorithms, which encompassed database-based target prediction, protein-protein interaction networks, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we unveiled the potential key targets and signaling pathways that these bioactive components might engage with. These discoveries were further validated in subsequent mouse models. An HFHC-induced NASH mouse model was used to validate the therapeutic effects and potential mechanisms of LQAtta on NASH.

Results: From the UHPLC-MS/MS analysis of LQAtta, a total of 1518 chemical components were identified, with 106 of them being absorbed into the bloodstream. Additionally, based on the acquisition of targets from both LQAtta and the NASH database, a total of 160 common targets were screened. KEGG enrichment analysis indicated that LQAtta may alleviate NASH by modulating pathways such as the Toll-like receptor signaling pathway, the NF-κB signaling pathway, and inflammation-related pathways. In vivo experimental results demonstrated that LQAtta could alleviate liver injury, steatosis, and inflammation induced by NASH, thereby slowing down the disease process. Additionally, LQAtta inhibited the expression and phosphorylation of NF-κB protein, playing a role in preventing NASH.

Conclusion: In this study, the combination of mass spectrometry analysis, network pharmacology, and animal experiments preliminarily elucidated the potential of LQAtta to treat NASH through NF-κB pathways.

Objective: This Phase I study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BGT-002, a novel ATP-citrate lyase (ACLY) inhibitor, in healthy Chinese adults.

Methods: This study included three parts: Part I (single-ascending-dose study), Part II (multiple-ascending-dose study), and Part III (food effect study). A total of 104 healthy subjects were enrolled in the study and were given BGT-002 tablet or placebo per protocol requirements. Blood samples were collected for pharmacokinetic and pharmacodynamic analysis. Safety was assessed by clinical examinations and adverse events.

Results: In Part I, BGT-002 demonstrated rapid absorption with a T_max of 0.67 to 1.75 hours, and slow elimination with a T_1/2 of 24.53 to 72.86 hours, prolonged with increased dosages. C_max and AUC_0-∞ ranged from 1.55 to 48.39 μg/mL, and 31.09 to 2930.69 h·μg/mL, respectively. In Part II, the accumulation index (Rac) of C_max and AUC_tau following 14 days of consecutive administration were 3.53 to 3.62 and 5.29 to 5.59, respectively, with a dose-proportionality PK profile. The levels of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), and low-density lipoprotein cholesterol (LDL-C) were maximally decreased by 15.80%, 18.50%, and 22.37%, respectively. In Part III, the geometric mean ratio (90% CI) of fed to fasting condition in C_max and AUC_0-∞ of BGT-002 were 73.11% and 98.36%, respectively, indicating a minor food effect on the absorption rate. Across the study, two cases of Grade 3 adverse events (elevated blood triglycerides) were reported, both of which were assessed as not related to BGT-002. No serious adverse events were observed.

Conclusion: BGT-002 demonstrated favorable safety, tolerability, and lipid-lowering effects, supporting its potential for further clinical development.

Clinical trial registration: ChiCTR2200057793(https://www.chictr.org.cn/showproj.html?proj=160210); ChiCTR2300067474(https://www.chictr.org.cn/showproj.html?proj=182183); ChiCTR2300067472(https://www.chictr.org.cn/showproj.html?proj=184079).

[This corrects the article DOI: 10.2147/DDDT.S489534.].