Frontiers in Pharmacology最新文献

Objective: The potential drug-drug interactions (pDDIs) seriously affecting the prognosis of colorectal cancer (CRC) patients. This study aimed to identify the risk factors of pDDIs in hospitalized CRC patients and construct a risk prediction model to provide a reference for clinical rational drug use.

Research design and methods: A retrospective cohort study was conducted, enrolling 2,868 patients from a tertiary hospital. Medscape was used to assess pDDIs, and a risk prediction model was constructed based on independent risk factors.

Results: A total of 1,790 (62.41%) patients experienced at least one pDDIs, with 1,458 (50.84%) cases of severe pDDIs. The number of drug varieties, hypoalbuminemia, and treatment were independent risk factors. The area under the receiver operating characteristic curve (AUC) of the model in the training and validation sets were 0.826 and 0.824, respectively. The calibration curve showed a good agreement between the predicted probability and the actual occurrence probability. Decision curve analysis (DCA) demonstrated that the model had a positive net clinical benefit within a wide range of 10%-90%.

Conclusion: The constructed model has good predictive performance and can be used to identify high-risk patients with pDDIs in clinical practice, thereby improving the safety of drug use.

Atherosclerotic cardiovascular disease (ASCVD) is known to be driven by chronic inflammation and pro-atherogenic dyslipidemia and remains as one of the leading causes of mortality globally. Despite the success of current lipid-lowering therapies, a significant residual inflammatory risk persists, highlighting the need for treatments with broader mechanisms. Probucol is a lipid-modulating agent with uniquely potent antioxidant and anti-inflammatory properties that is re-emerging as a compelling multifunctional drug against atherosclerosis. This review critically examines the available evidence on probucol's impacts on ASCVD, with special focus on its integrated effects on the cholesterol-inflammation pathway. We examine the pleiotropic mechanisms of this drug, including the inhibition of low-density-lipoprotein oxidation and reverse cholesterol transport potentiation, as well as appraise the clinical data demonstrating its ability to regress atherosclerotic plaques and reduce cardiovascular events. While acknowledging the controversies that have limited the use of probucol, such as its high-density-lipoprotein cholesterol-lowering effect and risk of QT prolongation, we provide an updated and balanced perspective on its risk-benefit profile. By compiling existing knowledge from mechanistic and clinical studies, this review argues for a reappraisal of probucol's role and outlines future directions needed to establish its place in the modern management of atherosclerosis.

Background: Opioid-induced constipation (OIC) is a common and serious side effect of long-term opioid analgesic therapy. As traditional laxatives often show limited efficacy, it is crucial to explore treatment strategies that effectively relieve constipation without compromising analgesic effects. In response to this clinical need, Opioid-receptor antagonists have been approved for OIC. Although new evidence has emerged in recent years, a comprehensive analysis of efficacy outcomes (such as constipation symptoms, quality of life, and satisfaction) is still lacking.

Objective: To summarise and analyze evidence on the efficacy and safety of opioid-receptor antagonists in treating patients with OIC.

Method: A systematic search of randomized controlled trials (RCTs) was conducted in PubMed, Embase, Web of Science, and the Cochrane Library up to 11 September 2025. A meta-analysis was carried out using RevMan and Stata, and the GRADE method was employed to evaluate the quality of evidence.

Results: A total of 20 studies (22 RCTs) involving 7,761 patients were included. Opioid-receptor antagonists significantly increased the change in spontaneous bowel movement (WMD = 1.10, 95% CI: 0.74-1.46); improved the proportion of responders (RR = 1.48, 95% CI: 1.28-1.70); enhanced quality of life (WMD = -0.20, 95% CI: -0.28 to -0.12) and treatment satisfaction (WMD = -0.32, 95% CI: -0.54 to -0.10). The patient assessment of constipation symptoms questionnaire showed a minor tendency of improvement (WMD = -0.16, 95% CI: -0.31 to 0.00). The incidence of serious adverse events indicates that no statistically significant difference was observed between treatment and placebo (RR = 0.88, 95% CI: 0.74-1.05). The incidence of other adverse events was higher in the treatment group than in the placebo group (RR = 1.22, 95% CI: 1.08-1.38).

