Naunyn-Schmiedeberg's archives of pharmacology最新文献

The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose-response profile and direct cardioprotective mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25-0.7 mg/kg) delivered via Krebs-Henseleit buffer during the first 10 min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide-protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5 mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia-reperfusion alone, improving heart rate, left ventricular developed pressure, and rate-pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5 mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.

Drug-associated deep vein thrombosis (DVT) poses a growing clinical concern, yet the thrombotic risk profiles of many medications are not fully established. This study aimed to systematically detect and characterize drug safety signals for DVT using real-world pharmacovigilance data. A disproportionality analysis was conducted using reports from the FDA adverse event reporting system (FAERS) spanning the first quarter of 2004 to the second quarter of 2025. After deduplication and filtering, 43,226 DVT cases linked to a primary suspect drug were analyzed. Four disproportionality metrics-the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS)-were applied to identify safety signals. Drugs were categorized using the anatomical therapeutic chemical (ATC) classification system. Time-to-onset (TTO) profiles were assessed via the Weibull distribution modeling and the Kaplan-Meier analysis. Among the included reports, 60.23% involved female patients, and 97.48% were classified as serious outcomes. Eighty-eight drugs met the predefined signal threshold. The ten highest-ranking agents by case count were drospirenone/ethinyl estradiol (ROR 69.09), ethinyl estradiol/etonogestrel (ROR 43.41), lenalidomide (ROR 4.89), testosterone (ROR 30.13), rofecoxib (ROR 5.41), ethinyl estradiol/norelgestromin (ROR 28.53), bevacizumab (ROR 3.53), thalidomide (ROR 9.26), pomalidomide (ROR 3.18), and celecoxib (ROR 3.90). These agents predominantly belonged to antineoplastic/immunomodulatory or genitourinary/hormonal therapeutic classes. The median TTO was 120 days (IQR 29-441), with 25.87% of events occurring within the first month of treatment. Early failure patterns were most frequent (52.6% of drugs), especially among hormonal contraceptives, immunomodulators, and chemotherapeutic agents. This large-scale pharmacovigilance analysis identifies robust DVT signals across multiple drug classes, notably hormonal therapies, immunomodulators, and targeted anticancer agents. The results highlight the importance of proactive thrombotic risk assessment and monitoring in clinical practice when using these medications.

Hyperuricemia is a metabolic disorder marked by elevated serum uric acid levels and is closely linked to the development of gout and progressive renal dysfunction. It is increasingly recognized as a major public health concern due to its association with chronic kidney disease and cardiovascular complications. Hyperuricemia induces kidney impairment through a complex interplay of oxidative and inflammatory stress. Harmaline, a β-carboline alkaloid primarily found in Peganum harmala, exhibits antioxidant and anti-inflammatory activities. Considering the roles of oxidative and inflammatory stress in renal dysfunction and the modulatory potential of harmaline, this study aimed to evaluate harmaline against potassium oxonate-induced hyperuricemia and renal impairment in mice. In this study, 25 Swiss albino mice were divided into five groups (n = 5). Hyperuricemia was induced by intraperitoneal administration of potassium oxonate (300 mg/kg) for 7 days. Harmaline (2.5 and 5 mg/kg, i.p.) and allopurinol (10 mg/kg, i.p.) were administered 1-h after potassium oxonate treatment. On day 8, serum was collected to measure uric acid, creatinine, and blood urea nitrogen (BUN), and thereafter, the kidneys were harvested for biochemical analyses. Potassium oxonate administration resulted in hyperuricemia-associated renal dysfunction, as evidenced by increased serum uric acid, creatinine, BUN, thiobarbituric acid (TBARS), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), along with decreased renal glutathione (GSH) and interleukin-10 (IL-10) levels. Treatment with harmaline significantly attenuated these potassium oxonate-induced biochemical and inflammatory alterations. Notably, the higher dose of harmaline exhibited the prominent effect. Overall, the results suggest that harmaline, particularly at 5 mg/kg, effectively alleviates potassium oxonate-induced hyperuricemia and renal dysfunction in mice.

Purpose: This Phase 1 study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of INTP23.1, a proposed denosumab biosimilar, compared with US- and EU-licensed reference denosumab (Xgeva®) in healthy male volunteers.

Methods: This randomized, double-blind, three-arm, 36 week, parallel-group trial (CTRI/2020/09/027619), assessed a single 35 mg subcutaneous dose of INTP23.1, Xgeva (US), or Xgeva (EU), administered in the upper arm. PK endpoints were statistically compared using geometric least-squares means (LSM) and 90% confidence intervals (CIs). PD markers were evaluated, immunogenicity and safety were assessed through validated assays, and adverse events (AEs) were monitored.

