Pharmacological Reports最新文献

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.

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.

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.

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, fibrosis, and dysregulation of the immune system. The therapeutic options available for SSc have limited efficacy, and there is a clear need for new pharmacological alternatives. Thiazolidinediones (TZD) are molecules that have therapeutic potential for SSc due to their pharmacological properties. In this study, we aimed to evaluate the immunomodulatory activity of a new TZD analogue (LPSF/CR-35) in peripheral blood mononuclear cells (PBMC) from SSc patients.

Materials and methods: PBMC response to LPSF/CR-35 (100µM) was examined from SSc patients (n = 19) and healthy control subjects (n = 8) following PBMC stimulation with anti-CD3/CD28. Cytokines (IFN-γ, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17 A) and chemokines (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in PBMC culture supernatants by cytometric bead array (CBA). In silico analyses were performed to evaluate the binding affinity of LPSF/CR-35 to peroxisome proliferator-activated receptor gamma (PPARγ).

Results: LPSF/CR-35 treatment significantly reduced the secretion of IL-17 A (p = 0.02), IL-10 (p = 0.001), IL-4 (p = 0.04), CCL2/MCP-1 (p = 0.003), and CXCL8/IL-8 (p = 0.03), while increasing TNF levels (p = 0.004) in PBMCs from SSc patients. Molecular docking predicted high binding affinity of both E (-9.987 kcal/mol) and Z (-9.992 kcal/mol) isomers of LPSF/CR-35 to PPARγ, supporting a possible PPARγ-dependent mechanism.

Conclusions: Our results indicate that LPSF/CR-35 modulates key cytokines and chemokines involved in SSc immunopathology, possibly through PPARγ activation. These findings support the potential of LPSF/CR-35 as an immunomodulatory agent in SSc. Further studies are needed to elucidate its effects on fibrosis and confirm its mechanism of action.

Anti-vascular endothelial growth factor (anti-VEGF), laser, and vitrectomy therapy are commonly used for the management of vision-threatening posterior eye disease (PED), but non-invasive alternatives have garnered increasing popularity as proactive preventative strategies for early retinopathy, such as targeted plant-based diets or herbal supplements. However, only some plants contain bioactive compounds that specifically target retinal degeneration and demonstrate potent pharmacological benefits that are cost-effective, safe, and accessible for at-risk individuals. This review pinpoints plant bioactive compounds, specifically polyphenols and carotenoids, that target retinopathy, with a focus on apoptotic, angiogenesis, inflammation, and oxidative pathways leading to visible, functional, and vascular macula improvements. Innovations accelerating therapeutic applications of these botanicals for ocular delivery were then explored. Finally, advancements in disease assessments and the computational methods for early retinopathy biomarker diagnosis and treatment, particularly designed to bio-prospect plant-based therapies, were also reviewed to guide future developments and address translational limitations.

Background: Schizophrenia and related psychotic disorders represent a major cause of global disability, while patients show wide variability in their response to antipsychotic therapy. Genetic variants in one-carbon metabolism (folate and vitamin B12-dependent), catecholamine degradation, and methylation pathways may influence symptom severity and treatment outcomes. This study aimed to assess whether polymorphisms in these pathways are associated with baseline symptomatology and treatment response in a naturalistic setting.

Methods: In this prospective observational study, we examined common polymorphisms in methylenetetrahydrofolate reductase (MTHFR; rs1801133), methionine synthase (MTR; rs1805087), methionine synthase reductase (MTRR; rs1801394), catechol-O-methyltransferase (COMT; rs4680), and a variable number tandem repeat in arsenite methyltransferase (AS3MT) in relation to baseline symptoms and four-week treatment response in 163 patients with schizophrenia spectrum or other psychotic disorders. Symptoms were assessed with the Positive and Negative Syndrome Scale and the Calgary Depression Scale.

Results: The COMT rs4680 polymorphism was associated with higher baseline severity of negative symptoms in methionine homozygotes and with greater reduction in depressive symptoms. The MTR rs1805087 polymorphism was significantly associated with improvement in positive symptoms, particularly in patients with higher baseline vitamin B12 levels, whereas the AS3MT variable number tandem repeat showed a nominal association with positive symptom improvement in patients with lower B12 levels. No significant effects were observed for MTHFR rs1801133 or MTRR rs1801394.

Conclusions: Polymorphisms in one-carbon metabolism, particularly MTR rs1805087, may predict positive symptom response under adequate vitamin B12 conditions, while AS3MT variation may influence outcomes at lower B12 levels. COMT rs4680 is linked to both negative symptom severity and improvement in depressive symptoms. Although limited by modest sample size, lack of dietary and homocysteine data, and inclusion of non-drug-naïve patients, these findings support the potential of genetic and metabolic profiling for personalized antipsychotic treatment.

Clinical trial number: Not applicable.