Pharmacological Reports最新文献

Background: The isobolographic analysis is a gold standard in the assessment of interactions between drugs in experimental studies. Although some isobolographic approaches are available, the most popular methods to characterize drug-drug interactions are the log-probit method accompanied with statistical analysis of interactions (by Tallarida) and the method based on mass-action law using CompuSyn software (elaborated by Chou-Talalay-Martin). The aim of this study was to compare the results from these two isobolographic approaches.

Methods: Two isobolographic methods (log-probit associated with Tallarida statistics and Chou-Talalay-Martin) were applied to analyze the interaction between two antiseizure medications - clonazepam and lamotrigine in the mouse maximal electroshock-induced seizure model.

Results: Both isobolographic approaches confirmed that the combination of clonazepam with lamotrigine produced synergistic interaction and allowed for detailed characteristics of the interaction at various effect levels for the two-drug mixture. Calculation of the combination index values (at various effect levels) confirmed that synergy slightly decreased when the antiseizure effect increased (combination index values increased from 0.44 for 16% to 0.65 for 84%).

Conclusions: The log-probit method with statistical analysis of data (by Tallarida) was more subtle and precise in the assessment of the synergistic interaction, whereas the isobolographic analysis by Chou-Talalay-Martin offered more automatic options facilitating visualization of the interaction.

Background: Triple-negative breast cancer (TNBC) is characterized by high invasiveness, high metastatic potential, and poor prognosis. TNBC is not sensitive to endocrine therapy or HER2-targeted treatment, highlighting the need for the development of standardized TNBC treatment regimens. Thus, the development of new TNBC treatment strategies has become an urgent need. MIM1 - BH3 mimetic, which inhibits Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MOXI) can modulate the Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of MIM1 and MOXI/MIM1 mixtures on the viability and apoptosis in MDA-MB-231 breast cancer cells.

Methods: The viability of cells was assessed by the WST-1 assay. The proapoptotic activity of the tested compounds was determined by cytometric technique.

Results: The results showed that MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of MOXI and MIM1 mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity - shown as a modulatory effect on mitochondrial membrane potential, cell cycle distribution, or DNA fragmentation, toward MDA-MB-231 cells when compared with MIM1 or MOXI alone.

Conclusions: We have reported, for the first time, the high proapoptotic activity of MIM1 toward MDA-MB-231 cells pointing to the Mcl-1 protein as an important molecular target. Moreover, the observed potential synergistic mode of action (expressed as a significant enhancement of the induction of apoptosis process) detected for MOXI and MIM1 in the two-component model may provide a new direction for further in vitro and in vivo experiments concerning the role of Mcl-1 protein in the treatment of TNBC.

Clinical trial number: Not applicable.

Background: The gut microbiome has been increasingly recognized for its potential role in schizophrenia through gut-brain interactions involving immune, neural, and metabolic pathways. This pilot study evaluated the impact of fecal microbiota transplantation (FMT) on the abundance and variability of selected fungal and archaeal species in the gut microbiota in the rat model of schizophrenia.

Methods: Sprague-Dawley rats using as a prenatal methylazoxymethanol acetate (MAM-E17) model of schizophrenia underwent FMT or placebo. Fecal DNA was extracted and analyzed via quantitative Real-Time PCR (qPCR) to quantify selected fungi (Candida tropicalis, Malassezia spp., Cryptococcus neoformans) and archaea (Methanobrevibacter smithii, Methanosphaera stadtmanae) before and after intervention RESULTS: A slightly higher prevalence of C. tropicalis was noted in MAM-exposed rats compared to healthy controls (19% vs. 10%). Post-FMT, C. tropicalis colonization increased to nearly 100% across all groups, irrespective of transplantation source, indicating natural microbiome maturation rather than FMT effect. Malassezia spp. were commonly present before treatment, with their abundance significantly declining after both FMT and placebo administration, suggesting procedural impacts rather than specific FMT effects. C. neoformans and methanogenic archaea were absent.

Conclusions: Overall, the results suggest that FMT has limited impact on gut fungal populations, possibly due to the developmental stage of microbiome maturation or procedural interventions. The absence of archaea underscores the complexity of the microbiome's role in neurodevelopmental disorders, highlighting the necessity for continued research into microbial influences on schizophrenia pathophysiology.

