A dose-escalation study of HP501, a highly selective URAT1 inhibitor, in male Chinese patients with hyperuricemia.

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor.Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.

Sustainable and Green Synthesis of Waste-Biomass-Derived Carbon Dots for Parallel and Semi-Quantitative Visual Detection of Cr(VI) and Fe3.

Carbon dot (CD)-based multi-mode sensing has drawn much attention owing to its wider application range and higher availability compared with single-mode sensing. Herein, a simple and green methodology to construct a CD-based dual-mode fluorescent sensor from the waste biomass of flowers of wintersweet (FW-CDs) for parallel and semi-quantitative visual detection of Cr(VI) and Fe3+ was firstly reported. The FW-CD fluorescent probe had a high sensitivity to Cr(VI) and Fe3+ with wide ranges of linearity from 0.1 to 60 µM and 0.05 to 100 µM along with low detection limits (LOD) of 0.07 µM and 0.15 µM, respectively. Accordingly, the FW-CD-based dual-mode sensor had an excellent parallel sensing capacity toward Cr(VI) and Fe3+ with high selectivity and strong anti-interference capability by co-using dual-functional integration and dual-masking strategies. The developed parallel sensing platform was successfully applied to Cr(VI) and Fe3+ quantitative detection in real samples with high precision and good recovery. More importantly, a novel FW-CD-based fluorescent hydrogel sensor was fabricated and first applied in the parallel and semi-quantitative visual detection of Cr(VI) and ferrous ions in industrial effluent and iron supplements, further demonstrating the significant advantage of parallel and visual sensing strategies.

Choline phosphate lipid as an intra-crosslinker in liposomes for drug and antibody delivery under guard.

Liposomes are used to deliver therapeutics in vivo because of their good biocompatibility, efficient delivery, and ability to protect the therapeutics from degradation. However, the instability of liposomes will cause the therapeutics to lose protection and become ineffective. To deliver therapeutics to the target under guard, we synthesized and used a bio-membrane mimetic choline phosphate lipid (CP-lip) to intra-crosslink liposomes to highly improve their stability. We found that when the ratio of PC-lip to CP-lip is 1 : 2, the intra-crosslinked liposome (PC-CP-lipo) showed higher stability, better biocompatibility and improved anti-protein adsorption than other common liposomes. We used doxorubicin (Dox) loaded PC-CP-lipo to treat melanoma and the tumor inhibition ratio could reach 86.3%. After the combined Dox@PC-CP-lipo treatment with PD-L1 antibody to block the immune checkpoints, the tumor suppression rate could reach 94.4%, and 60% of the mice did not suffer from tumor rechallenge. The method of using a CP-lip to intra-crosslink liposomes is applicable to all liposomes, solving the key problem of liposome disintegration, thus enhancing the protection of drugs and antibodies by liposomes in vivo.

Epidemiology and Mortality of Sepsis in Intensive Care Units in Prefecture-Level Cities in Sichuan, China: A Prospective Multicenter Study.

BACKGROUND Studies on the epidemiology of sepsis in intensive care units (ICUs) of prefecture-level hospitals in China are rare. This study aimed to investigate the epidemiological characteristics and mortality risk factors of sepsis in ICUs of tertiary hospitals in Sichuan, China. MATERIAL AND METHODS In this prospective, multicenter, observational study, patients admitted to the ICU of 7 tertiary hospitals in Sichuan (China) between October 10, 2017 and January 9, 2018 were screened for sepsis using the Sepsis-3 criteria. Patients with sepsis were included. RESULTS Of the 1604 patients screened for sepsis, 294 (18.3%) had sepsis, and 140 (47.6%) had septic shock. Of these, 169 (57.5%) died. Multivariable analysis showed that central nervous system dysfunction (odds ratio [OR]=2.59, 95% confidence interval [CI]: 1.15-5.84, P=0.022), lowest blood phosphorus level (OR=2.56, 95% CI: 1.21-5.44, P=0.014), highest lactate level (OR=1.20, 95% CI: 1.10-1.32, P<0.001), 24-h Acute Physiologic Assessment and Chronic Health Evaluation-II (APACHE-II) score (OR=1.08, 95% CI: 1.03-1.13, P=0.002), and lung infection (OR=2.57, 95% CI: 1.30-5.09, P=0.007) were independently associated with mortality in patients with sepsis. CONCLUSIONS The prevalence and mortality rates of sepsis are high in tertiary hospital ICUs in Sichuan, China. The APACHE-II score on day 1 after diagnosis, acute central nervous system dysfunction, lowest blood phosphorus, high serum lactate, and lung infection were independent risk factors of mortality in patients with sepsis.