Results: A total of 234 healthy male volunteers were enrolled. Baseline demographics were similar across the three treatment sequence groups. PK equivalence was demonstrated, with all geometric LSM ratios and 90% CIs for maximum serum concentration, area under the concentration-time curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity falling within the predefined bioequivalence range of 80.00% to 125.00%. PD responses showed comparable suppression of C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) across treatment groups. Immunogenicity profiles were similar, with low anti-drug antibody incidence and no neutralizing antibodies detected. AEs were generally mild or moderate in intensity, and no unexpected safety signals were observed.

Conclusions: INTP23.1 demonstrated comparable PK, PD, immunogenicity, and safety to US- and EU-licensed denosumab reference products in healthy male volunteers. These findings support further clinical development of INTP23.1 as a denosumab biosimilar for approved indications.

Trial registration number: CTRI/2020/09/027619; Registered 07/09/2020.

Luteolin and chrysoeriol, active flavonoids found in Fagopyrum dibotryis Rhizoma (FDR), possess similar molecular structures and demonstrate anti-tumor activity; however, their efficacy and mechanisms in non-small cell lung cancer (NSCLC) are still incomplete. This research aimed to reveal the therapeutic potential and mechanisms of these phytoconstituents in NSCLC through an integrated strategy of network pharmacology, molecular docking, and experimental validation. We used network pharmacology to discover possible targets and pathways for luteolin and chrysoeriol in NSCLC, which involved predicting targets, constructing protein-protein interaction (PPI) networks, and performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and dynamics simulations assessed the binding affinities of both phytoconstituents to core targets. Hub gene expression in NSCLC tissues was further examined using bioinformatics tools. The anti-NSCLC effects were evaluated by measuring A549 and PC9 cell viability, migration, apoptosis, and modulation of the PI3K/AKT pathway. We identified 64 potential therapeutic targets for NSCLC. Enrichment analysis revealed the PI3K-Akt signaling pathway as the most significantly associated. Molecular simulations indicated stable binding of both phytoconstituents to core targets, with luteolin exhibiting stronger binding affinity. In experimental validation, luteolin more potently inhibited NSCLC cell viability and migration, alleviated mitochondrial damage, and induced apoptosis relative to chrysoeriol. Luteolin also more effectively regulated PI3K/AKT signaling. Both luteolin and chrysoeriol represent promising natural agents for NSCLC treatment, with luteolin demonstrating superior bioactivity.

Endometriosis, an atypical benign disorder, may disrupt epithelial-mesenchymal transition (EMT) due to a dysregulated balance between matrix metalloproteinases (MMPs) and their inhibitors. Ramipril, an angiotensin converting enzyme (ACE) inhibitor, is crucial in mediating angiogenesis, inflammation, oxidative stress, and apoptosis. In the current work, we investigated how ramipril modulates EMT in endometriosis rats. Five adult virgin female Wistar rats were donor rats, and thirty rats were randomly divided into three groups following peritoneal uterine tissue transplantation (group 2 and group 3). The sham control group was group 1. Morphological alterations were predominantly assessed through hematoxylin-eosin (H-E) staining, succeeded by the immunoreactivity analysis of MMP9, tissue inhibitor of metalloproteinases 1 (TIMP1), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), and vimentin in the uteri and ectopic lesions of the specified groups. Zymography was conducted to assess the activities of MMP9 and MMP2. Immunoblotting was subsequently conducted for MMP9, TIMP1, snail, E-cadherin, N-cadherin, and vimentin in both uteri and ectopic lesions. Immunoblotting was conducted for phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mechanistic target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 (S6K1), and hypoxia-inducible factor 1-alpha (HIF-1ɑ) in the ectopic lesions. A significant reduction in the average quantity of ectopic endometrial glands was recorded in group 3. A significant decrease in the expressions of MMP9:TIMP1 (RECK) ratios (p = 0.00012; p = 0.001), snail, p-PI3K, p-AKT, p-mTOR, p-S6K1, and HIF-1ɑ (p < 0.05) proteins was observed in the ectopic lesions of group 3. A significant increase in the E-cadherin to N-cadherin (vimentin) ratios (p = 0.001) was observed in group 3 ectopic lesions. In conclusion, the administration of ramipril led to the reversal of EMT-like process by disrupting the MMP9/PI3K/AKT/S6K1 pathway in rats induced with endometriosis.

Cardiovascular dysfunction represents a major global health challenge due to its high morbidity and mortality, underscoring the urgent need for more efficient drug discovery paradigms. This study developed and applied an integrative computational-experimental strategy to systematically explore and prioritize bioactive component combinations with crude extract-comparable activity (BECC) from traditional herbs, using Salvia miltiorrhiza (Danshen, DS) as a representative case relevant to cardiovascular protection. LC-MS/MS-based exposure-informed metabolite profiling, reverse target fishing, molecular docking, pharmacophore analysis were integrated to develop multidimensional component-target networks. Through this framework, 139 potential targets associated with 26 bioactive components and 41 metabolites were collected. Target activity spectrum (TAS) and pharmacodynamic activity spectrum (PAS) analyses were further employed to prioritize BECC, comprising rosmarinic acid, salvianolic acids A and B, cryptotanshinone, and tanshinone I. Within the tested in vitro systems and concentration ranges, this combination exhibited pharmacological activity profiles that were broadly comparable to those of the crude DS extract, as evaluated in three cardiovascular-relevant cellular models, supporting its potential as a representative multi-component candidate. In conclusion, this study provides a proof-of-concept case study demonstrating an integrative strategy to narrow complex herbal extracts into defined component combinations for subsequent translational evaluation, offering a methodological reference for studying the multi-component basis of traditional medicines in the context of cardiovascular-related research.

