Pharmacological Reports最新文献

Background: The present study investigated the combined effects of zofenoprilat (ZOFE) and nebivolol (NEBI) on endothelial function, focusing on their anti-inflammatory and antioxidant properties. The purpose was to evaluate whether these drugs, commonly used in clinical practice, offer a synergistic therapeutic strategy for managing hypertension and protecting vascular health. ZOFE, an ACE inhibitor, demonstrated significant anti-inflammatory activities by reducing inflammatory cytokines, thereby mitigating vascular inflammation, a key factor in hypertension and atherosclerosis. NEBI, a third-generation beta-blocker, exhibited strong antioxidant effects by enhancing nitric oxide (NO) levels, crucial for maintaining endothelial function and reducing oxidative stress.

Methods: The potential effect of ZOFE and NEBI treatment was evaluated using human umbilical vein endothelial cells (HUVEC) as a model. Specifically, cells were challenged with tumor necrosis factor-α (TNF-α) to induce endothelial dysfunction. Subsequently, cell viability, NO production, protein levels of superoxide dismutase (SOD) and catalase (CAT), enzymatic activity of SOD and CAT, intracellular levels of glutathione (GSH), inflammatory status, and levels of interleukin-6 (IL-6) monocyte chemoattractant protein-1 (MCP-1), macrophage inhibitory cytokine-1 (MIC-1), and the active form of nuclear factor kappa B (p-NFκB), were analyzed.

Results: Our results showed that NEBI significantly counteracted oxidative stress, increasing the main antioxidant defenses (SOD, CAT, and GSH). The combination of ZOFE and NEBI resulted in a potentiated effect, enhancing both anti-inflammatory and antioxidant activities. This dual mechanism of action provides a comprehensive approach to protecting endothelial cells and improving vascular function. The combined therapy not only lowered blood pressure more effectively but also offered greater protection against endothelial damage compared to monotherapy with either drug alone. These findings suggest that the combination of ZOFE and NEBI could be particularly beneficial for patients with hypertension, especially those with coexisting inflammatory and oxidative stress-related conditions.

Conclusions: This combination therapy, by addressing multiple pathogenic pathways simultaneously, could potentially be beneficial in patients with cardiovascular risk conditions. In conclusion, the combination of ZOFE and NEBI offers a potentially promising therapeutic approach for managing hypertension and protecting vascular health, aiming at improving clinical outcomes for patients with cardiovascular diseases.

Clinical trial number: Not applicable.

Background: Methotrexate (MTX) is a widely used chemotherapeutic agent in pediatric oncology, where high-dose protocols (HDMTX; ≥500 mg/m²) are standard for treating hematological and central nervous system malignancies. Due to its narrow therapeutic index and potential for severe toxicity, therapeutic drug monitoring (TDM) of plasma MTX concentrations is essential to guide leucovorin rescue therapy and prevent adverse effects.

Methods: The presented study aimed to compare the analytical performance of two immunoassays-enzyme-multiplied immunoassay technique (EMIT) and enzyme immunoassay (EIA)-against a newly developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.

Results: The LC-MS/MS assay demonstrated excellent linearity, sensitivity (LLOQ = 0.01 µmol/L), and precision, meeting ICH M10 regulatory guidelines. Clinical samples from pediatric patients receiving HDMTX were analyzed using all three methods. Results showed strong correlations (r > 0.93) between methods; however, immunoassays exhibited biases related to cross-reactivity with MTX metabolites such as DAMPA (2,4-diamino-N₁₀-methylpteroic acid) and 7-OH-MTX, which may lead to overestimation of MTX levels and unnecessary prolongation of leucovorin rescue.

Conclusions: While immunoassays remain practical for routine monitoring due to their accessibility and speed, LC-MS/MS provides superior accuracy and should be the method of choice in critical clinical situations. These findings underscore the importance of selecting the appropriate assay to optimize HDMTX therapy and ensure patient safety.

Background: The synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates provided novel compounds with relevant affinities for imidazoline 2 (I2) receptors in human brain tissues. A selected compound, 12d, showed improved cognitive and analgesic properties at the preclinical level through the modulation of I2 receptors, but its potential innovative use as an antidepressant is still unknown.

Methods: Male and female adult Sprague-Dawley rats were treated with 3 ip injections of compound 12d (10 or 20 mg/kg), or vehicle (1 ml/kg DMSO), 24, 5, and 1 h prior to scoring its antidepressant-like efficacy under the stress of the forced-swim test. Hippocampal neuroplasticity markers (i.e., FADD, p-ERK/ERK, mBDNF) were evaluated 24 h post-treatment (and post-forced-swim test exposure).

