Discovery of digallic acid as XOD/URAT1 dual target inhibitor for the treatment of hyperuricemia.

The development of XOD/URAT1 dual target inhibitors has emerged as a promising therapeutic strategy for the management of hyperuricemia. Here, through virtual screening, we have identified digallic acid as a novel dual target inhibitor of XOD/URAT1 and subsequently evaluated its pharmacological properties, pharmacokinetics, and toxicities. Digallic acid inhibited URAT1 with an IC50 of 5.34 ± 0.65 µM, which is less potent than benzbromarone (2.01 ± 0.36 µM) but more potent than lesinurad (10.36 ± 1.23 µM). Docking and mutation analysis indicated that residues S35, F241 and R477 of URAT1 confer a high affinity for digallic acid. Digallic acid inhibited XOD with an IC50 of 1.04 ± 0.23 µM. Its metabolic product, gallic acid, inhibited XOD with an IC50 of 0.91 ± 0.14 µM. Enzyme kinetic studies indicated that both digallic acid and gallic acid act as mixed-type XOD inhibitors. It shares the same binding mode as digallic acid, and residues E802, R880, F914, T1010, N768 and F1009 contribute to their high affinity. The anion group (carboxyl) of digallic acid contribute significantly to its inhibition activity on both XOD and URAT1 as indicated by docking analysis. Remarkably, at a dosage of 10 mg/kg in vivo, digallic acid exhibited a stronger urate-lowering and uricosuric effect compared to the positive drug benzbromarone and lesinurad. Pharmacokinetic study indicated that digallic acid can be hydrolyzed into gallic acid in vivo and has a t1/2 of 0.77 ± 0.10 h. Further toxicity evaluation indicated that digallic acid exhibited no obvious renal toxicity, as reflected by CCK-8, biochemical analysis (CR and BUN) and HE examination. The findings of our study can provide valuable insights for the development of XOD/URAT1 dual target inhibitors, and digallic acid deserves further investigation as a potential anti-hyperuricemic drug.

Improving timely treatment with a stroke emergency map: The case of northern China.

OBJECTIVE: The Chinese stroke emergency map (SEM) was implemented in 2017 to reduce prehospital and hospital delays for acute ischemic stroke (AIS) patients suitable for intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis. However, data on the time delay following the implementation of an SEM in China are limited. METHODS: Data for suspected stroke patients from the SEM registry center of Taiyuan, Shanxi Province, from August 2017 to July 2019, patients' characteristics, thrombolysis rate, and functional outcome at 90 days were analyzed. RESULTS: One thousand seven hundred and eighty six patients who arrived at hospitals within 4.5 hr of onset were included; 35.9% arrived by emergency medical services (EMSs), and 1,207 (67.6%) of the population received intravenous rt-PA. As a result of the SEM, the number of patients treated with rt-PA increased from 63.9% in phase 1 (August 2017 to July 2018) to 70.5% in phase 2 (August 2018 to July 2019). The median onset-to-door and onset-to-needle times decreased by five minutes (100 [IQR: 62-135] vs. 105 [IQR: 70-145], p = .005) and nine minutes (158 [IQR: 124-197] vs. 167 [IQR: 132-214], p = .001), respectively. Patients in phase 2 achieved greater independent function outcome at 90 days (79.9% vs. 72.1%; adjusted odds ratio, 2.010; 95% confidence interval, 1.444-2.798). The binary logistic regression models revealed that shorter onset-to-needle time (OR: 0.994; 95% CI: 0.992-0.997; p < .001) and lower baseline NIHSS scores (OR: 39.120; 95% CI: 23.477-65.188; p < .001 and OR: 18.324; 95% CI: 11.425-29.388; p < .001 and OR: 3.123; 95% CI: 2.044-4.773; p < .001) were significant predictors for the independent function outcome. CONCLUSION: The implementation of a stroke emergency map is more likely to reduce prehospital delays and improve function outcomes. Future efforts should attempt to increase EMS usage.

Effect of short-term blood pressure variability on functional outcome after intra-arterial treatment in acute stroke patients with large-vessel occlusion.

BACKGROUND: Endovascular treatment (EVT) is advocated for acute ischaemic stroke with large-vessel occlusion (LVO), but perioperative periods are challenging. This study investigated the relationship between post-EVT short-term blood pressure variability (BPV) and early outcomes in LVO patients. METHODS: We retrospectively reviewed 72 LVO patients undergoing EVT between June 2015 and June 2018. Hourly systolic and diastolic blood pressures (SBP and DBP, respectively) were recorded in the first 24 h post-EVT. BPV were evaluated as standard deviation (SD), coefficient of variation (CV), and successive variation (SV) separately for SBP and DBP. Functional independence at 3 months was defined as a modified Rankin Scale (mRS) score of 0-2. RESULTS: For 58.3% patients with favorable outcomes, the median National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT scores on admission were 14 and 8, respectively. The maximum SBP ([154.3 ± 16.8] vs. [163.5 ± 15.6], P = 0.02), systolic CV ([8. 8% ± 2.0%] vs. [11.0% ± 1.8], P < 0.001), SV ([11.4 ± 2.3] vs. [14.6 ± 2.0], P < 0.001), and SD ([10.5 ± 2.4] vs. [13.8 ± 3.9], P < 0.001) were lower in patients with favorable outcomes. On multivariable logistic regression analysis, systolic SV (OR: 4.273, 95% CI: 1.030 to 17.727, P = 0.045) independently predicted unfavorable prognosis. The area under the curve was 0.868 (95% CI: 0.781 to 0.955, P < 0.001), and sensitivity and specificity were 93.3% and 73.8%, respectively, showing excellent predictive value for 3-month poor-outcomes. CONCLUSIONS: Decreased systolic SV following intra-arterial therapies result in favorable outcomes at 3 months. Systolic SV may be a novel predictor of functional prognosis in LVO patients.