Aortic aneurysm and dissection (AAD) are common arterial diseases with high mortality. Recently, AAD have been reported as adverse events associated with fluoroquinolones. Previous studies showed ...fluoroquinolones could induce AAD through arterial media disorder, but the influence of fluoroquinolones to vascular endothelium is unknown. The aim of current study is to evaluate the effect of fluoroquinolone to vascular endothelium on the development of AAD. We analyzed the association in clinical situation between fluoroquinolones and AAD using VigiBase, the World Health Organization’s global database. We evaluated whether levofloxacin (LVFX) affects the AAD development using human umbilical vein endothelial cells (HUVECs) and aortic dissection model mice which induced by three drugs; nitric oxide synthase inhibitor, angiotensin II, and lysyl oxidase inhibitor. VigiBase analysis showed that the fluoroquinolones had the association of high reporting rate of AAD. Although LVFX did not significantly increase the incidence of AAD in mice, LVFX treatment increased VCAM-1 expression in HUVECs. Our results suggested that the endothelial dysfunction might be one candidate mechanism of fluoroquinolone-associated AAD.
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the adverse events associated with the anticancer drugs, however, almost available analgesic drugs lack efficacy against CIPN. Previously ...our results using medical database, FAERS, suggested that HMG-CoA reductase inhibitors (statins) have the potential to ameliorate oxaliplatin-induced peripheral neuropathy (OIPN). In this study, we elucidated the effect and mechanism of statins to OIPN model mice and PC12 cell. Three statins (simvastatin, atorvastatin, and rosuvastatin) could not show the therapeutic and preventive effects against oxaliplatin-induced cold allodynia. On the other hand, repeated orally administration of each statins ameliorate development of oxaliplatin-induced mechanical allodynia and significantly suppressed already established allodynia induced by oxaliplatin. A gene-related database revealed that the expression of glutathione S-transferase (GST) family members is regulated by statins. Decreased survival rate of PC12 cells by treatment of oxaliplatin was canceled cotreatment of each statin for 24 hours. Furthermore, cell protective effect of statin was disappeared transfection of gstmu1 siRNA into PC12 cells. These our results suggest that statins might be one of the novel supportive care, which have neuroprotective effect to OIPN.
Aortic dissection is highly lethal, and the risk factors such as hypertension, aging, and atherosclerosis are thought to contribute to its onset. Recently, there has been increasing reports that ...vascular endothelial growth factor (VEGF) inhibitors can induce the aortic dissection as an adverse event. However, the association between VEGF inhibitors and aortic dissection has been unclear. Therefore, we investigated if VEGF inhibitor increases the onset of aortic dissection using acute aortic dissection model mice (AAD mice).Sunitinib (100 mg/kg/day) was administered orally for 28days to AAD mice induced by nitric oxide inhibitor, angiotensin II, and lysyl oxidase inhibitor. Blood pressure was measured every week. After 28days, the incidence rate of AAD was estimated. For in vitro study, human umbilical vein endothelial cells (HUVEC) were treated by sunitinib for 24 hours. Then, mRNA expressions of intracellular cell adhesion molecule-1 (ICAM-1) and endothelin-1 (ET-1) were measured. Sunitinib increased systolic blood pressure (182 mmHg vs 288 mmHg with sunitinib ; p<0.01) and the incidence of AAD (40% vs 59% with sunitinib; p=0.26). Moreover, sunitinib increased mRNA expressions of ICAM-1 and ET-1 in HUVEC. These results suggested that VEGF inhibitors induced high blood pressure and developed AAD via endothelial damage.