Conclusion: Opioid-receptor antagonists are effective in treating patients with OIC. The risk of serious adverse events did not change statistically. The incidence of adverse events appears to increase with longer treatment duration, although this observation seems to require further validation.

Systematic review registration: CRD420251154280.

Background: Liuwei Dihuang pills (LW) are widely used as the traditional tonic prescription for the treatment of diabetes and diabetic kidney disease (DKD). This study aimed to investigate the potential mechanism underlying LW-mediated prevention and treatment of DKD from the perspective of host-gut microbiome co-metabolism.

Methods: A rat model of DKD was established using high-fat diet and streptozotocin. Levels of type IV collagen (Col IV), fibronectin (FN), laminin (Lam), transforming growth factor-β (TGF-β), SMAD family member 7 (SMAD7), and SMAD3 in the kidneys were determined by real time-polymerase chain reaction and Western blot. Fecal metabolites were profiled using ultra-high-performance liquid chromatography-tandem mass spectrometry. Metagenomic sequencing of the feces was performed using high-throughput sequencing.

Results: When combined with metformin (MET)-based therapy, LW significantly improved serum creatinine and blood urea nitrogen levels, kidney index, 24-h urine volume, urine protein content and excretion rate, and urinary creatinine and cystatin C levels. It also attenuated morphological changes. Correspondingly, LW intervention reduced the renal expression of TGF-β, SMAD3, Col IV, LAM, FN, interleukin (IL)-6, and IL-1β, while increasing SMAD7 expression. Additionally, it normalized metabolic pathway abnormalities in galactose, butyric acid, fructose, mannose, amino sugar, and nucleotide sugar metabolism. Moreover, LW regulated bacterial imbalances, notably in specific species such as Allobaculum unclassified, Escherichia coli, Pseudoflavonifractor capillosus, Desulfovibrio porci, Oscillibacter sp. CU971, Parablautia muri, Phocaeicola dorei, Phocaeicola faecalis, Phocaeicola vulgatus, and Raoultella unclassified.

Conclusion: The combination of LW and MET ameliorated renal impairment in DKD rats by regulating the TGF-β/SMAD signaling pathway, metabolic disturbances in endogenous metabolites, and gut microbiota dysbiosis.

Background: This study analyzed neuropsychiatric adverse drug events (ADEs) associated with cetirizine and levocetirizine using data from the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases to inform safer clinical use for different age and gender groups.

Methods: We performed disproportionality analyses (ROR, PRR, BCPNN, MGPS) using data from the FAERS (Q1 2004 to Q3 2025) and the EudraVigilance database (January 2002 to December 2025). In addition, stratified analysis was conducted for the top 20 reported ADEs across different sex and age groups.

Results: Somnolence, dizziness, headache, and insomnia are common adverse drug reactions (ADRs) with high disproportionality signals for both cetirizine and levocetirizine. Cetirizine was generally associated with higher signal intensities for depression, anxiety, and drug abuse/dependence compared to levocetirizine, with unique reports of cognitive impairment and migraine. In contrast, levocetirizine showed stronger signals not only for sleep-related ADRs but also for serious psychiatric events, including suicide attempts and suicidal ideation. Among levocetirizine users, febrile convulsions were more frequently reported in males. Additionally, pediatric patients exposed to levocetirizine were reported to have febrile convulsion and epilepsy. In the elderly, reports associated with cetirizine included subarachnoid hemorrhage, transient ischemic attack, and carotid artery occlusion, while those for levocetirizine included hepatic encephalopathy.

Conclusion: These findings highlight the distinct neuropsychiatric risk profiles associated with cetirizine and levocetirizine. This underscores the importance of age- and sex-informed drug selection to optimize their safe use.

Introduction: Energy metabolic remodeling represents a critical pathological mechanism in myocarditis progression. Levocarnitine (LC), an essential cofactor for fatty acid oxidation, demonstrates potential in modulating cardiac metabolism. This study investigated the therapeutic effects of LC on myocardial energy metabolic remodeling and explored the underlying molecular mechanisms.