Results: The novel results proved a sex-dependent efficacy of 12d, with dose-dependent antidepressant-like effects in adult male rats, and an inefficacious response for females. Moreover, compound 12d did not alter any of the hippocampal markers evaluated.

Conclusions: These results presented 12d as a novel therapeutic antidepressant candidate at the tested conditions, although only for male rats, thus requiring further studies to better understand the observed sex disparities as well as its molecular underpinnings. Moreover, compound 12d joins the list of other I2 receptor ligands with known antidepressant-like efficacy, validating and strengthening this receptor as a target in this field for future drug development.

Epigenetic modulation has emerged as a central strategy that can change the fate of tumour cells to offer more rational and precise approaches by modulating reversible changes in chromatin structure, regulating gene expression without altering DNA sequence. Many reports have indicated the contributions of abnormal epigenetic alterations, particularly DNA methylation and histone modification patterns, as well as their association with non-coding RNA interactions during cancer emergence, development or resistance to standard therapies. Ongoing studies on various inhibitors also demonstrate encouraging preclinical results and potent inhibitory activity. Furthermore, combining epigenetic medicines with conventional treatment approaches such as chemotherapy and radiotherapy is proven to improve therapeutic efficacy in resistant cases of various malignancies. This article also briefly reviews RNA modifications (epitranscriptomics, such as m6A and m5C), novel acetylation modifications, chromosomal interaction studies, and the role of AlphaFold. The present review further illustrates these translational challenges and future opportunities in epigenetic drug development, while shedding light on the necessity of developing predictive biomarkers capable of informing personalized therapies to reduce off-target effects. The ability to target epigenetic modulators has the potential to improve patient outcomes and increase treatment options when coupled with traditional guidelines, as evidenced by on-going clinical trials and FDA approvals.

Background: Urinary tract infection (UTI) is a serious problem in the healthcare system. It is caused by bacteria from the gastrointestinal tract. The risk factors that impact the UTI incidence include administration of certain drugs (flozins), sex, use of urinary catheter, and diabetes. This is a retrospective study of the records of 76 patients from a Nursing and Treatment Facility at County Hospital in Drezdenko (Poland) aimed to assess the factors that may have an impact on the incidence of UTI.

Methods: The following factors were taken into consideration: dapagliflozin administration (yes/no), diabetes (yes/no), sex (male/female), kidney failure (yes/no), and use of urinary catheter (yes/no). The impact of the above variables on the UTI incidence was estimated using multivariate regression analysis and machine learning, such as logistic regression, artificial neural networks (ANN), and decision trees (recursive partitioning).

Results: As revealed by the multivariate regression analysis, UTI was significantly affected only by dapagliflozin administration. The machine learning techniques showed greater sensitivity in detecting significant factors - dapagliflozin administration was identified as the most important one. Moreover, the logistic regression analysis also indicated sex (female). In the case of ANN and decision tree, the other significant factors, besides dapagliflozin intake, in the model were the use of a urinary catheter, sex (female), diabetes, and kidney failure (in descending importance). The variables were listed in the same order of descending importance for both the ANN and the decision tree.

Conclusions: In the case of catheterized patients, the administration of flozins should be cautiously approached, as should the catheterization of patients taking flozins.

Clinical trial number: Not applicable.

Perinatal hypoxia, also known as neonatal hypoxia-ischemia (HI), can pose a significant threat to the life and health of newborns, leading to hypoxic-ischemic encephalopathy (HIE) and numerous organ dysfunctions, including the nervous system. Mitochondria, which are key organelles in maintaining cellular homeostasis, adenosine triphosphate (ATP) production, regulation of apoptosis, and the cell's response to oxidative stress, appear to be particularly vulnerable to hypoxic damage. In the course of HIE, a number of mitochondrial functions may be impaired, including inhibition of the respiratory chain, increased production of reactive oxygen species (ROS), loss of mitochondrial membrane potential, or activation of apoptotic pathways. As a result of HI, mitochondrial dynamics related to the processes of mitochondrial fusion, division, and autophagy are also changed, which contributes to exacerbating neuralcell damage. Because of the significant role of mitochondria in the pathophysiology of HIE, they represent a promising therapeutic target. This article presents the current state of knowledge on mitochondrial damage mechanisms in HI and discusses potential therapeutic strategies, such as modulators of mitochondrial dynamics, antioxidant compounds, or inhibitors of specific mitochondrial pathways. A better understanding of these mechanisms may contribute to the development of more effective treatments for neurodegeneration associated with perinatal hypoxia.