E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerabil...E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.展开更多
Background: Diabetes mellitus (DM) especially type 2 is a major health problem and diabetic nephropathy is the main cause of end stage renal disease (ESRD). Renal ischemia/reperfusion (I/R) injury is common in diabeti...Background: Diabetes mellitus (DM) especially type 2 is a major health problem and diabetic nephropathy is the main cause of end stage renal disease (ESRD). Renal ischemia/reperfusion (I/R) injury is common in diabetic patients. Recent studies reported increased vulnerability of kidneys to I/R injury in diabetic rats. In view of the reported efficacy of incretin enhancer on I/R injury. Aim: This study was designed to assess the effect of sitaglipten on renal I/R in type 2 diabetes mellitus . Methods: Type 2 DM in rats were induced by administration of nicotinamide (230 mg/kg, i.p.), 15 min prior to the single dose of streptozotocin (65 mg/kg, i.p.). Renal I/R were performed in both diabetic and normal rats. Results: The lipid peroxidation, xanthine oxidase activity, and nitric oxide levels were significantly increased after I/R in diabetic rats compared to I/R in normal rats. Antioxidant enzymes such as glutathione, superoxide dismutase, catalase, and glutathione peroxidase were significantly reduced after I/R in diabetic rats compared to normal rats. Sitaglipten treatment significantly normalized these biochemical parameters compared to diabetic I/R rats. Serum TNF-α level and myeloperoxidase activity were also significantly normalized after administration of sitaglipten. Furthermore, treatment with sitaglipten (10 mcg/kg) had preserved the normal morphology of the kidney compared to I/R performed in diabetic rats. Conclusion: Sitaglipten protects exaggerated renal I/R injury in type 2 DM. These findings have major implication in the treatment of ischemic injury that is prone to develop in DM.展开更多
文摘E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relationship study suggested that a piperazine group N-linked to the 2-position of the 5,6-membered fused heterocyclic rings was a key structural element for triggering histamine release.
文摘Background: Diabetes mellitus (DM) especially type 2 is a major health problem and diabetic nephropathy is the main cause of end stage renal disease (ESRD). Renal ischemia/reperfusion (I/R) injury is common in diabetic patients. Recent studies reported increased vulnerability of kidneys to I/R injury in diabetic rats. In view of the reported efficacy of incretin enhancer on I/R injury. Aim: This study was designed to assess the effect of sitaglipten on renal I/R in type 2 diabetes mellitus . Methods: Type 2 DM in rats were induced by administration of nicotinamide (230 mg/kg, i.p.), 15 min prior to the single dose of streptozotocin (65 mg/kg, i.p.). Renal I/R were performed in both diabetic and normal rats. Results: The lipid peroxidation, xanthine oxidase activity, and nitric oxide levels were significantly increased after I/R in diabetic rats compared to I/R in normal rats. Antioxidant enzymes such as glutathione, superoxide dismutase, catalase, and glutathione peroxidase were significantly reduced after I/R in diabetic rats compared to normal rats. Sitaglipten treatment significantly normalized these biochemical parameters compared to diabetic I/R rats. Serum TNF-α level and myeloperoxidase activity were also significantly normalized after administration of sitaglipten. Furthermore, treatment with sitaglipten (10 mcg/kg) had preserved the normal morphology of the kidney compared to I/R performed in diabetic rats. Conclusion: Sitaglipten protects exaggerated renal I/R injury in type 2 DM. These findings have major implication in the treatment of ischemic injury that is prone to develop in DM.
