Drug Design, Development and Therapy最新文献

Background: Modified Suanmei-Tang (MST) comprises four plants common to both traditional Chinese medicine and culinary applications, and it can potentially alleviate metabolic-associated fatty liver disease (MAFLD) triggered by a high-fat diet (HFD).

Purpose: This research aims to investigate the impact and underlying mechanisms of MST in ameliorating MAFLD caused by an HFD.

Methods: UHPLC-Q-Orbitrap-MS/MS was used to determine the constituents of MST and to evaluate its effects on MAFLD mouse models. Transcriptomics, network pharmacology, and bioinformatics analysis (including Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis) were utilized to further clarify the mechanisms by which MST acts on MAFLD. The experimental methods included ELISA, real time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, molecular docking, and metabolomics. Transcriptomics was integrated with metabolomics to find correlations between differentially expressed genes and metabolites, and crucial genes were validated through RT-qPCR.

Results: A total of 23 components of MST were identified. The formulation was found to alleviate metabolic disorders, obesity, insulin resistance, inflammation, and oxidative stress in mice with MAFLD. The findings indicate that MST promoted autophagy by suppressing phosphorylation in the PI3K/AKT/mTOR pathway and enhancing lipid management in the livers of MAFLD mice.

Conclusion: MST could effectively improve lipid metabolism disorders and liver lipid deposition in MAFLD mice, and its mechanism might be related to regulating the PI3K/AKT/mTOR pathway to improve autophagy.

Purpose: This study aimed to compare the impact of remimazolam-based versus propofol-based intravenous anesthesia on surgical stress and post-operative immune function in patients undergoing gastric radical surgery.

Patients and methods: Sixty-eight patients aged 50 to 80 undergoing gastric radical surgery were randomly assigned to the remimazolam group (group R) or the propofol group (group P), receiving remimazolam or propofol-based intravenous anesthesia, respectively. The primary outcome measured was peri-operative serum stress indicators and lymphocyte subtypes. Secondary outcomes included hemodynamic vitals, recovery quality, postoperative pain profiles and potential adverse effects.

Results: The demographic and surgical characteristics of the 60 analyzed patients were comparable. The absolute counts of CD3+CD4+ and CD3+CD8+ cell decreased significantly on POD1 compared with baseline. On POD3, the numbers of CD3+CD4+ cells in group R were lower than baseline and Group P, whereas the CD3+CD8+ cell counts in both groups were lower than baseline, with group R higher than group P. The CD3-CD16+CD56+ cell numbers in both groups on POD1 and POD3 decreased significantly compared to baseline with group P lower than group R on POD3. The serum levels of IL-1β, IL-6, TNF-α, ACTH and COR rose sharply 2 hours after the beginning of surgery compared to baseline. Notably, all these parameters in group R were higher than those in group P. Additionally, blood pressure and intra-operative vasoactive drug frequency in group R were higher than that in group P. No significant differences in recovery quality, postoperative pain profiles, and potential adverse effects were observed.

Conclusion: Remimazolam-based intravenous anesthesia might favour the recovery of cellular immune function in early postoperative period compared to propofol. On the contrary, remimazolam was inferior to propofol in suppressing surgical stress. Further studies with larger sample sizes are needed to confirm our findings.

Background: In response to the urgent need for continuous discovery of new anti-proliferative agents, a new series of quinazoline compounds 5a-r was prepared.

Methods: As a reference, four cancer cell lines-HCT116, HePG2, Hela, and MCF-7-and sorafenib (SOR) were used to assess the novel motifs' in vitro anticancer efficacy. The most cytotoxic compounds were tested in a VEGFR-2 suppressive test and flow cytometric test. Docking analysis was done to the three novel motifs.

Results: Compound 5d showed the best anti-tumor activity of the tested compounds with IC₅₀ 6.09, 2.39, 8.94 and 4.81 μM in succession. In addition, compound 5h revealed a potent anticancer effect against HCT116 and HePG2 with IC₅₀ 5.89 and 6.74 μM, respectively. Also, compound 5p exhibited very strong activity against HCT116, HePG2 & MCF7 with IC₅₀ 8.32, 9.72 and 7.99, respectively. Compound 5p had the highest inhibition against VEGFR-2 with an IC₅₀ of 0.117 μM, in contrast to 0.069 μM for SOR. According to flow cytometric testing, the most effective VEGFR-2 inhibitory agent, 5p, was shown to suppress the G1/S cell population in MCF-7 cells. Docking analysis confirmed that the three novel motifs could bind to the VEGFR-2 enzyme's binding region like the co-crystallized ligand SOR did.

