Drug Design, Development and Therapy最新文献

Purpose: To evaluate the efficacy and safety of intranasal dexmedetomidine (Dex), oral lorazepam, and a placebo in managing preoperative anxiety-related insomnia.

Patients and methods: A total of 90 patients exhibiting symptoms of preoperative anxiety and insomnia were randomly assigned to three groups: Dex (receiving 2.5 µg/kg Dex intranasally and starch tablets orally), lorazepam (receiving saline intranasally and 2 mg lorazepam orally), and placebo (receiving saline intranasally and starch tablets orally). Interventions were conducted the night before surgery. The primary outcome was measured using the Leeds Sleep Evaluation Questionnaire (LSEQ) to evaluate changes in sleep quality pre- and post-intervention. Secondary outcomes included monitoring sleep on the night of the intervention, sleep satisfaction scores, changes in vital signs within 2 hours post-intervention, and adverse reaction rates.

Results: According to sleep assessments using the LSEQ, the Dex group demonstrated significant improvements in ease of getting to sleep (GTS), ease of awakening (AFS), and alertness and behavior after waking (BFW) compared to the lorazepam group (p < 0.05). However, no significant differences were observed in the quality of sleep (QOS) between the two groups (p > 0.05). Sleep monitoring indicated that the Dex group had a median sleep onset latency (SOL) of 19.0 min, significantly shorter than those recorded for the lorazepam group at 33.5 min and the placebo group at 57.0 min (p < 0.001). The total sleep time (TST) and sleep efficiency (SE) were 403.7 min and 84.5% for the Dex group, similar to the lorazepam group (408.6 min, 83.2%)(p >0.999) and superior to the placebo group (278.8 min, 57.4%)(p < 0.001). Sleep satisfaction scores did not significantly differ between the Dex and lorazepam groups (p > 0.999). No serious adverse reactions were reported across the groups.

Conclusion: Both 2.5 μg/kg intranasal Dex and 2 mg oral lorazepam effectively improved sleep quality in patients with preoperative anxiety-related insomnia. While both treatments were comparable in maintaining sleep, intranasal Dex was more effective in initiating sleep and enhancing daytime functionality than lorazepam.

Cryptotanshinone (CTS) is an important active ingredient of Salvia miltiorrhiza Bge. In recent years, its remarkable pharmacological effects have triggered extensive and in-depth studies. The aim of this study is to retrieve the latest research progress on CTS and provide prospects for future research. The selection of literature for inclusion, data extraction and methodological quality assessment were discussed. Studies included (1) physicochemical and ADME/Tox properties, (2) pharmacological effects and mechanism, (3) conclusion and bioinformatics analysis. A total of 915 titles and abstracts were screened, resulting in 184 papers used in this review; CTS has shown therapeutic effects on a variety of diseases by modulating multiple molecular pathways. For example, CTS primarily targets NF-κB pathway and MAPK pathway to have a therapeutic role in cardiovascular diseases; in cancer, CTS shows superior efficacy through the PI3K/Akt/mTOR pathway and the JAK/STAT pathway; CTS act on the Nrf2/HO-1 pathway to combat neurological diseases. In addition, key targets of CTS were predicted by bioinformatics analysis, referring to disease ontology (DO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis, with R Studio; AKT1, MAPK1, STAT3, P53 and EGFR are predicted to be the key targets of CTS against diseases. The key proteins were then docked by Autodock software to preliminarily assess their binding activities. This review provided new insights into research of CTS and its potential applications in the future, and especially the targets and directly binding modes for CTS are waiting to be investigated.

Background: Dexmedetomidine has received increasing attention for its sedative, analgesic, anxiolytic, anti-inflammatory and anti-stress effects in perioperative medicine. Numerous studies have been carried out to explore its influence on perioperative patients.

Objective: This study aimed to identify the most influential literature, trends and hotspots in dexmedetomidine research by bibliometric analysis.

Methods: Articles and reviews related to dexmedetomidine in perioperative medicine were collected from Web of Science Core Collection. VOSviewer and Citespace software were used for bibliometric analysis and data visualization.

Results: A total of 1652 suitable publications were extracted from the database for analysis, including 1,497 articles and 155 reviews. The number of publications in the field of dexmedetomidine research has increased markedly since 2013, with China being the major contributor, followed by United States. BMC Anesthesiology published the highest number of papers on this topic. Anesthesiology ranked first in terms of average citations per paper and co-citation journal. Ji Fuhai was the most prolific author, and Ma Daqing was the most cited authors. The main hotspots during this period were "elderly patients", "postoperative cognitive dysfunction", "injury" and "risk factors".

Conclusion: This study presents an overview of the development related to dexmedetomidine in perioperative medicine using bibliometric analysis. Dexmedetomidine research is thriving and expanding rapidly around the world. The effect of dexmedetomidine on cognitive function has been the latest research hotspot. To advance research in this field, more rigorous and scientific multi-center studies should be designed and further cooperation and academic exchange should be strengthened.