Infrared Responsive Choline Phosphate Lipids for Synergistic Cancer Therapy.

Choline phosphate lipids have been designed and developed as new-generation zwitterionic nanocarriers with excellent biocompatibility and bioorthogonality to provide a more programmable performance for cancer therapy. However, there is a lack of spatiotemporal and reversible control for drug release at target tumor cells, which can lead to severe adverse effects to normal tissue and discounted treatment outcome. Here, light-inducible Lip-cRGDfk/ICG/Dox liposomes were developed for synergistic cancer therapy. ICG can effectively convert light energy into selective heating in a local environment upon laser irradiation, thus inducing thermal ablation of tumor cells, and further reversibly trigger the spatiotemporal release of anticancer drugs (Dox) at tumor cells due to the conformation transformation of CP lipids to synergistically kill tumor cells. That Lip-cRGDfk/ICG/Dox exhibited a significant improvement for breast cancer therapy in vitro and in vivo is also demonstrated, thus it can serve as an efficient platform to noninvasively and spatiotemporally control the activation of cytotoxicity at tumor cells for precision cancer therapy.

Constrained Parameter Estimation for a Mechanistic Kinetic Model of Cobalt-Hydrogen Electrochemical Competition during a Cobalt Removal Process.

A mechanistic kinetic model of cobalt-hydrogen electrochemical competition for the cobalt removal process in zinc hydrometallurgical was proposed. In addition, to overcome the parameter estimation difficulties arising from the model nonlinearities and the lack of information on the possible value ranges of parameters to be estimated, a constrained guided parameter estimation scheme was derived based on model equations and experimental data. The proposed model and the parameter estimation scheme have two advantages: (i) The model reflected for the first time the mechanism of the electrochemical competition between cobalt and hydrogen ions in the process of cobalt removal in zinc hydrometallurgy; (ii) The proposed constrained parameter estimation scheme did not depend on the information of the possible value ranges of parameters to be estimated; (iii) the constraint conditions provided in that scheme directly linked the experimental phenomenon metrics to the model parameters thereby providing deeper insights into the model parameters for model users. Numerical experiments showed that the proposed constrained parameter estimation algorithm significantly improved the estimation efficiency. Meanwhile, the proposed cobalt-hydrogen electrochemical competition model allowed for accurate simulation of the impact of hydrogen ions on cobalt removal rate as well as simulation of the trend of hydrogen ion concentration, which would be helpful for the actual cobalt removal process in zinc hydrometallurgy.

Nanoscale Hierarchically Micro- and Mesoporous Metal-Organic Frameworks for High-Resolution and High-Efficiency Capillary Electrochromatographic Separation.

Metal-organic frameworks (MOFs) have been widely applied in a variety of fields. However, most of the developed MOFs are micrometer scale in crystal size and contain only micropores, which will limit the mass transport and diffusion of various analytes into their internal interaction sites, severely restricting the potential of MOFs in separation science. Herein, nanoscale hierarchically porous MOFs (NHP-MOFs) were first explored as a novel MOF-based stationary phase with excellent mass transfer performance and abundant accessible interaction sites for high-performance chromatographic separation. As a proof-of-concept demonstration, the nanoscale hierarchically micro- and mesoporous UiO-66 (NHP-UiO-66) was firmly immobilized on the capillary inner surface and utilized as the porous stationary phase for high-resolution and high-efficiency electrochromatographic separation. A wide range of low-, medium-, and high-molecular-weight analytes, including substituted benzenes, chlorobenzenes, polycyclic aromatic hydrocarbons, nucleosides, polypeptides, and proteins were all separated well on a NHP-UiO-66-coated column with excellent resolution and repeatability, exhibiting significantly improved column efficiency and separation ability compared to those of a microporous UiO-66-modified column. The maximum column efficiencies for all the six kinds of analytes reached up to 1.2 × 105 plates/m, and the relative standard deviations of the migration times of substituted benzenes for intraday, interday, and column-to-column were all lower than 5.8%. These results reveal that NHP-MOFs can effectively combine the advantages of the high specific surface area of microporous MOFs and the excellent mass transfer performance and abundant accessible interaction sites of NHP materials, possessing great prospect for high-performance chromatographic separation.