Conclusion: The enzyme inhibitory test of compound 5p showed that it is the most potent hybrid that caused MCF-7 cells to undergo apoptosis and generated a G1/S cell cycle arrest. Confirmation of the obtained results was done with the aid of the docking study, which showed that the three motifs might adhere to the enzyme's major active sites, and the results were in good accordance with the experimental VEGFR-2 inhibitory results. We can conclude that the new quinazoline compounds 5a-r could be used as candidates for development of more efficient anticancer inhibitors.

Background: Jianweixiaoshi tablets (JWXS) is widely used in traditional Chinese medicine for treating functional dyspepsia with spleen deficiency (SD-FD) in China. However, the molecular mechanisms underlying the therapeutic effects of JWXS remain incompletely understood.

Methods: Functional dyspepsia was induced in rats with spleen deficiency by iodoacetamide in combination with the modified multiple platform method. The SD-FD rats were administered JWXS at both low and high doses, as well as domperidone. We conducted a comprehensive evaluation of the treatment effects of JWXS, including body weight, gastrointestinal motility, immune organ index, biochemical analysis, gastrointestinal hormones, and hematological studies. Quantitative proteomic analysis based on data-independent acquisition (DIA) was used to determine the changes in protein profiles of gastric and duodenal tissues in SD-FD rats and JWXS intervention rats.

Results: The results showed that JWXS effectively alleviated gastrointestinal motility disorders in SD-FD rats, as indicated by accelerated gastric emptying and intestinal propulsion, increased levels of gastrin, motilin, and ghrelin, and reduced levels of cholecystokinin-octapeptide, vasoactive intestinal peptide, and somatostatin. Additionally, JWXS increased the spleen and thymus index, increased %lymphocyte in blood, reduced white blood cell count and %neutrophil, and improved immune function. Through quantitative proteomic analysis of gastric tissues, we identified 333 differentially expressed proteins in the JWXS treatment group and the model group. Notably, the mechanism by which JWXS accelerated gastric emptying may be related to PLC-γ and SERCA2 in the calcium signaling pathway. Furthermore, JWXS treatment altered the expression of 732 proteins in rat duodenal samples. The differentially expressed proteins were enriched in immune-related functions and pathways, including antigen processing and presentation, as well as the intestinal immune network for IgA production.

Conclusion: In conclusion, JWXS exhibits a multi-faceted impact on various pathways, demonstrating its efficacy in treating SD-FD. These findings provide a foundation for the clinical application of JWXS in managing SD-FD.

Purpose: Pharmacokinetic and pharmacodynamic (PKPD) models exist for remimazolam, but data for target-controlled infusion (TCI) are limited. The Schüttler PKPD model, a three-compartment model including body weight as a covariate, does not account for age as a variable. This study aimed to investigate remimazolam's effect-site concentration (Ce) in different age groups during sedation and general anesthesia with TCI using Schüttler PKPD model.

Patients and methods: Records of patients who underwent remimazolam TCI with the Schüttler model were reviewed. During anesthesia induction, the target Ce of remimazolam was gradually increased until loss of responsiveness, and it was titrated to maintain bispectral index of 40-70 during operation. Patients were categorized into young (20-40 years, n=24), middle-aged (41-60 years, n=27), and elderly (61-80 years, n=35) groups. Bispectral index and hemodynamic variables were also assessed.

Results: The elderly group had significantly lower remimazolam Ce compared to the young and middle-aged groups at all sedation levels, intubation, and surgery. Mean highest intraoperative Ce was 0.78±0.10, 0.71±0.07, and 0.61±0.10 µg/mL in young, middle-aged, and elderly groups, respectively (P<0.001). The recovery of responsiveness during emergence occurred at significantly lower Ce in the elderly group (0.28±0.06 µg/mL) than in the young (0.41±0.07 µg/mL) and middle-aged groups (0.35±0.07 µg/mL, P<0.001). Ce during sedation and general anesthesia was comparable between the young and middle-aged groups. The bispectral index was similar across groups but fluctuated more in the elderly group during general anesthesia. Elderly patients also showed the greatest systolic blood pressure suppression (18.4 ± 13.29% before intubation and 34.31 ± 14.91% during surgery).

Conclusion: Older patients may require lower target Ce during remimazolam TCI for sedation and anesthesia, with emergence occurring at lower Ce. Blood pressure suppression may be greater in elderly patients under deep sedation or general anesthesia.

