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OBJECTIVE：To excavate the safety warning signals induced by azole antifungal agents ，including fluconazole ， ketoconazole，itraconazole and voriconazole after marketing ，and to provide references for rational drug use in the clinic. METHODS：Reporting odds ratio （ROR）data mining algorithm was used to investigate signals of adverse drug event （ADE）for fluconazole，ketoconazole，itraconazole and voriconazole from FDA Adverse Event Reporting System （FAERS）during January 1st，2004 to March 30th，2019. ROR data mining method was used to excavate the ADR signals of the drugs ，and main ADR involved in the safety information of azole antifungal agents instructions were analyzed. RESULTS ：A total of 27 831，5 712， 5 381 and 11 333 reports were picked out for fluconazole ，ketoconazole，itraconazole and voriconazole ，respectively. All of these drugs had exhibited high-risk signals detection by ROR ，including medical examination ，blood and lymphatic system disorders ， renal and urinary disorders ，endocrine diseases ，hepatobiliary disorders. The hepatotoxic-related ADR signals were mainly concentrated in fluconazole and voriconazole （fluconazole ROR ＝6.51，voriconazole ROR ＝14.65）；ADR detection results of Cushing’s-like syndrome （ROR＝24.86） and adrenal suppression （ROR＝44.06） by itraconazole showed high-risk signals ； ketoconazole and itraconazole had showed a strong ADR signal in adrenocortical dysfunction （ketoconazole ROR ＝15.64， itraconazole ROR ＝23.26），and the signal intensity of ketoconazole （ROR＝2.81）in skin and subcutaneous tissue disorders was significantly higher than that of other drugs . In addition ，hemorrhagic cystitis caused by fluconazole，itraconazole and voriconazole were not included in the drug instructions （fluconazole ROR ＝17.73，itraconazole ROR ＝31.43，voriconazole ROR ＝17.06）； netted green spot caused by fluconazole （ROR＝10.50）were not included in the drug instructions . CONCLUSIONS：Clinical staff should pay more attention to the differences in serious ADR related to fluconazole ，ketoconazole，itraconazole and voriconazole ； particularly some ADRs not mentioned in the drug instructions but have high incidence such as hemorrhagic cystitis caused by fluconazole，itraconazole，voriconazole and netted green spot caused by fluconazole ，as well as ADRs mentioned in the drug instructions but have abnormally high signal ，such as Cushing ’s-like syndrome and adrenal suppression caused by itraconazole .
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Objective To study the inhibitory effect and mechanism of dipeptide peptidase inhibitors analogues on LPS -induced inflam-matory response on microglia .Methods Microglia cells were cultured ,isolated and purified from the neonatal Sprague-Dawley rats.Divided them into blank group ,negative control ,LPS group and medicine group ( parallel determination for 3 times each group ) after pharmacological preconditioning for 48 hours.The optimal concentration of microglia proliferation induced by LPS were measured by MTT assay .Observed the role of dipeptide peptidase inhibitors analogues on LPS-induced microglia in different concentrations .The interleukin1β( IL-1β) ,tumor necro-sis factor alpha ( TNF-α) were assayed by enzyme-linked immunorrbent assay ( ELISA ) .The expression of TLR-4 was detected by Western blotting and the expression of NF-κB was detected by RT-PCR.Results LPS induced the proliferation of microglia and significantly in-creased the release of inflammatory cytokines in LPS-stimulated primary microglia .Compared with the blank group ,dipeptide peptidase inhibi-tors analogues could inhibit this effect and the IC 50 values was 1.014 ×10 -2 mol/L to MG after pretreatment for 48 hours.Dipeptide peptidase inhibitors analogues could inhibit the release of TNF-αand IL-1 significantly(P<0.01),and it decreased the expression of TLR4 and NF-κB signif-icantly(P<0.01).Conclusion This research suggests that dipeptide peptidase inhibitors analogues restrain cell proliferation and inflammatory re-sponse of LPS-stimulated microglia,and the possible mechanism may be related to the inhibition of the expression of TLR-4 and NF-κB.