Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model.

AIM: Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent. MATERIAL AND METHODS: DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats. RESULTS: RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900-9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P<0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats. CONCLUSIONS: The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.

Quantifying exposure to diagnostic medical radiation in patients with inflammatory bowel disease: are we contributing to malignancy?

BACKGROUND: While potential risks of diagnostic medical radiation are acknowledged, actual exposure of patients in routine clinical practice is poorly documented. AIM: To quantify such exposure to vulnerable abdominal organs in patients with inflammatory bowel disease who are already at risk of intestinal cancer. METHODS: All incidences of exposure to diagnostic medical radiation were documented in a consecutive series of 100 patients with inflammatory bowel disease (62 Crohn's disease, 37 ulcerative colitis, 1 indeterminate colitis) attending a hospital-based clinic. Total effective dose (mSv) was calculated using published tables. Predictors of high or no irradiation were evaluated by multivariate logistic regression analysis. RESULTS: Thirteen patients had no documented diagnostic irradiation. Twenty-three patients received an effective dose greater than 25 mSv. An at-risk effective dose >50 mSv was received by 11 patients. Dosage was higher in patients with Crohn's disease than ulcerative colitis (P = 0.02) and in patients undergoing surgery (P = 0.004). However, no predictive factors for high radiation dosage or for no exposure were identified. CONCLUSIONS: At-risk irradiation from diagnostic medical radiation is common in patients with inflammatory bowel disease, and might potentially contribute to the elevated risk of intra-abdominal and other cancers. The level of irradiation should be considered in clinical decisions regarding abdominal imaging.