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 A 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 A receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.

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  < 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  < 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  < 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  < 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  < 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 4.0

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), PA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; PA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.

Abstract licence: CC BY