Antidiabetic effects and safety profile of chitosan delivery systems loaded with new xanthine-thiazolidine-4-one derivatives: in vivo studies

Abstract

Based on important biological effects associated with xanthine and thiazolidine-4-one moieties, especially hypoglycemic and antioxidant, new xanthine derivatives with thiazolidine-4-one scaffold (XTDs, 6a-k) have been synthesized and reported by our research group, as new potential multitarget antidiabetic drugs. The goal of this work was to evaluate the in vivo antidiabetic potential and safety profile of the most proper XTDs (6c, 6e) and their chitosan based formulations, CS-XTDs (CS-6c, CS-6e) selected based on previous results in terms of their in vitro antioxidant effects and physic-chemical characteristics. Using a streptozotocin-induced diabetes model, the hypoglycemic effect (postprandial glycemia and glycated hemoglobin), biochemical markers of liver and kidney function, as well as hematological markers have been evaluated. The effect on lipid profile and clinical parameters (body weight, food, and water intake) has been also monitored. Moreover, the biopharmaceutical characteristics of 6c and 6e were predicted using in silico computerized methods. The treatment of diabetic rats with CS-XTDs, especially CS-6c was associated with appreciable hypoglycemic effect, the values of postprandial glycemia and glycated hemoglobin being similar with pioglitazone, used as reference drug. In addition, the recorded values for liver enzymes (AST, ALT, LDH), bilirubin (direct, total) and kidney biochemical markers (creatinine, uric acid, urea) were also comparable with pioglitazone. Also, CS-6c was associated with good hematological markers and clinical parameters. The results highlighted the efficiency of the developed chitosan delivery system CS-6c for the treatment of diabetes mellitus syndrome, acting as a potential multitarget agent.