Purpose: Inflammatory bowel disease (IBD) is a serious disease that affects the metabolism and inflammatory responses of human beings. From the perspective of traditional Chinese medicine, damp-heat syndrome is one of the main syndromes of IBD. Rhizoma Paridis, also known as the root of Paris polyphylla, a well-known herbal medicine used in China, is used to treat IBD with damp-heat syndrome (IBD-DH). However, uncertainty still exists regarding the underlying mechanisms and the impact of Rhizoma Paridis on IBD-DH.

Methods: The rats in the model (DAT) and medication administration (Rhizoma Paridis total saponins (RPTS) and Pennogenin (PN)) groups were given a high temperature and high humidity environment, high fat and high sugar diet combined with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish the model of experimental colitis of damp-heat type, and the normal control group (RNC) rats were given a normal diet at normal temperature and humidity. Damp-heat control group (DNC) was set with the same condition as DAT without TNBS. Hematoxylin-Eosin (HE) staining was used to observe the histopathological morphology of the rat colorectum. The expression of the metabolism-related genes (Phospholipase A2 (sPLA2, cPLA2), and phosphatidylethanolamine N-methyltransferase (PEMT)) was assessed by using real-time quantitative PCR analysis (RT-qPCR). And the levels of the metabolism-related proteins (sPLA2, cPLA2), S100A8/9, Arg-1, and cytokines were detected by enzyme-linked immunosorbent assay (ELISA) kit. To investigate lipids and amino acids which closely associated with the IBD and IBD-DH, lipid pseudotargeted metabolomics with UHPLC-TQ/MS analysis method, as well as targeted quantitative amino acid analysis were performed.

Results: Our data showed that RPTS (50 mg/kg) and PN (20 mg/kg) significantly ameliorated the severity of TNBS-induced colitis and downregulated the levels of circulating proinflammatory cytokines. Compared with RNC group, lipid pseudotargeted metabolomics demonstrated that glycerophospholipids, sphingolipids, carnitine, and glycerolipids were the four most perturbed lipid classes, and amino acids targeted metabolomics demonstrated that serine, N-acetylneuraminic acid, histidine, proline, taurine, and kynurenine changed significantly in DAT group . Correlation analyses showed tight associations between most of differential metabolites and proinflammatory cytokines. RPTS and PN both regulated glycerophospholipid metabolism and sphingolipid metabolism. However, both of them did not have a significant effect on amino acid modulation. RPTS and PN potentially regulated sPLA2, cPLA2, and PEMT.

Conclusion: These results showed that RPTS (50 mg/kg) and PN (20 mg/kg) effectively alleviated rats' colitis of damp-heat type, affected cytokines, and altered lipid metabolism without significant modulation on amino acid metabolism.

Purpose: The optimal treatment strategy in patients with hospital-acquired pneumonia (HAP) due to Gram-positive bacteria and renal insufficiency remains challenging. The objective of this study was to compare the outcomes of linezolid versus teicoplanin in HAP patients with renal insufficiency and to explore optimal dosage strategy for linezolid.

Methods: The retrospective study enrolled adult patients treated with intravenous linezolid or teicoplanin at Suzhou Municipal Hospital between July 2018 and August 2023. For the comparative pharmacodynamic study, effectiveness, safety and target attainment of trough concentration (C_min) for teicoplanin versus linezolid treatment in HAP patients with document Gram-positive bacteria and renal insufficiency were compared. For the population pharmacokinetics (PPK) analyses, linezolid concentrations collected exclusively from HAP patients with renal insufficiency were used and the optimal dosage strategy was investigated using Monte Carlo simulations.

Results: Linezolid-treated patients had a higher bacterial eradication rate than teicoplanin-treated patients (88.5% vs 63.4%, P < 0.001). A higher proportion of patients in the linezolid group experienced at least one adverse reaction (42.0% vs 25.0%, P = 0.025). Significantly more supratherapeutic C_min, less therapeutic C_min were achieved in the linezolid group (adjusted P < 0.05). A total of 207 linezolid concentrations from 166 patients with renal insufficiency were available for the PPK analysis. Age and creatinine clearance (CrCL) were identified as significant covariates that influenced clearance. Simulations show that 300 mg q12h provide the optimal exposure in patients with a CrCL of 60 or 45 mL/min, and 200 mg q12h was recommended for patients with a CrCL of 30 or 15 mL/min.

Conclusion: Linezolid-treated patients with HAP and renal insufficiency had higher bacterial eradication rates, supratherapeutic exposure and adverse reactions than teicoplanin-treated patients. Linezolid dose reduction in patients with renal insufficiency improved the probability of achieving optimal exposure.

