Background: Febuxostat and allopurinol are the most commonly used uric acid-lowering medications, and their safety is of great concern, especially the cardiovascular adverse reactions associated with febuxostat. We propose to study the cardiovascular toxicity of febuxostat and allopurinol using the FDA Adverse Event Reporting System (FAERS) database. Methods: A total of 64 quarters of FAERS data were downloaded from 2004 to 2019. Febuxostat- and allopurinol-related cardiovascular adverse events were extracted after data cleaning. Signal detection was conducted by reporting odds ratio (ROR) and proportional reporting ratio (PRR). Results: There were 2939 and 25,219 reports of febuxostat- and allopurinol-related cardiovascular adverse events (CVAEs), respectively. The most frequent CVAEs with febuxostat and allopurinol were edema peripheral (14.38%) and peripheral swelling (8.76%), respectively. In elderly gout patients, febuxostat is associated with an increased risk of heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Febuxostat in combination with acetic acid derivatives nonsteroidal anti-inflammatory drug (NSAIDS) also increases the risk of cardiovascular adverse events. Conclusions: Compared with allopurinol, febuxostat may increase cardiovascular toxicity in patients with gout.

Introduction: Diabetes mellitus (DM) has been proved to contribute to multiple comorbidities that are risk factors for abdominal aortic aneurysm (AAA). Remarkably, evidences from epidemiologic studies have demonstrated a negative association between the two disease states. On the other hand, hyperglycemic state was linked to post-operative morbidities following AAA repair. This review aims to provide a thorough picture on the double-edged nature of DM and major hypoglycemic medications on prevalence, growth rate and rupture of AAA, as well as DM-associated prognosis post AAA repair.Methods: We performed a comprehensive search in electronic databases to look for literatures demonstrating the association between DM and AAA. The primary focus of the literature search was on the impact of DM on the morbidity, enlargement and rupture rate, as well as post-operative complications of AAA. The role of antidiabetic medications was also explored.Results: Retrospective epidemiological studies and large database researches associated the presence of DM with decreased prevalence, slower expansion and limited rupture rate of AAA. Major hypoglycemic drugs exert similar protective effect as DM against AAA by targeting pathological hallmarks involved in AAA formation and progression, which were demonstrated predominantly by animal studies. Nevertheless, presence of DM or postoperative hyperglycemia was linked to poorer short-term and long-term prognosis, primarily due to greater risk of infection, longer duration of hospital stays and death.Conclusion: While DM is a positive factor in the formation and progression of AAA, it is also associated with higher risk of negative outcomes following AAA repair. Concomitant use of antidiabetic medications may contribute to the protective mechanism of DM in AAA, but further studies are still warranted to explore their role following AAA repair.

Objective(s): Neuroinflammation is considered an important step in the progression of secondary brain injury (SBI) induced by cerebral hemorrhage (ICH). The nucleotide -binding and oligomerization structural domain -like receptor family of pyridine structural domain -containing 3 (NLRP3) inflammasomes play an important role in the immune pathophysiology of SBI. Febuxostat (Feb) is a xanthine oxidase inhibitor that is approved for the treatment of gout and has been found to have potent anti-inflammatory effects. However, it has been less studied after ICH and we aimed to explore its protective role in ICH. Materials and Methods: We established an autologous blood -brain hemorrhage model in C57BL/6 mice. Functions of co -expressed genes were analyzed by trend analysis and bioinformatics analysis. Enzyme -linked immunosorbent assay were used to assess the inflammatory factor levels. Fluoro-Jade B histochemistry and TUNEL staining were used to detect neuronal apoptosis. Immunofluorescence staining and western blotting were used to detect the expression of NLRP3 inflammasomes. Results: Pretreatment with Feb reduced neuronal cell death and degeneration and alleviated neurobehavioral disorders in vivo. Feb was found to modulate inflammation -related pathways by trend analysis and bioinformatics analysis. In addition, Feb inhibited microglia activation and elevated cytokine levels after ICH. Furthermore, double immunofluorescence staining showed that co -localization of NLRP3 with Iba1 positive cells was reduced after treatment with Feb. Finally, we found that Feb inhibited the activation of the NLRP3/ASC/caspase-1 pathway after ICH. Conclusion: By inhibiting the NLRP3 inflammasome, preconditioning Feb attenuates inflammatory injury after ICH. Our findings may provide new insights into the role of Feb in neuroprotection.

Febuxostat is a urate-lowering medication for the treatment of patients with gout. This study was performed to elucidate the effects and underlying mechanisms of febuxostat on neuronal injury induced by intracerebral hemorrhage (ICH) in mice. The results showed that the administration of febuxostat improved neurological severity scores and blood–brain barrier (BBB) permeability. Moreover, febuxostat attenuated neuronal cell death and cytokine levels compared with the ICH group. Next, we conducted a transcriptome analysis of the neuroprotective effects of febuxostat. The overlapping significant differentially expressed genes (DEGs) were identified. Gene ontology (GO) analysis revealed that the overlapping significant DEGs were most enriched in five items. The intersecting DEGs of the aforementioned five pathways were Wisp1, Wnt7b, Frzb, and Pitx2. In addition, GO terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that DEGs were mainly involved in the wnt signaling pathway. Furthermore, the expression of Wisp1 and Wnt7b in the perihematomal region at 72 h post-ICH was observed. The results showed that both Wisp1 and Wnt7b were increased in the ICH group and were decreased by the administration of febuxostat. Taken together, the study showed that febuxostat protected against secondary brain injury after ICH and the Wnt7b-Wisp1 pathway was closely related to neuroprotective effects.