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.

Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.

Characteristics and requirements of hypertensive patients willing to use digital health tools in the Chinese community: a multicentre cross-sectional survey.

BACKGROUND: Digital health tools (WeChat or mobile health apps) provide opportunities for new methods of hypertension management for hypertensive patients. However, the willingness of these patients to use social media and mobile health apps for hypertension management remains unclear. This study explored the characteristics and requirements of patients willing to use digital health (WDH) tools to manage hypertension. METHODS: From February to March 2018, we administered questionnaires to 1089 patients with hypertension at eight Chinese primary medical units. We assessed independent risk factors of WDH and requirement among WDH patients. RESULTS: Overall, 43% (465/1089) of participants were WDH patients, who were younger (58 ± 12 vs 61 ± 13 years) and had a greater proportion of employed individuals (31% vs 14%) and higher education levels (65% vs 52%) than the non-WDH patients (all P < 0.0001). After adjusting for other risk factors, higher education (OR: 0.52; 95% CI: 0.34-0.79), good medicine adherence (OR: 1.5; 95% CI: 1.0-2.3) and blood pressure self-monitoring (OR: 1.6; 95% CI: 1.2-2.3) remained significantly associated with WDH (all P < 0.05). WDH patients responded that digital health tools should try to provide a platform for blood pressure monitoring (42%), medication reminders (41%), hypertension knowledge (39%) and doctor-patient communication (32%). CONCLUSION: Our survey suggested that among hypertensive patients, willingness to use digital health tools was significantly associated with education, medicine adherence and blood pressure self-monitoring. Digital health tool developers and researchers should pay particular attention to recruiting older, less educated and unemployed patients with less willingness and who are less technologically savvy and research the requirements of WDH patients (blood pressure monitoring, medication reminders, and knowledge education) in the future.

Optimizing the robustness of higher-low order coupled networks.

Enhancing the robustness of complex networks is of great practical significance as it ensures the stable operation of infrastructure systems. We measure its robustness by examining the size of the largest connected component of the network after initial attacks. However, traditional research on network robustness enhancement has mainly focused on low-order networks, with little attention given to higher-order networks, particularly higher-low order coupling networks(the largest connected component of the network must exist in both higher-order and low-order networks). To address this issue, this paper proposes robust optimization methods for higher-low order coupled networks based on the greedy algorithm and the simulated annealing algorithm. By comparison, we found that the simulated annealing algorithm performs better. The proposed method optimizes the topology of the low-order network and the higher-order network by randomly reconnecting the edges, thereby enhancing the robustness of the higher-order and low-order coupled network. The experiments were conducted on multiple real networks to evaluate the change in the robustness coefficient before and after network optimization. The results demonstrate that the proposed method can effectively improve the robustness of both low-order and higher-order networks, ultimately enhancing the robustness of higher-low order coupled networks.

A Survey of Prescription Errors in Paediatric Outpatients in Multi-Primary Care Settings: The Implementation of an Electronic Pre-Prescription System.