The effect of clinical medications for common diseases on cancer risk has attracted extensive attention. However, whether they have a causal relationship with lung cancer remains unclear. Genome-wide association study datasets on 23 drugs and lung cancer were extracted from publicly available databases. Mendelian randomization methods were utilized to assess the causal effects of the drugs on the risk of lung cancer. Sensitivity analyses were also conducted to evaluate the stability and reliability. Our results found that salicylic acid and derivatives (OR = 0.779; 95% CI, 0.676-0.898; P = 5 × 10^-4, P-adjusted = 0.0125) significantly reduced lung cancer risk, while opioids (OR = 1.16; 95% CI, 1.065-1.263; P = 6 × 10^-4, P-adjusted = 0.0148) significantly increased lung cancer risk. These findings remained robust after removing outliers. Suggestive evidence for a protective effect was also found for antithrombotic agents, antihypertensives, β-blockers, thyroid preparations, and anilines (all 0.0022 < P < 0.05). Notably, after outlier correction, the suggestive association for antithrombotic agents became statistically significant, while that for β-blockers disappeared, and the other suggestive associations persisted. Sensitivity analyses further confirmed the robustness of these findings. This study identified several clinical drugs that were causally associated with lung cancer, involving cardiovascular and endocrine system medications, anti-inflammatory/antipyretic analgesics, and centrally acting analgesics. It provides a theoretical reference for clinical medication guidance and understanding medication risks.

Withaferin A (WA) is an effective withanolide compound derived from Withania somnifera that exhibits a multifaceted pharmacological profile, making it a promising candidate for managing several types of carcinomas. WA has been shown to regulate multiple oncosignaling pathways, proteins, and molecular determinants critical for cancer cell survival, proliferation, and resistance. Its pro-apoptotic, anti-metastasis, antiangiogenic, and anti-proliferative properties demonstrate its efficacy as a multitargeted anticancer agent to manage persistent challenges associated with the complex etiology of cancer. Although several investigations have shown the anticancer efficacy of WA, comprehensive insights into the multitargeted modulation of oncosignaling pathways and synergistic therapeutic potential remain fragmented. Therefore, this review focused on bridging these gaps by providing an integrated overview of WA's mechanistic and translational relevance in cancer therapy. Specifically, this review explores the therapeutic potential of WA in targeting key oncogenic pathways, which are implicated in various types of malignancies. Additionally, this study illustrates the synergistic role of WA in combination with current cancer therapies including immunotherapy, radiation, and chemoradiotherapy. Alongside investigating WA's pharmacological potential as an anticancer agent, this study also examines its pharmacokinetics, bioavailability, and toxicity profile.

To develop an LC-MS/MS method for simultaneous quantification of mildronate and L-carnitine, and to investigate the pharmacokinetic profile of mildronate in rats, its effect on L-carnitine homeostasis, as well as the exposure characteristics, underlying mechanisms, and their associations with therapeutic efficacy and toxicity risks. We quantified mildronate using its deuterated analog ([²H₃]-mildronate) as an internal standard, while endogenous L-carnitine was relatively quantified using a surrogate matrix. A pharmacokinetic study was conducted in rats following oral administration of mildronate at doses of 40-160 mg/kg. Tissue distribution and excretion studies of mildronate were performed at the 80 mg/kg dose level. Mildronate exhibited nonlinear pharmacokinetics at 160 mg/kg, demonstrated by a greater-than-dose-proportional increase in systemic exposure. It exhibited high distribution and prolonged retention in cardiac and skeletal muscle. The cumulative urinary excretion of the parent drug amounted to only 3.01%. Furthermore, mildronate dose-dependently reduced plasma L-carnitine concentrations, depleted L-carnitine levels in cardiac and skeletal muscle tissues, and increased its urinary excretion. The developed LC-MS/MS method is reliable for simultaneous quantification of mildronate and L-carnitine. The integrated PK-PD findings, including nonlinear exposure, target tissue accumulation, and disruption of L-carnitine homeostasis, collectively elucidate mildronate's mechanism of action through energy substrate depletion, as well as its intrinsic efficacy-toxicity duality. These findings thus lay a robust scientific foundation for optimizing the drug's clinical dosing regimens and guiding safety monitoring practices.