Methods: The experimental autoimmune myocarditis (EAM) mouse model was constructed using α-myosin. Cardiac function, myocardial inflammatory infiltration, and mitochondrial structure were evaluated using echocardiography, HE staining, and transmission electron microscopy, respectively. Metabolic parameters including free fatty acid (FFA), lactic acid (LAC), mitochondrial complex IV (COX IV) activity, and adenosine triphosphate (ATP) levels were measured using colorimetry. Serum heart-type fatty acid-binding protein (H-FABP) levels were measured by ELISA, and reactive oxygen species (ROS) levels were determined by flow cytometry. The expression of organic carnitine transporter type 2 (OCTN-2) and carnitine palmitoyltransferase-1B (CPT-1B) were determined by Western blot. Furthermore, network pharmacology and molecular docking were employed to predict the therapeutic targets and mechanisms of LC in myocarditis. The activity of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway and the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) were verified by Western blot.

Results: LC treatment significantly improved cardiac function and attenuated myocardial inflammatory infiltration in EAM mice. It ameliorated mitochondrial structural damage, enhanced COX IV activity and ATP production, and reduced the accumulation of FFA, LAC and ROS in myocardial tissues. It also lowered serum H-FABP levels while upregulating the expression of OCTN-2 and CPT-1B. Combining network pharmacology and molecular docking, Akt was identified as the key therapeutic target of LC in cardiomyopathy and demonstrated good binding affinity with LC. In vivo validation confirmed that LC decreased Akt phosphorylation in the myocardium of EAM mice, while PGC-1α expression increased.

Conclusion: LC effectively improved myocardial metabolic remodeling and alleviated cardiac insufficiency in myocarditis. The underlying mechanism may involve LC-mediated suppression of the PI3K/Akt signaling pathway, potentially linked to increased expression of the key mitochondrial regulator PGC-1α.

Epilepsy is a neurological disorder affecting almost 50 million people worldwide, with genetic epilepsy (GE) representing a subset caused by specific gene mutations. While cognitive deficits are frequently reported in epilepsy, the contribution of GE itself remains poorly defined. We conducted a systematic review to evaluate the cognitive and behavioral phenotypes in rodent models of GE, focusing on cognition as the primary outcome and behavior as secondary. Literature searches of PubMed, Ovid MEDLINE, and Scopus identified 16 eligible studies in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Across models, rodents with GE commonly exhibited impairments in the neurocognitive and behavioral paradigms. Mutant rodent models were exhibit poorer memory and learning abilities, alongside behavioral abnormalities such as autism spectrum disorder (ASD)-like phenotype, anxiety, and depression. However, the severity and domains of impairment varied across mutations, strains, and developmental stages, reflecting the heterogeneity of GE. Our findings highlight both seizure-driven and gene-driven mechanisms of cognitive impairment and underscore the need for syndrome-specific investigations. Overall, rodent models provide valuable insights into the cognitive comorbidities of GE, but future research requires improved methodological rigor and broader use of complementary models to clarify underlying mechanisms and guide targeted interventions.

Objectives: This study investigates the formal definitions of "off-label" medication use among five major Western regulatory authorities-FDA, EMA, Health Canada, MHRA, and TGA. The primary research question is whether these agencies provide explicit, official definitions of off-label use.

Design: The study employs a mixed-methods design, combining direct inquiries via standardized questionnaires with AI-assisted text mining of publicly available regulatory documents.

Setting: Regulatory agencies at a national level across North America, Europe, and Oceania.

Participants: Five agencies, with data collected through direct contact and automated document analysis; no human participants were involved.

Intervention: Analysing agency webpages and documents for sentences that resemble formal definitions, followed by manual review and categorization based on linguistic and contextual criteria.

Main outcome: The presence or absence of official definitions, the content and clarity of any definitional statements, and their prominence within regulatory documents.

Result: None of the agencies provide a formal, official definition of off-label use. However, all agencies' publicly available documents contain statements that resemble definitions, generally describing off-label use as prescribing beyond the conditions approved by the drug's marketing authorization. Despite similarities in language, the clarity and prominence of these statements vary across agencies.

Conclusion: The lack of formal off-label definitions may contribute to legal ambiguity, clinical uncertainty, and challenges in guideline development, particularly affecting paediatric populations where off-label prescribing is common. The regulatory agencies should adopt clear, standardized official definitions of off-label use to improve transparency, legal coherence, and patient safety.