Drug Design, Development and Therapy最新文献

Purpose: In order to scientifically evaluate the clinical value of the comprehensive attributes of Calcitonin gene-related peptide (CGRP) inhibitor drugs, a comprehensive literature-based clinical evaluation of CGRP-targeted therapy drugs was conducted using the drug evaluation method modified by expert discussion in the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition).

Methods: Based on evidence-based data and the relevant elements and weighting in the "Selection Guidelines" quantification record form for drug evaluation and selection in medical institutions, adjustments were made according to the characteristics of CGRP-targeted therapy drugs. We systematically evaluated erenumab, galcanezumab, fremanezumab, eptinezumab, rimegepant, ubrogepant, atogepant, zavegepant for safety, efficacy, economy, and pharmacological properties.

Results: The final assessment result scores from highest to lowest were rimegepant (84.5 points), erenumab (75.78 points), galcanezumab (74.02 points), fremanezumab (73.93 points), atogepant (72.64 points), eptinezumab (71.69 points), ubrogepant (70.37 points), zavegepant (56.44 points).

Conclusion: Rimegepant, erenumab, fremanezumab, atogepant, galcanezumab, eptinezumab, ubrogepant can be entered into the medication list of medical institutions as strongly recommended drugs.

Background and objective: Lung cancer stands as the leading cause of cancer-related fatalities worldwide. While chemotherapy remains a crucial treatment option for managing lung cancer in both early-stage and advanced cases, it is accompanied by significant drawbacks, including severe side effects and the development of chemoresistance. Overcoming chemoresistance represents a considerable challenge in lung cancer treatment. Amlodipine cytotoxicity was previously demonstrated and could make lung cancer cells more susceptible to chemotherapies. This research aims to examine the metabolomics changes that may occur due to amlodipine's anticancer effects on non-small cell lung cancer (NSCLC) cells.

Methods: Amlodipine's effects on A549 and H1299 NSCLC were evaluated using a colorimetric MTT assay, a scratch wound-healing assay and Matrigel invasion chambers to measure cell viability, cell migration and cell invasion. Ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) was used for the untargeted metabolomics investigation.

Results: Our study revealed that amlodipine significantly reduced proliferation of cancer cells in a dose-dependent fashion with IC₅₀ values of 23 and 25.66 µM in A549 and H1299 cells, respectively. Furthermore, amlodipine reduced the invasiveness and migration of cancer cells. Metabolomics analysis revealed distinct metabolites to be significantly dysregulated (Citramalic acid, L-Proline, dGMP, L-Glutamic acid, Niacinamide, and L-Acetylcarnitine) in amlodipine-treated cells.

Conclusion: The present study illustrates the anticancer effects of amlodipine on lung cancer proliferation, migration, and invasion in vitro and enhance our understanding of how amlodipine exerts its anticancer potential by casting light on these mechanisms.

Background: The 2023 American Heart Association/American Stroke Association guideline and Wessels et al's 2024 randomized controlled trial highlight the potential benefits of intracranial nicardipine for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to systematically identify the publication trends and research hotspots in this field through bibliometric analysis.

Methods: Relevant publications were sourced from the Web of Science Core Collection (WoSCC). Bibliometric and visualization analyses were conducted using the online tools of the WoSCC database and CiteSpace 6.2.R6.

Results: Analysis of 28 articles published by 158 researchers from 55 institutions across 8 countries revealed an intermittent small-scale growth in annual publication volume from 1994 to 2024, with a continuous rise in annual citation volume since 2005, indicating growing interest in the field. Japan, Germany, and the United States of America (USA) were the most prolific and influential countries. Institutions such as Tokyo Women's Medical University showed particularly significant contributions. Kasuya Hidetoshi was the most prolific author. There was little global collaboration among countries, institutions, and authors, with distinct regional research characteristics: Japan and Germany focused on intracranial implants, while the USA concentrated on intrathecal injections. Major publishing and co-cited journals included Neurocritical Care, Acta Neurochirurgica, Journal of Neurosurgery, and Stroke. Popular keywords in 2024 included "preventing cerebral vasospasm", "delayed cerebral ischemia", "outcome events", and "clinical trials", revealing current research hotspots.

Conclusion: This study maps the global clinical research landscape of intracranial application of nicardipine for aSAH from 1994 to 2024, providing valuable references and guidance for future research.

Objective: Etoposide is an antineoplastic agent widely used to treat pediatric and adult cancers. Critically ill patients are expected to receive several intravenous pharmaceutical drugs while admitted to hospitals. When compatibility data are available, intravenous drugs may be administered simultaneously through the Y-site. This study aimed to determine the compatibility of etoposide during simulated Y-site administration with 45 continuous-infusion drugs that are commonly administered in tumor critical care units.

Methods: Etoposide was diluted to a concentration of 0.25 mg/mL in 0.9% sodium chloride (NS) and other intravenously tested drugs were reconstituted according to the manufacturer's recommendations to the final clinical desired concentrations. Y-site administration was simulated in vitro by mixing 5 mL etoposide with other diluted intravenous medications under aseptic conditions in a 1:1 ratio. Compatible solutions were withdrawn at certain time intervals (0, 1, 2, 4 hours) after mixing and tested visually, using a Tyndall beam, pH, turbidity, insoluble particles, and UV absorption as measures of compatibility.