Background: Prescription errors impact the safety and efficacy of therapy and are considered to have a higher impact on paediatric populations. Nevertheless, information in paediatrics is still lacking, particularly in primary care settings. There exists a need to investigate the prevalence and characteristics of prescription errors in paediatric outpatients to prevent such errors during the prescription stage. Methods: A cross-sectional study to evaluate paediatric prescription errors in multi-primary care settings was conducted between August 2019 and July 2021. Prescriptions documented within the electronic pre-prescription system were automatically reviewed by the system and then, potentially inappropriate prescriptions would be reconciled by remote pharmacists via a regional pharmacy information exchange network. The demographics of paediatric patients, prescription details, and types/rates of errors were assessed and used to identify associated factors for prescription using logistic regression. Results: A total of 39,754 outpatient paediatric prescriptions in 13 community health care centres were reviewed, among which 1,724 prescriptions (4.3%) were enrolled in the study as they met the inclusion criteria. Dose errors were the most prevalent (27%), with the predominance of underdosing (69%). They were followed by errors in selection without specified indications (24.5%), incompatibility (12.4%), and frequency errors (9.9%). Among critical errors were drug duplication (8.7%), contraindication (.9%), and drug interaction (.8%) that directly affect the drug's safety and efficacy. Notably, error rates were highest in medications for respiratory system drugs (50.5%), antibiotics (27.3%), and Chinese traditional medicine (12.3%). Results of logistic regression revealed that specific drug classification (antitussives, expectorants and mucolytic agents, anti-infective agents), patient age (<6 years), and prescriber specialty (paediatrics) related positively to errors. Conclusion: Our study provides the prevalence and characteristics of prescription errors of paediatric outpatients in community settings based on an electronic pre-prescription system. Errors in dose calculations and medications commonly prescribed in primary care settings, such as respiratory system drugs, antibiotics, and Chinese traditional medicine, are certainly to be aware of. These results highlight an essential requirement to update the rules of prescriptions in the pre-prescription system to facilitate the delivery of excellent therapeutic outcomes.

Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia.

Verinurad (RDEA3170) is a selective URAT1 inhibitor under investigation for the treatment of gout and hyperuricemia. In an effort to further improve the pharmacodynamics/pharmacokinetics of verinurad and to increase the structural diversity, we designed novel verinurad analogs by introducing a linker (e.g. aminomethyl, amino or oxygen) between the naphthalene and the pyridine ring to increase the flexibility. These compounds were synthesized and tested for their in vitro URAT1-inhibitory activity. Most compounds exhibited potent inhibitory activities against URAT1 with IC50 values ranging from 0.24 µM to 16.35 µM. Among them, compound KPH2f exhibited the highest URAT1-inhibitory activity with IC50 of 0.24 µM, comparable to that of verinurad (IC50 = 0.17 µM). KPH2f also inhibited GLUT9 with an IC50 value of 9.37 ± 7.10 µM, indicating the dual URAT1/GLUT9 targeting capability. In addition, KPH2f showed little effects on OAT1 and ABCG2, and thus was unlikely to cause OAT1/ABCG2-mediated drug-drug interactions and/or to neutralize the uricosuric effects of URAT1/GLUT9 inhibitors. Importantly, KPH2f (10 mg/kg) was equally effective in reducing serum uric acid levels and exhibited higher uricosuric effects in a mice hyperuricemia model, as compared to verinurad (10 mg/kg). Furthermore, KPH2f demonstrated favorable pharmacokinetic properties with an oral bioavailability of 30.13%, clearly better than that of verinurad (21.47%). Moreover, KPH2f presented benign safety profiles without causing hERG toxicity, cytotoxicity in vitro (lower than verinurad), and renal damage in vivo. Collectively, these results suggest that KPH2f represents a novel, safe and effective dual URAT1/GLUT9 inhibitor with improved druggabilities and is worthy of further investigation as an anti-hyperuricemic drug candidate.

Risk factors for contrast-induced acute kidney injury (CI-AKI): protocol for systematic review and meta-analysis.

INTRODUCTION: Identifying the patients who are at risk for contrast-induced acute kidney injury (CI-AKI), which is defined as an increase in serum creatinine after exposure to contrast media, is a critical step in targeted prevention strategies. The absolute and relative importance of individual risk factors have not been systematically evaluated, let alone the new, controversial and modifiable risk factors of CI-AKI. METHODS AND ANALYSIS: On 1 July 2019, a search was performed on MEDLINE, Embase and the Cochrane Database of Systematic Reviews. We will perform a systematic review and meta-analysis to assess the important risk factors for developing CI-AKI, including those new, modifiable factors, which are considered controversial. The secondary endpoint will be all-cause mortality. Two authors will then independently screen studies that meet the criteria for inclusion, consulting with a third author to resolve any dispute. The quality of the included studies will be assessed according to the Newcastle-Ottawa scale. ETHICS AND DISSEMINATION: Ethics approval in this systematic review and meta-analysis protocol is not needed. We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019121534.