HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies

G-protein coupled receptor 119 (GPR119) has emerged as a novel target for the treatment of type 2 diabetes mellitus. GPR119 is involved in glucose-stimulated insulin secretion (GSIS) from the pancreatic beta-cells and intestinal cells. In this study, we identified a novel small-molecule GPR119 agonist, HD047703, which raises intracellular cAMP concentrations in pancreatic beta-cells and can be expected to potentiate glucose-stimulated insulin secretion from human GPR119 receptor stably expressing cells (CHO cells). We evaluated the acute efficacy of HD047703 by the oral glucose tolerance test (OGTT) in normal C57BL/6J mice. Then, chronic administrations of HD047703 were performed to determine its efficacy in various diabetic rodent models. Single administration of HD047703 caused improved glycemic control during OGTT in a dose-dependent manner in normal mice, and the plasma GLP-1 level was also increased. With respect to chronic efficacy, we observed a decline in blood glucose levels in db/db, ob/ob and DIO mice. These results suggest that HD047703 may be a potentially promising anti-diabetic agent.

In Vitro Activities of Cefatrizine-Clavulanic Acid against Gram-Negative Bacilli Isolated from Community-acquired Urinary Track Infection / 대한진단검사의학회지

BACKGROUND: A high proportion of currently isolated gram-negative bacilli are resistant to beta-lactams by producing beta-lactamases. beta-lactam and beta-lactamase inhibitor combinations have been successfully used to overcome the resistance. In this study, in vitro antimicrobial activity of a new combination, cefatrizine-clavulanic acid, was determined against gram-negative bacilli isolated from community-acquired urinary track infections. METHODS: Nonduplicate strains of Enterobacteriaceae, isolated in 2003 from urine specimens of outpatients and inpatients of less than 3 hospital days at Severance Hospital, were tested by the NCCLS agar dilution method. RESULTS: Of a total of 204 isolates, 144 (71%) were Escherichia coli and 30 (15%) were Klebsiella spp. MIC50 and MIC90 of cefatrizine for E. coli were 2 microgram/mL and 16 microgram/mL, respectively. MIC90s of both cefaclor and cefoxitin were also 16 g/mL. MIC50 and MIC90 of cefatrizine-clavulanic acid for E. coli were 1 microgram/mL and 4 microgram/mL, respectively, which were 1/2-1/4 of those of cefaclor and cefoxitin. For Klebsiella spp., MIC90 of cefatrizine was 4 microgram/mL with an MIC range of 1->128 microgram/mL, whereas that of cefatrizine-clavulanic acid was 2 microgram/mL with an MIC range of 0.5-32 microgram/mL. In vitro activity of cefatrizine-clavulanic acid was higher than that of cefatrizine. CONCLUSIONS: Improved in vitro activity of cefatrizine-clavulanic acid against isolates of E. coli and Klebsiella spp. from community-acquired urinary track infection suggested that the combination is useful for an empirical treatment of the infection.