Purpose: Typically, labor analgesia is initiated with a manual loading dose. The programmed intermittent epidural bolus (PIEB) effectively maintains labor analgesia. However, no PIEB method has been studied for the initial loading dose. This study aimed to compare the effectiveness of loading doses administered via a PIEB versus a manual bolus.

Patients and methods: In total, 164 full-term singleton parturients were randomly assigned to receive a 12 mL loading dose (0.1% ropivacaine and 0.3 μg·mL^-1 sufentanil) via manual or pump-driven injection. A standardized maintenance protocol was employed. The primary outcome was the percentage of parturients with adequate analgesia 20 min after the initial epidural injection. Adequate analgesia was defined as a numeric rating score (NRS) of ≤3 during two consecutive uterine contractions, without an additional analgesia request. Kaplan-Meier survival curves were constructed for the time interval needed to achieve adequate analgesia. A non-inferiority analysis was conducted by comparing the 90% confidence interval of the pain score difference with the non-inferiority margin.

Results: The percentage of parturients achieving adequate analgesia was comparable (75.61% manual injection vs 76.83% pump injection, P=0.05 for non-inferiority). The median NRS was similar, except at 2 min (7 [5-8] manual injection vs 8 [6-9] pump injection, P=0.04). Median time to adequate analgesia, median ropivacaine consumption, median duration of epidural analgesia, incidence of requests for patient-controlled epidural analgesia (PCEA), median number of PCEA boluses, percentage of bilateral S₂ blocks at 20 min, incidence of breakthrough pain, percentage of highest block level ≥T6 at 20 min, adverse effects, and obstetric and neonatal outcomes were similar between the groups.

Conclusion: Within 20 min of administering a loading dose through a PIEB pump, non-inferior analgesia comparable to that achieved with manual injection was observed. This hands-free approach could help mitigate the impact of individual operational differences on analgesic efficacy.

Registration: This trial was registered at chictr.org.cn (ChiCTR2300074063).

Protein PEGylation represents a significant technological advancement in the development of protein-based therapeutics and is widely used to reduce immunogenicity, enhance pharmacokinetics, and/or improve stability. The improved pharmacokinetic profile of PEGylated proteins compared with the native protein results in sustained versus fluctuating plasma concentrations and carries the potential of less frequent administration. However, attachment of PEG to therapeutic proteins can alter their structural conformation, which exposes new epitopes to the immune system. The design of PEGylated proteins thus needs to balance the intended benefits with the potential risks associated with the immunogenicity of the PEG moiety itself or resulting from alterations in the conformation of the therapeutic protein. In recent years, advancements in protein PEGylation chemistry have offered the capability to target PEG attachment to specific amino acids to create more stable and bioactive therapies. The biophysical and biopharmaceutical features of PEGylated proteins can vary based on polymer size, shape, density, and conjugation site, and the immunogenicity of the conjugate can be further impacted by the properties of the therapeutic protein itself and the characteristics of the patient. It is important to note that not all patients will develop an immune response toward the PEG moiety, and not all immune responses are clinically meaningful. A comprehensive understanding of the factors that influence immunogenic responses to PEGylated proteins is important to optimize their therapeutic benefits. This article reviews the design and optimization of PEGylation strategies to enhance the clinical performance of protein-based therapeutics while minimizing immunogenic responses to the PEG moiety or PEGylated proteins.

Lung cancer is the leading cause of mortality worldwide, and non-small cell lung cancer accounts for the majority of lung cancer cases. Chemotherapy and radiotherapy constitute the mainstays of lung cancer treatment; however, their associated side effects involving the kidneys, nervous system, gastrointestinal tract, and liver further add to dismal outcomes. The advent of antibody‒drug conjugates (ADCs) could change this situation. Trophoblast surface antigen 2 (TROP-2), a human trophoblast surface antigen, is a tumor-associated antigen that is expressed at low levels in normal tissues and is overexpressed in a variety of malignant tumors. The differential expression of the TROP-2 protein in a variety of tumors makes tumor immunotherapy with ADCs targeting TROP-2 a promising approach. Previous studies have shown that the expression of TROP-2 is related to the prognosis of patients with lung cancer and that TROP-2 expression is different across different histological types; however, research on TROP-2 and TROP-2 ADCs in patients with lung cancer is not comprehensive. The aims of this study were to review the mechanism of action and clinical efficacy of TROP-2 and related drugs in the treatment of lung cancer, to elucidate the prognostic value of TROP-2 in lung cancer, and to discuss the future prospects of TROP-2 ADCs to provide a reference for the precise treatment of lung cancer.