Targeting B cells through monoclonal antibodies against CD20 has emerged as a highly effective strategy in managing disease activity in patients with relapsing forms of multiple sclerosis. This efficacy was initially demonstrated with rituximab and further affirmed with ocrelizumab. Ofatumumab is the first fully human IgG1 monoclonal antibody (mAb) approved for the treatment of MS. It is characterized by its convenient self-administered regimen of once-monthly subcutaneous injections. Its human antibody nature contributes to a significantly lower risk of immunogenicity compared to rituximab. Clinical trials have consistently shown its effectiveness in significantly reducing annualized relapse rates, MRI-detected lesion activity, and disability progression when compared to teriflunomide, a standard therapy for MS. Additionally, ofatumumab exhibits a manageable tolerability profile, with adverse events primarily comprising infections and injection-related reactions. This review describes ofatumumab pharmacology, core clinical trial data and clinical efficacy in addition to safety issues.

Objective: Depression and osteoporosis are usually concurrent health problems. This study aimed to explore the development of osteoporosis in depressive mice model and investigate the beneficial effects of the classical herbal formula Chaihu-Shugan-San (CHSG) on the brain and bone.

Methods: CHSG powder was prepared by spray-drying following extraction with water. The fingerprint of CHSG was analyzed using liquid chromatography. The depressive-like model was established by chronic unpredictable mild stress (CUMS) in female mice. The depressive behaviors and trabecular bone properties (measured by micro-CT) were detected at 2, 4, 6, and 8 weeks of CUMS. RT-PCR, immunoblotting and immunofluorescence were applied to measure expression of inflammatory cytokines and morphology of microglias in the hippocampus. Biochemical measurements and histological staining on the adrenal gland were carried out to assess the activity of hypothalamic-pituitary-adrenal (HPA) axis. Histological staining, three-point bending strength, and the expression of regulators involved in bone metabolism were determined.

Results: The treatment with CHSG for 8 weeks could ameliorate depressive behaviors, and down-regulate mRNA expression and tissue content of inflammatory factors IL-1β and IL-6 in hippocampus of CUMS mice. The inhibition of CHSG on neuroinflammation might be attributed to its repression of activity in microglias and NLRP3-triggered inflammation pathway. The serum of rats dramatically alleviated LPS-induced phosphorylation of nuclear NFκB (P65) and IκBα and up-regulation of IL-1β and IL-6 proteins in microglia BV2 cells. CUMS induced over-activity of HPA axis shown by the elevation in serum level of ACTH and corticosterone and in area percentage of zona fasciculata, intriguingly, CHSG reversed those changes in HPA system, ameliorated the reduction in mechanical strength and bone mineral density, and regulated bone metabolism factors of CUMS mice.

Conclusion: The chronic stress-induced depression resulted in bone disorders developing to osteoporosis. Chaihu-Shugan-San exerted beneficial effects on skeletal tissue by ameliorating neuroinflammation and HPA over-activity of mice with depression.

Portulaca oleracea L. (POL) has a long history of medicinal use worldwide, and numerous clinical and experimental studies demonstrated the therapeutic effects of POL and its active ingredients in the treatment of Ulcerative colitis (UC). In this review, we summarized the underlying mechanisms and roles of POL in UC treatment based on experimental and clinical studies. The research articles cited in this study were obtained by employing specific keywords, such as "purslane", "IBD", "UC", "inflammation", "gut microbiota", and "intestinal barrier", in PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure databases. Clinical studies found that both POL monotherapy and POL traditional Chinese medicine compound are effective in treating UC. Meanwhile, experimental studies found that POL intervenes in UC by regulating intestinal flora, repairing mucosal barrier, and regulating immune response. Increasing evidence suggests the therapeutic potential of POL in UC treatment.

Background: Precancerous lesions of gastric cancer (PLGC) represent critical stages in gastric cancer progression, with a high risk of malignancy. Current treatments, such as Helicobacter pylori eradication, show limited efficacy in reversing precancerous molecular changes. Zuojin Pill (ZJP), a traditional Chinese medicine, has demonstrated potential for treating digestive disorders and may offer a promising approach for PLGC intervention.

Objective: This study aims to investigate the therapeutic effects and mechanisms of ZJP in treating PLGC, focusing on its active components, target pathways, and molecular interactions. By using advanced analytical techniques, we provide a scientific foundation for ZJP's potential application in early gastric cancer intervention.

Methods: Using ultra-high performance liquid chromatography-quadrupole orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS), we identified active components in ZJP. A network pharmacology approach was then applied to construct a "ZJP-compound-target-disease" network. Molecular docking and molecular dynamics simulations were conducted to analyze the stability and interactions of the main active components of ZJP with core protein targets in PLGC. Animal experiments were used to validate significant targets and pathways in vivo.

Results: Tangeritin, Isorhamnetin, Caffeic Acid, Azelaic Acid, and Adenosine were identified as the main active components of ZJP in the treatment of PLGC, with key targets including PIK3R1, MAPK3, SRC, JAK2, STAT3, and PIK3CA. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of ZJP predicted by network pharmacology analysis was confirmed in PLGC rats. ZJP downregulated IL-6, TNF-α, c-myc, p-MEK1 and p-ERK1/2, effectively reversing the progression of PLGC.

