Naunyn-Schmiedeberg's archives of pharmacology最新文献

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.

Glioblastoma multiforme (GBM) remains the most aggressive and treatment-refractory brain tumor, largely due to its heterogeneity and immunosuppressive microenvironment. Recent discoveries have highlighted a compelling strategy to overcome GBM resistance mechanisms using ferroptosis, an iron-dependent, non-apoptotic type of regulated cell death marked by lipid peroxidation. This review systematically explores the molecular regulators of ferroptosis, including GPX4, SLCA11, ACSL4, and iron metabolism pathways that dictate susceptibility to oxidative damage. The integration of ferroptosis with immune checkpoint inhibition and conventional modalities such as radiotherapy and chemotherapy demonstrated synergistic sensitization of tumor cells while enhancing antitumor immune responses. Ferroptosis induces immunogenic damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP release, promoting dendritic cell maturation, macrophage repolarization, and CD8⁺ cell infiltration, transforming the "cold" GBM milieu into an immunogenic microenvironment. Emerging nanotechnology-based ferroptosis inducers (FINs), including iron oxide nanoparticles and liposomal formulations, further optimize drug delivery across the blood-brain barrier while reducing systemic toxicity. Moreover, the regulation of ferroptosis by non-coding RNAs provides an additional avenue for therapeutic modulation through immunotherapy and redox-modulating strategies, offering a transformative direction in GBM management and redefining treatment beyond apoptosis resistance toward precision immunometabolic targeting.

Pertuzumab, administered as an injection, is an antagonist of human epidermal growth factor receptor 2 (HER2). This study sought to compare the pharmacokinetic (PK) profiles, safety, and immunogenicity between pertuzumab biosimilar SYSA1901 injection and the reference product (Perjeta®) in healthy males. In this single-center, randomized, double-blind, parallel-group, single-dose trial, 88 male subjects were enrolled and randomized into two groups, each receiving a single 420 mg (14 mL) intravenous infusion of SYSA1901 or pertuzumab (Perjeta®), respectively. Primary endpoint: serum concentration-time curve area from 0 to infinity (AUC_0-∞). Secondary endpoints: AUC from 0 to last quantifiable concentration (AUC_0-t), maximum serum concentration (C_max), safety, and immunogenicity. For the key PK parameters of SYSA1901 relative to Perjeta®, the geometric mean ratios (GMRs) were as follows: AUC_0-∞ at 90.23% (95% CI: 84.41%-96.45%), AUC_0-t at 90.25% (95% CI: 84.48%-96.42%), and C_max at 94.69% (95% CI: 90.46%-99.12%). All GMRs fell within the pre-specified bioequivalence range of 80.00%-125.00%. SYSA1901 and Perjeta® demonstrated comparable PK profiles, with no clinically significant differences in safety or immunogenicity. In this study, SYSA1901 injection and Perjeta® showed similar PK profiles, safety, and immunogenicity. These findings support further clinical investigations of the investigational drug in breast cancer. TRIAL REGISTRATION: This trial was registered on the Chinese Clinical Trial Registry (URL: http://www.chinadrugtrials.org.cn/index.html ) under Test Protocol No. SYSA1901-001 and Registration No. CTR20212874. Registration date: 3 September 2021.

This review offers a comprehensive assessment of synergistic immune checkpoint inhibitor (ICI) strategies and their evolving combinations for cancer immunotherapy, highlighting dual and strategically designed treatment options. It emphasizes essential insights into checkpoint blockade, the tumor microenvironment (TME), and innovative inhibitory and stimulatory targets, including CTLA-4, PD-1/PD-L1, LAG-3, TIM-3, and TIGIT. It discusses preclinical and clinical data demonstrating how combination therapies, such as chemotherapy, radiation, targeted medications, and adoptive cell transfer, can enhance therapeutic responses and circumvent drug resistance. The review systematically outlines important clinical research and regulatory approvals, highlighting improved results in melanoma, non-small cell lung cancer, renal cell carcinoma, and colorectal cancer. A comprehensive assessment of biomarker development, sequencing and timing optimization, and the management of immune-related adverse events is undertaken, in conjunction with novel methodologies such as AI-driven biomarker identification and the impact of the gut microbiome on the efficacy of immune checkpoint inhibitors. The research indicates that the optimal approach to enhance treatment efficacy and precision in cancer immunotherapy is through the implementation of rational combination strategies that address multiple immune evasion mechanisms and incorporate manipulation of the tumor microenvironment. This will improve long-term survival and clinical outcomes across all cancer types.