Background: Serum canrenone concentrations have so far only been measured in patients with acute heart failure or heart failure with preserved ejection fraction. The results of these studies showed that low or undetectable canrenone concentrations could contribute to the lack of pharmacological effect of spironolactone, while patients with detectable canrenone concentrations had significantly higher potassium concentrations. However, no detailed information on serum canrenone concentrations in patients with heart failure with reduced ejection fraction (HFrEF) has been published to date. The aim of the study was to determine serum canrenone concentrations in samples collected from patients with HFrEF during routine medical care and correlate them with selected clinical parameters such as left ventricular ejection fraction (LVEF), systolic and diastolic blood pressure, and the levels of N-terminal pro-B-type natriuretic peptide, serum potassium, liver enzymes, and renal function markers.

Methods: This cross-sectional study analyzed data from 64 patients treated for HFrEF with oral spironolactone. Patients were recruited from the Cardiology Outpatient Clinic of the University Hospital, Ostrava, Czech Republic. Blood samples were collected in an outpatient setting from each patient between November 2022 and October 2023 as part of a routine examination to determine steady-state serum canrenone concentrations.

Results: Serum canrenone concentrations ranged from 5.0 to 336.2 µg/L. A correlation was observed between canrenone concentration and both the daily spironolactone dose and dose per kilogram of body weight. However, wide inter-individual variability was observed in canrenone concentrations achieved after administering the same dose of spironolactone and in the concentration-to-dose ratio. Patients with LVEF < 30% used the same dose per day and kilogram of body weight as patients with LVEF ≥ 30% but achieved significantly higher canrenone concentrations. A correlation was observed between canrenone and serum urea, creatinine, and potassium concentrations. An inverse correlation was observed between diastolic blood pressure and dose per kilogram of body weight.

Conclusions: Wide inter-individual variability in the minimum serum concentrations of canrenone was observed after the same dose of spironolactone was administered. Patients with impaired renal and/or myocardial function were found to be at a higher risk of canrenone accumulation, leading to increased serum potassium concentrations.

Anxiety and depressive disorders constitute a public health concern with a high negative impact on patients' quality of life. These disorders are among the prevalent neuropsychiatric conditions significantly contributing to the global burden. Although the precise mechanisms underlying the development of anxiety- and depressive-like behaviors remain incompletely understood, increasing evidence indicates that these disorders arise from complex and multifactorial processes involving dysfunction across multiple body organs. The gut microbiota (GM) seem to play certain role in developing of these conditions, as supported by studies demonstrating its influence on brain function and behavior. Indeed, several studies have recently reported that alterations in GM composition and function are linked with immune system dysregulation (inflammation/neuroinflammation) and subsequently influence brain pathways and systems, including neurotransmitters, the hypothalamic-pituitary-adrenal axis (HPA), and neurotrophic factors. Also, therapeutic agents targeting gut dysbiosis (GD) have yielded significant results. This review summarizes the role of GM in the pathophysiology of anxiety and depressive behaviors, its interaction with some psychotropic drugs, and its potential use as a therapeutic target for these conditions.Clinical trial number: Not applicable.

The intricate interplay between the brain and gut, often referred to as the gut-brain axis, has emerged as a cornerstone of health and disease. This bidirectional communication network, mediated by neural, hormonal, immune, and microbial signals, plays a pivotal role in maintaining homeostasis and influencing both neurological and gastrointestinal functions. Dysregulation of the gut-brain axis is implicated in various neurological and gastrointestinal disorders, highlighting the need to explore novel therapeutic strategies targeting this axis. Uridine, an endogenous pyrimidine nucleoside that is also obtained through dietary sources, has recently gained increasing attention for its neuroprotective and gut-modulating properties. Known for its critical role in RNA synthesis, membrane phospholipid production, and neurotransmitter regulation, uridine has demonstrated potential in enhancing synaptic plasticity, reducing inflammation, and supporting neuronal survival. Emerging evidence also suggests that uridine may influence gut health by promoting epithelial integrity, modulating the gut microbiota, and reducing intestinal inflammation. Given the interconnected nature of the gut and brain, uridine's dual actions present a compelling opportunity to explore its role in modulating the gut-brain axis as a means of achieving neuroprotection. This review aims to provide a comprehensive overview of the effect of uridine on brain and gut health, with a particular focus on its potential to influence the gut-brain axis.