Conclusion: ZJP can reverse MNNG-induced PLGC, potentially through inhibition of the MEK/ERK/c-myc pathway and regulation of cellular proliferation and apoptosis.

Over the past two decades, synthetic FFAR1 agonists such as TAK-875 and TSL1806 have undergone meticulous design and extensive clinical trials. However, due to issues primarily related to hepatotoxicity, no FFAR1 agonist has yet received regulatory approval. Research into the sources of hepatotoxicity suggests that one potential cause lies in the molecular structure itself. These structures typically feature lipid-like carboxylic acid head groups, which tend to generate toxic metabolites. Strategies to mitigate these risks focus on optimizing chemical groups to reduce lipophilicity and prevent the formation of reactive metabolites. Recent studies have concentrated on developing low-molecular-weight compounds that more closely resemble natural products, with CPL207280 showing promising potential and liver safety, currently in Phase II clinical trials. Moreover, ongoing research continues to explore the potential applications of FFAR1 agonists in diabetes management, as well as in conditions such as non-alcoholic fatty liver disease (NAFLD) and cerebrovascular diseases. Utilizing advanced technologies such as artificial intelligence and computer-aided design, the development of compact molecules that mimic natural structures represents a hopeful direction for future research and development.

Background: Nemonoxacin is a novel non-fluorinated quinolone antibiotic for the treatment of community-acquired pneumonia. To investigate the pharmacokinetics (PK) of nemonoxacin, a simple and sensitive high-performance liquid chromatography assay (HPLC) was needed.

Methods: An HPLC method with fluorescence (FL) detection was developed for the quantification of nemonoxacin in plasma and bile. Ultraviolet (UV) and FL characteristics were examined for the optimal detection conditions. Nemonoxacin and the internal standard gatifloxacin were extracted from plasma utilizing ethyl acetate-isopropanol (70/30, v/v). For bile sample preparation, direct dilution with the mobile phase buffer was used. Chromatographic separation was achieved on a C6-phenyl column (5 μm, 25 cm × 4.6 mm i.d.) at 30 °C with a flow rate of 1 mL/min. The mobile phase was composed of methanol and 50 mM potassium dihydrogen phosphate containing 0.5% (v/v) triethylamine (pH 7.5) (45/55 and 35/65 (v/v) for plasma and bile samples, respectively). FL was measured at an emission wavelength of 465 nm with excitation at 285 nm.

Results: The calibration curves were linear with a lower limit of quantification of 5 and 100 ng/mL in a small volume of plasma (50 μL) and bile (10 μL). The intra- and inter-day precision was within 9.0% and the accuracy was within 7.6% deviation of the nominal concentration. Nemonoxacin was stable under various storage/handling conditions tested. The method was successfully employed to describe the plasma and biliary profiles of nemonoxacin in rats following a single intravenous dose of 1 mg/kg. Nemonoxacin displayed two-compartment disposition kinetics. The bile-to-plasma area under concentration-time curve ratio (AUC_bile/plasma) estimated was 50.7, indicating that nemonoxacin was actively secreted into bile.

Conclusion: A validated method was developed and found to be specific, precise and accurate. The applicability of this proposed method was substantiated in pharmacokinetic studies in rats.

Objective: To investigate the effect of sodium bicarbonate Ringer's solution (BRS) on the degradation of endothelial glycocalyx components in patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, and to evaluate its impact on endothelial glycocalyx preservation and postoperative recovery.

Patients and methods: A total of eight patients scheduled for elective CPB heart surgery were included and randomly divided into two groups: the sodium lactate Ringer's solution (LRS) group and the BRS group. ELISA was used to measure plasma concentrations of syndecan-1, matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-3 (MMP-3), IL-6, IL-8, TNF-α, and TGF-β at predefined time points: T0 (before induction of anesthesia), T3 (immediately after weaning from CPB), T5 and T6 (24 and 72 hours postoperatively). Serum creatinine concentrations were measured within 48 hours postoperatively. The incidence of postoperative delirium (POD) was assessed three days after surgery. Postoperative mechanical ventilation time, duration of stay in the intensive care unit and hospital stay were also documented.

Results: The BRS group had significantly lower plasma concentrations of syndecan-1 at T3 (7.98 [7.43, 8.92] ng/mL vs 9.54 [8.4, 10.73] ng/mL, P < 0.001) and T5 (4.20 [3.31, 4.96] ng/mL vs 5.40 [3.95, 6.55] ng/mL, P = 0.001) in comparison with the LRS group (P<0.01). Syndecan-1 levels in both groups were similar at T6 (3.18 [2.88, 3.5]ng/mL vs 3.12 [2.77, 3.45] ng/mL, P > 0.05). Additionally, MMP-9, MMP-3, IL-6 and IL-8 were significantly lower at T3 and T5 in the BRS group (P<0.05 and P<0.01, respectively). However, no significant differences were observed between the two groups in the incidence of acute kidney injury (AKI) or POD (P > 0.05).

Conclusion: BRS has the potential to reduce glycocalyx degradation in patients undergoing heart valve surgery with CPB. However, both groups demonstrated similar post-postoperative clinical outcomes, including the rates of AKI and POD.