Sitaxentan 100mg tablets

Receptor tyrosine kinase inhibitors (RTKIs) suppress tumour growth by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) which is an important mediator of angiogenesis. Here, we demonstrate that two potent RTKIs, axitinib and lenvatinib, are associated with hypertensive side effects. Doppler flowmetry was used to evaluate regional haemodynamic profiles of axitinib and lenvatinib. Male Sprague Dawley rats (350–500 g) were instrumented with Doppler flow probes (renal and mesenteric arteries and descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta, via the caudal artery). Rats were dosed daily with axitinib (3 or 6 mg.kg−1) or lenvatinib (1 or 3 mg.kg−1) and regional haemodynamics were recorded over a maximum of 4 days. Both RTKIs caused significant (p < 0.05) increases in mean arterial pressure (MAP), which was accompanied by significant (p < 0.05) vasoconstriction in both the mesenteric and hindquarters vascular beds. To gain insight into the involvement of endothelin-1 (ET-1) in RTKI-mediated hypertension, we also monitored heart rate (HR) and MAP in response to axitinib or lenvatinib in animals treated with the ETA receptor selective antagonist sitaxentan (5 mg.kg−1) or the mixed ETA/ETB receptor antagonist bosentan (15 mg.kg−1) over two days. Co-treatment with bosentan or sitaxentan markedly reduced the MAP effects mediated by both RTKIs (p < 0.05). Bosentan, but not sitaxentan, also attenuated ET-1 mediated increases in HR. These data suggest that selective antagonists of ETA receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.

Abstract licence: CC BY

Idiopathic pulmonary fibrosis (IPF) progression involves dysregulation of anoikis-related mechanisms, though the precise molecular drivers remain unclear. Through integrated analysis of IPF and normal lung tissue datasets, we identified 19 anoikis-related genes (ARGs) with EDNRB, MMP7, and CXCL12 showing significant differential expression ( p &amp;lt; 0.05). Functional characterization revealed these ARGs predominantly regulate cell chemotaxis and inflammatory pathways, with protein network analysis identifying CXCL12 and CCL5 as central regulators. Clinically relevant findings demonstrated that EDNRB downregulation correlates with fibrotic progression, while ROC analysis validated multiple ARGs as diagnostic biomarkers (AUC &amp;gt; 0.8). Crucially, we discovered that FDA-approved endothelin receptor antagonists (bosentan/sitaxentan) attenuate fibrosis through EDNRB upregulation, positioning these repurposable drugs as novel therapeutic candidates. These findings establish EDNRB-mediated anoikis regulation as a key mechanism in IPF and urgently warrant clinical trials to validate endothelin receptor antagonists for targeted anti-fibrotic therapy.

Abstract licence: CC BY

Some studies have investigated the role of cholesterol in the progression of colorectal cancer (CRC). However, the underlying mechanism of action is not clear. In this study, we used bioinformatics tools to elucidate the molecular mechanisms involved. We initially obtained CRC datasets from the Gene Expression Omnibus (GEO) database and hypercholesterolemia data from GeneCards and DisGeNE. Common differentially expressed genes (DEGs) were determined by using Venn diagram web tools. Next, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The hub gene was identified through common expression pattern analysis and survival analysis. Finally, we conducted an immune regulatory point analysis and predicted target drugs based on the hub gene. The results of our analysis revealed 13 common DEGs, with endothelin receptor type A (EDNRA) identified as the hub gene linking hypercholesterolemia and CRC. The results of the GO analysis showed that the common DEGs were primarily associated with the G-protein coupled receptor signaling pathway, extracellular space, and receptor binding. The results of the KEGG pathway enrichment analysis indicated enrichment in pathways related to cancer and the phospholipase D signaling pathway. Additionally, we identified potential target drugs, including Podocarpus montanus, Diospyros kaki, Herba Salviae japoniae, sitaxentan, and ambrisentan. We found that EDNRA might be an underlying biomarker for both hypercholesterolemia and CRC. The predicted target drugs provide new strategies for treating CRC.

Abstract licence: CC BY-NC-ND

Background Cardiopulmonary bypass is widely used in cardiac surgery but often leads to lung ischemia–reperfusion injury, a major cause of morbidity and mortality. Despite advances in critical care, effective prevention remains challenging. Sitaxentan, a selective endothelin receptor antagonist, has shown protective effects in ischemia–reperfusion models, suggesting its potential in mitigating lung ischemia–reperfusion injury. This study investigated the efficacy of sitaxentan in reducing lung ischemia–reperfusion injury during cardiopulmonary bypass. Methods Twenty-four female beagles were divided into sham, cardiopulmonary bypass, and endothelin receptor antagonist (sitaxentan-treated) groups. Hemodynamics, arterial blood gas, lung damage scores, wet/dry ratio, and levels of various biomarkers were evaluated. Results Lung damage scores in the endothelin receptor antagonist group were lower than those in the cardiopulmonary bypass group but higher than those in the sham group ( P &lt; 0.05). The wet/dry ratio was lowest in the sham group and higher in the cardiopulmonary bypass group than that in the endothelin receptor antagonist group ( P &lt; 0.05). Caspase-3 and hypoxia inducible factor-1α levels were intermediate in the endothelin receptor antagonist group compared with those in the cardiopulmonary bypass and sham groups ( P &lt; 0.05). In contrast, phosphorylated-endothelial nitric oxide synthase, phosphorylated protein kinase B, tumor necrosis factor-α, and interleukin-6 levels were higher in the endothelin receptor antagonist group than in the cardiopulmonary bypass and sham groups ( P &lt; 0.05). Malondialdehyde level was higher and superoxide dismutase level was lower in the cardiopulmonary bypass and endothelin receptor antagonist groups than in the sham group ( P &lt; 0.05). Conclusions Sitaxentan may offer a novel therapeutic approach to attenuate lung ischemia–reperfusion injury in clinical settings by regulating the hypoxia inducible factor-1α/phosphorylated protein kinase B/phosphorylated-endothelial nitric oxide synthase pathway.

Abstract licence: CC BY-NC