CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [14C]-uric acid in URAT1-expressing HEK293 cells with an IC50 value of 2.08 ± 0.31 µM, which was similar to that of RDEA3170 (its IC50 value was 1.47 ± 0.23 µM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC50 value of 91.55 ± 15.28 µM, whereas RDEA3170 at 100 µM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg-1 · d-1) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg-1 · d-1) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 µM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

Association Between Thionamides and Acute Pancreatitis: A Case-Control Study.

Background: Thionamides have been extensively used to treat patients with hyperthyroidism worldwide. Recent pharmacovigilance studies have revealed a safety signal between carbimazole or methimazole and pancreatitis. The associated risk remains unclear. Methods: We identified patients with newly diagnosed acute pancreatitis from 2000 to 2013 as the case group from the Taiwan Longitudinal Health Insurance Database 2000, which contains data from 1996 to 2013. Each patient with acute pancreatitis was matched for age, sex, comorbidities, and cancer with four controls through propensity score matching. A total of 52 patients without matched controls were excluded. Sensitivity analyses including the 52 excluded patients were performed using a matching ratio of 1:2. Odds ratios (ORs) along with 95% confidence intervals (CIs) for the association were estimated using multivariate logistic regression. Results: We included 9204 and 36,816 patients in the case and control groups, respectively. The proportions of patients who had used thionamides, carbimazole, methimazole, and propylthiouracil were similar in these two groups. In addition, the adjusted OR (CI) for the association of acute pancreatitis with thionamides was 1.03 (0.86-1.24), with carbimazole it was 0.90 (0.63-1.30), with methimazole it was 1.05 (0.84-1.31), and with propylthiouracil it was 1.00 (0.74-1.34). The sensitivity analysis results were unchanged. Conclusions: We were unable to demonstrate an association between acute pancreatitis and usage of thionamides.

The association of dipeptidyl peptidase IV inhibitors and other risk factors with bullous pemphigoid in patients with type 2 diabetes mellitus: A retrospective cohort study.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder with unknown etiology. Evidence revealed that dipeptidyl peptidase IV inhibitors (DPP4i) may increase the associated risk. This study aimed to evaluate the relationship of BP with the administration of DPP4i and other risk factors in patients with type 2 diabetes mellitus (T2DM). METHODS: Using the Taiwan National Health Insurance Database (NHIRD) from 2009 to 2013, we identified patients with T2DM and the use of DPP4i 12 weeks or greater as a DPP4i cohort and patients with T2DM who never use DPP4i as a control cohort. They were frequency matched on gender and age within 5 years at a ratio of 1:2. The Cox proportional hazard regression model was used to estimate the hazard ratios (HRs) and confidence intervals (CIs) for the cohorts. RESULTS: A total of 14,187 individuals taking DPP4i and 28,374 matched cohorts without taking DPP4i were included. The incidence rate of BP was higher in DPP4i cohort than in control cohort (1.41 vs. 0.59 per 1000 person-years; adjusted HR 2.14, 95% CI = 1.02-4.50). The cumulative event rate of BP in DPP4i cohort was higher than in control cohort (log-rank test, p = .01). Patients with dementia and taking spironolactone had a higher associated risk to develop BP; lower associated risk in patients taking metformin. CONCLUSIONS: In patients with T2DM, subjects taking DPP4i, having dementia, and taking spironolactone were associated with an increased risk for the development of BP.

Urinary Metabolomics Study of the Intervention Effect of Hypoglycemic Decoction on Type 2 Diabetes Mellitus Rats Model.

The hypoglycemic decoction (HD) is a traditional Chinese medicine (TCM) preparation for the treatment of diabetes mellitus (DM), with a remarkable therapeutic effect. However, its mechanism of action is still unclear at the metabolic level. In this study, the biochemical markers from type 2 DM (T2DM) rats, induced by a high-sugar and high-fat diet combined with streptozotocin (STZ), were detected. The metabolomics-based analysis using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was conducted to evaluate urine samples from control, model, metformin, and HD groups. After oral administration of HD for 28 days, the general state, weight, fasting blood glucose (FBG), blood lipid level, oral glucose tolerance test (OGTT), fasting insulin (FINS), insulin sensitivity index (ISI), and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly improved (P < 0.01). The western blotting showed that HD can enhance the protein expression of glucose transporter 4 (GLUT4) and adenosine monophosphate-activated protein kinase (AMPK). The metabolomics results revealed that after treatment with HD, the levels of L-carnitine, 1-methyladenosine, 1-methylhistamine, and 3-indoleacrylic acid were upregulated and the levels of riboflavin, phenylalanine, atrolactic acid, 2-oxoglutarate, citrate, isocitrate, cortisol, and glucose were downregulated. The main mechanism may be closely related to the regulation of the tricarboxylic acid (TCA) cycle, phenylalanine metabolism, glyoxylate metabolism, and dicarboxylate metabolism. Additionally, it was also found that HD can regulate the protein expression of GLUT4 and AMPK to interfere with TCA cycle and carbohydrate metabolism to treat T2DM.

[Assessment and application of a molecular diagnostic method on the detection of four types of diarrheagenic Escherichia coli].

OBJECTIVE: To establish and evaluate a molecular diagnostic method for routine monitoring of four types of diarrheagenic Escherichia (E.) coli (DEC)and to study the distribution of four types of DEC isolated from diarrheal patients in Shanghai. METHODS: DEC-PCR standard operation procedure(SOP)had been developed for DEC detection and isolation, using the Statens Serum Institute (SSI) DEC PCR kits with multiplex PCR technique after verification tests on reference strains. Diarrhea specimens from 3 clinical hospitals in Shanghai were tested from June to September, 2012. RESULTS: Specificity of the PCR kit was 100% by verification on the 26 DEC reference strains. A total number of 218 DEC isolates, including 181 fermented lactose and 37 unfermented lactose were identified from the 1887 stool specimens of diarrhea patients, with positive rate as 11.6%. The most common pathogen(54.1%, 118/218)was enteropathogenic E. coli(EPEC), followed by enterotoxigenic E. coli(ETEC, 41.3%, 90/218), enteroinvasive E. coli (EIEC, 4.1%, 9/ 218) and Shigatoxin-producing E. coli(STEC, 0.5%, 1/218)in addition to 18 Shigella isolates. ETEC dominated in diarrhea patients with foreign residency, as well as 1/3 were perinatal stage of neonatal ETEC of all diarrhea cases under the age of 5, while EPEC dominated in the Chinese diarrhea patients especially among young kids under the age of 2. CONCLUSION: Data was reliable after assessment on this molecular diagnostics and seperation procedures used for the routine monitoring on four types of DEC, while the diagnosis and reference ability of DEC regarding the laboratories net-working on food-borne pathogens need to be built up and improved.