Old Drug,New Application:Hypouricaemic Action And Mechanism Of Olsalazine Sodium

With rapid economic development and prolonged life expectancy,the prevalence of gout varied greatly and appeared to be increasing.Gout is the second metabolic diseases.The United Nations has listed gout as one of the twenty most serious illnesses of 21 century.Hyperuricemia is not only the biochemical basis of gout,but also related to many diseases.Hyperuricemia has become "the fourth high" threating factor to human health.A few drugs for hyperuricemia,such as allopurinol,febuxostat and benzbromarone are clinically available for treatment of the disease.Xanthine oxidase(XO)is a key enzyme in the production of uric acid and has been considered as a target for anti-hyperuricemia drugs.To screen potential small-molecule inhibitors of XO,we screened FDA-approved drugs by combination of the computer-design and the inhibition activities on XO in vitro,and olsalazine sodium has shown both highest matching score and activity on XO.Eventually we also investigated the hypouricemic effects and its mechanism of olsalazine sodium in hyperuricemic animals.The results show that:firstly,the FDA-approved compounds were able to inhibit XO activities in vitro,and the inhibitory rates were ranged from 9.8%to 86.5%at the concentration of 50 mg/L.Particularly,olsalazine sodium suppressed the activity of XO at an IC50 value of 3.4 mg/L,and was a hybrid-type inhibitors in vitro.Following by the computation of iview software,olsalazine sodium was shown activity of XO by occupying the hydrophobic channel of xanthine oxidase active site.However,olsalazine sodium did not influence the uricase activity.Furthermore,olsalazine sodium profoundly reduced the elevated uric acid levels in the potassium oxonate-induced hyperuricemic mice by inhibiting the activities of XO/XDH.Moreover,olsalazine sodium promoted urate excretion and protected the kidney.Finally,we demonstrated that the uricosuric effect of olsalazine sodium was related to regulating the mRNA expression levels in GLUT9,OAT1,OAT3,MRP4,NPT1,NPT4 and increased the protein expression of OAT3.This present study provides a valuable example for the "old drug,new application".Here,olsalazine sodium showing a strong effect on reducing uric acid was reported for the first time.Therefore,we proposed that olsalazine sodium is a candidate with dual actions for management of hyperuricemia.