Klebsiella pneumoniae has a long history of causing infections as an opportunistic pathogen. There is an upsurge in infections caused by K. pneumoniae, mainly due to its two pathotypes, classical K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). Various infections associated with these pathotypes include pneumonia, urinary tract infections, bloodstream infections, and pyogenic liver abscesses. This review provides an update on the pathogenicity, virulence factors, mechanisms of virulence, emergence and dissemination of multidrug resistance, as well as the convergence of virulence and resistance in K. pneumoniae, which is considered a significant threat to human health. The cKP infects only immunocompromised individuals, and these infections are mostly curable. However, hvKP can infect both healthy and immunocompromised individuals, and exhibits a strong defense against antibacterial therapy due to its hypermucoviscous characteristic. The increasing development of multidrug resistance among these strains poses a significant treatment challenge. Due to its enhanced pathogenicity, resistance against multiple antibacterial drugs, and capability for widespread transmission, multidrug-resistant hypervirulent K. pneumoniae (MDR-hvKP) has emerged as a global public health concern. The cKP may acquire virulence and resistance plasmids, resulting in MDR-cKP, which later transitions into MDR-hvKP. The hvKP becomes MDR-hvKP by acquiring resistance plasmids. Virulence plasmids are a characteristic feature of hvKP and are non-conjugative; however, these could be horizontally transferred with resistance plasmids. Additionally, virulence and resistance plasmids undergo recombination, resulting in hybrid MDR-hvKP plasmids aiding in the dissemination of virulence and resistance determinants. The convergence of virulence and resistance makes K. pneumoniae a very aggressive pathogen. The acquisition and recombination of virulence and resistance plasmids drive the emergence and global spread of MDR-hvKP, severely limiting therapeutic options. Understanding the genetic mechanisms underlying this convergence is essential for developing effective surveillance, infection control, and targeted therapeutic strategies to minimise the growing impact of MDR-hvKP infections.

Abaloparatide, a 34-amino acid synthetic peptide analog of parathyroid hormone-related protein (PTHrP), was approved for treating postmenopausal osteoporosis in high-risk individuals or those resistant to existing drugs. This study aimed to investigate the impact of abaloparatide (20 µg/kg/d; s.c.), an osteoanabolic drug with an antiresorptive drug zoledronate (125 µg/kg i.v.) twice weekly for a month against 4-vinylcyclohexene diepoxide (VCD)-induced postmenopausal osteoporosis in mice. Female Swiss albino mice were made ovotoxic by treatment with VCD (160 mg/kg/d) for 15 days to mimic a postmenopausal state, confirmed by primordial follicle destruction in histopathological assessment. Microarchitectural analysis of distal femoral epiphysis and cortical mid-diaphysis was carried out using micro-computed tomography. Histopathological evaluation of bone, along with bone markers such as N-terminal propeptide of type 1 procollagen (P1NP) levels, C-terminal cross-linking telopeptide of type 1 collagen (CTX-1), soluble receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) were assessed. The VCD-treated mice exhibited bone loss as evidenced through micro CT and histopathology. Treatment with abaloparatide and zoledronate combination for 30 days reversed VCD-induced alterations of BV/TV, BMD, Tb.N, and Tb.Sp, while the individual treatments were only partially effective. Serum analysis indicated reduced bone turnover in VCD-treated mice. The abaloparatide individually and in combination reversed the VCD-induced alterations in P1NP, CTX-1, and RANKL. The combination therapy also lowered the RANKL/OPG ratio. These findings suggest that the combined approach of osteoanabolic and antiresorptive treatment may offer superior protection compared to individual therapies, holding promise for postmenopausal osteoporosis treatment.

Enavogliflozin is a sodium‒glucose cotransporter 2 inhibitor that can be administered in combination with metformin in patients with type 2 diabetes mellitus. This study aimed to compare the pharmacokinetics (PKs) between the fixed-dose combination (FDC) and the corresponding loose combination of enavogliflozin 0.3 mg and metformin 1000 mg. A randomized, open-label, 2-sequence, 4-period crossover study with a single oral dose was conducted in healthy subjects. Subjects received either the FDC or the corresponding loose combination of enavogliflozin 0.3 mg and metformin hydrochloride (HCl) 1000 mg in fasting and fed states. Serial blood samples were collected up to 72 h post-dose. Forty-four subjects were enrolled, and 37 subjects completed the study. In the fasting state, the geometric mean ratios (GMRs) (90% confidential interval (CI)) of the maximum plasma concentration (C_max) and the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC_last) of the FDC to those of the corresponding loose combination were 1.03 (0.97-1.10) and 1.08 (1.03-1.13), respectively. The GMRs (90% CI) of the metformin C_max and AUC_last of the FDC to those of the corresponding loose combination were 1.10 (1.01-1.19) and 1.05 (1.00-1.11), respectively. In a high-fat-fed state, the GMRs (90% CI) of the enavogliflozin C_max and AUC_last of the FDC to those of the corresponding loose combination were 0.88 (0.82-0.93) and 1.03 (0.98-1.09), respectively. The GMRs (90% CI) of the metformin C_max and AUC_last of the FDC to those of the corresponding loose combination were 1.01 (0.98-1.05) and 1.00 (0.97-1.04), respectively. All the results were within the conventional bioequivalence range (0.80-1.25). There were no deaths, serious adverse events in fasting high-fat-fed states. The FDC of enavogliflozin 0.3 mg and metformin HCl and the corresponding loose combination were pharmacokinetically equivalent without safety concerns in fasting and high-fat-fed states. The FDC can be an alternative option for combination therapy with enavogliflozin and metformin HCl with improved compliance.