Results: Etoposide was compatible with 38 (84%) of the 45 drugs tested within four hours. Glutathione and human granulocyte colony-stimulating factor immediately showed incompatibility with etoposide. Within 1 h, four medications (cefuroxime sodium, ilaprazole sodium, mycophenolate, and xuebijing) were incompatible. Within 4 h, one medications (ceftazidime) were also found to be incompatible with etoposide under observation.

Conclusion: Seven of the 45 common medications in tumor critical care tested with etoposide were incompatible within 4 h. If co administration is inevitable and the drug is infused through a port catheter, a larger volume of saline (NS) or dextrose 5% in water (D5W) should be used to flush the port catheter before and after the etoposide infusion to clean the lumen of the port catheter.

Purpose: To explore the efficacy and safety of lenvatinib, either as a monotherapy or in combination with programmed death-1 (PD-1) blockades, as re-challenging treatment in patients with metastatic osteosarcoma following treatment failure with previous tyrosine kinase inhibitors (TKIs).

Patients and methods: We retrospectively reviewed the data of 26 patients with metastatic osteosarcoma who received rechallenge treatment with lenvatinib monotherapy or lenvatinib plus PD-1 blockades after failure of the initial TKI treatment from January 2020 to June 2024 in our center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), and safety.

Results: Of the 26 patients, ORR and CBR were 11.5% and 61.5%, respectively. The median duration of follow-up was 15 months (range, 4.3-25.6) with a median PFS of 7.2 months (95% CI: 1.9-12.5). A total of 14 patients received lenvatinib as a monotherapy, and 12 received a combination therapy of lenvatinib and PD-1 blockade. No significant differences were observed in ORR (0 vs 25%) and CBR (57.1 vs 66.7%) between the two groups. Additionally, the combination cohort exhibited a significantly longer PFS compared to the monotherapy cohort (8.6 [95% CI: 5.0-12.1] vs 4.0 months [95% CI: 1.0-7.0], p = 0.022). 96.2% of patients experienced grade 1 or more adverse events (AEs). Grade 3 adverse events occurred in 6 (23.1%) patients. The safety profiles of the lenvatinib and PD-1 blockade combination group were found to be comparable to those of the lenvatinib monotherapy group.

Conclusion: Our data indicated that patients with metastatic osteosarcoma could potentially benefit from lenvatinib rechallenge after progress with initial TKI treatment. The combination of lenvatinib and PD-1 blockade therapy demonstrated promising survival outcomes in patients with metastatic osteosarcoma, accompanied by a manageable toxicity profile.

Infantile hemangiomas (IHs) are a kind of skin soft tissue benign tumors in infants, with a high incidence rate and significant harm. Rapid early proliferation can cause severe cosmetic deformities and organ development disorders. Propranolol Hydrochloride (PRH), a non-selective adrenergic β-receptor blocker, has become the first-line treatment for IHs due to its good efficacy and safety compared to other drugs. To further improve the bioavailability of PRH, deliver it more safely and effectively to the lesion site, and enhance patient compliance, researchers are continually developing new PRH formulations for the treatment of IHs. This article briefly introduced the pathogenesis of IHs and the therapeutic mechanism of PRH. It also provided a detailed overview of various new PRH formulations developed over the past 12 years for the treatment of IHs, including improved oral formulations, topical creams, gels, liposomes/nanoparticles, transdermal patches, microneedles, and targeted injectable formulations. This article summarized the development prospects and technical challenges of these new formulations. It aims to provide a comprehensive review of recent advances in new propranolol formulations and technologies for treating IHs, offering a reference for further research and application. At the same time, it is hoped that various new formulations of PRH can be safely and efficiently used in clinical practice in the future.

Purpose: To investigate the effects and underlying mechanisms of indirubin in treating ALL using network pharmacology and experimental validation.

Methods: Potential targets of indirubin- and ALL-related genes were identified using public databases. Core genes were filtered through protein-protein interaction analysis in Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to explore the potential mechanisms of indirubin against ALL. Drug-disease-functional annotation-signaling pathway network maps were constructed. Molecular docking between indirubin and core proteins was performed using AutoDock Vina software. Finally, both in vitro and in vivo experiments were performed to validate these findings.

Results: PPI network analysis identified eight potential core targets of indirubin in ALL: AKT1, CASP3, and the mammalian target of rapamycin. GO and KEGG enrichment analyses suggested that the mechanism of action of indirubin against ALL involves multiple biological functions and signaling pathways, with the PI3K-AKT pathway likely playing a central role. Molecular docking findings further confirmed the strong binding affinity of indirubin for the core targets. Both in vitro and in vivo experiments demonstrated that indirubin inhibited ALL cell proliferation and induced cell cycle arrest and apoptosis; the underlying mechanism may involve the PI3K-AKT signaling pathway.

Conclusion: The action and mechanism of indirubin in ALL through network pharmacology, as well as in vivo and in vitro experimental validation were elucidated, offering new insights and potential therapeutic avenues for the treatment of ALL.

Background: Dexmedetomidine is a central α-2 adrenergic agonist characterized by its sedative, analgesic, and sympatholytic properties. We investigated the effect of low dose dexmedetomidine on the dose-response relationship of propofol for sedation in patients undergoing operative hysteroscopy.

Methods: The patients were firstly randomly assigned to receive either propofol and fentanyl (P group, n = 100) or a combination of propofol, dexmedetomidine, and fentanyl (DP group, n = 100). Subsequently, participants were further randomized to receive propofol at doses of 1.0, 1.5, 2.0, and 2.5 mg/kg in P group, and 0.5, 1.0, 1.5, and 2.0 mg/kg in DP group. The primary outcome of this study was the incidence of patients achieving effective propofol dose, defined as the dosage at which a patient exhibited no body movement during cervical dilation and had a BIS value below60. The Probit method was used to calculate the ED50 and ED95 of propofol in the inhibition of body movement reaction to cervical dilation during hysteroscopic surgery.

Results: The ED50 and ED95 values for propofol in the inhibition of body movement reaction to cervical dilation during hysteroscopic surgery were 1.781 (95% CI 1.507~2.118) and 4.670 (95% CI 3.555~7.506) mg/kg, respectively, in P group; while in the DP group, these values were found to be 0.983 (95% CI 0.800~1.173) and 2.578 (95% CI 2.013~3.895) mg/kg.

Conclusion: Low-dose dexmedetomidine (0.5μg/kg) could reduce the requirement of propofol for suppression of body movement in patients undergoing operative hysteroscopy.

Purpose: Artocarpus heterophyllus leaves, rich in phytochemicals, present a promising source of natural bioactive compounds for therapeutic and cosmetic applications. This study evaluated the phytochemical composition, antioxidant potential, and tyrosinase inhibition activities of leaf extracts while assessing the enzyme inhibition properties of key compounds through molecular docking and dynamics simulations.

Patients and methods: Ethanol and ethyl acetate extracts were analyzed using Thin Layer Chromatography (TLC) and Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS). Antioxidant activity was determined via DPPH radical scavenging and tyrosinase inhibition was compared against kojic acid. Molecular docking and molecular dynamics simulations explored binding interactions of Artocarpin and Sitosterol with matrix metalloproteinases (MMPs) and tyrosinase.

Results: Artocarpin and Sitosterol were identified as primary bioactive compounds. Ethanol extracts exhibited stronger tyrosinase inhibition (IC₅₀: 177.24 ppm), while ethyl acetate extracts showed superior antioxidant activity (IC₅₀: 117.64 ppm). Molecular docking highlighted high binding affinities of Artocarpin and Sitosterol with MMP-13 and tyrosinase. MD simulations confirmed stable interactions, particularly between Artocarpin and MMP-13, supporting its potential as a therapeutic agent.

Conclusion: Artocarpin and Sitosterol from Artocarpus heterophyllus leaf extracts demonstrate potent antioxidant, enzyme inhibitory, and tyrosinase inhibition activities. These findings underscore their potential for managing oxidative stress, inflammation, and pigmentation disorders, warranting further investigation into their bioavailability and formulation for therapeutic and cosmetic uses.

Objective: Extended meropenem infusion is increasingly employed to enhance clinical outcomes in critically ill patients. Nonetheless, investigations into such dosing regimens in renal-impaired patients undergoing continuous renal replacement therapy (CRRT) are scarce. This study aims to perform a population pharmacokinetic (PK) analysis of prolonged meropenem infusion in critically ill CRRT patients to inform optimal dosing regimens.

Methods: Ninety-four concentrations from 21 Chinese critically ill CRRT patients receiving 1 g meropenem every 8-12 hours infused over 2-3 hours were utilized to construct the population PK model. Monte Carlo simulations were employed to assess the efficacy based on PK/PD targets (100% fT_>MIC or 100% fT_>4×MIC) and the risk of nephrotoxicity (trough concentration ≥45 mg/L) for extended meropenem dosing regimens (0.5-2 g with a 3-hour infusion administered every 6-12 hours).

Results: Meropenem concentration data was adequately described by a one-compartment model with linear elimination, and creatinine clearance (CLCR) significantly influenced meropenem's endogenous clearance. 0.5 g q6h and 1 g q8h could achieve desirable attainment of 100% fT_>MIC target against an MIC≤4 mg/L, with negligible risk of toxicity for CRRT patients across a CLCR range of 10-50 mL/min. 2 g q6h and 2 g q8h is required for targeting 100% fT_>4×MIC for the patients, but the associated risk of toxicity is very high (>20%).

Conclusion: A population PK model was developed for prolonged meropenem infusion in Chinese CRRT patients, and 0.5 g q6h and 1 g q8h may be the optimal regimen for prolonged infusion.