National Institutes of Pharmaceutical Research and Development (China)

Neuroexcitotoxicity mediated by NMDA receptor is a central contributor to ischemic stroke pathology. Neuroprotective effect and mechanism of the new compound GW201, which targets NMDA receptor, were studied. We evaluated the neuroprotective effects of GW201 using in vivo and in vitro models of ischemic stroke, including the middle cerebral artery occlusion/reperfusion (MCAOi/r) model, permanent MCAO (pMCAO) model and primary neuronal oxygen-glucose deprivation (OGD) model. Pharmacodynamic studies examined the dose-response relationship and therapeutic time window of GW201 neuroprotective effects. Electrophysiological membrane clamp experiments assessed the NMDA receptor subunit selectivity of GW201 and its influence on neuronal currents under ischemia-mimicking conditions. The mechanism of its action was further analysed using molecular docking technology. Live-cell fluorescence imaging was employed to evaluate the impact of GW201 on intracellular calcium levels in simulated ischemic stroke. Furthermore, bioinformatics analysis of the GEO database identified 16 significant calcium-related genes, with their regulation by GW201 validated in the MCAOi/r model. Across all models tested, GW201 exhibited marked neuroprotective effects. Membrane clamp studies identified GW201 as an allosteric modulator of the NMDA receptor GluN2A subunit reducing current amplitude under high glutamate/NMDA + glycine conditions and subsequently lowering intracellular calcium levels. Bioinformatics analysis revealed 16 calcium-related genes, with GW201 significantly modulating Ccl3, Stat3, Anxa1, Anxa2, Mgp, S100A8, S100A9 and Cacna1a. These results suggest that the neuroprotective effects of GW201 are mediated by its ability to allosterically modulate NMDA receptor activity, reducing calcium overload, influence downstream gene expression and suppress inflammatory responses.

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ABSTRACT Sanghuangporus vaninii , a traditional Chinese medicinal fungus with notable biological activities, was investigated in this study regarding the physicochemical properties and antioxidant capacity of six types of superfine grinding powders prepared via jet milling. As particle size decreased, the width of particle size distribution significantly narrowed (from 3.92 ± 0.50 to 1.92 ± 0.10). Compared with coarse powder, the superfine grinding powders exhibited increased angles of repose and slide (from 48.61° ± 0.15° to 55.21° ± 0.40° and 20.57° ± 0.72° to 28.43° ± 0.46°, respectively), while demonstrating reduced water absorption (5.90 ± 0.11 to 3.62 ± 0.12 g/g) and oil absorption capacities (5.12 ± 0.02 to 3.36 ± 0.01 g/g). The micronization process enhanced bioactive polysaccharide, flavone, and triterpenoid compound release, particularly improving polysaccharide solubility by 0.20%. These findings suggest that S. vaninii superfine grinding powders hold significant potential for applications in the food and pharmaceutical industries. This encompasses facilitating the release of active pharmaceutical ingredients and advancing the development of premium nutraceutical products.

The objective of this study was to investigate the biotransformation characteristics and stereoselective pharmacokinetic profiles of ibuprofen (IBU) enantiomers following administration of single isomers or a racemic mixture in rats, mice, and guinea pigs. A chiral LC-MS/MS method was employed to simultaneously determine (R)-(-)-ibuprofen and (S)-(+)-ibuprofen in trace whole blood samples (5 μL). Enantiomeric inversion of IBU was assessed after separate administration of single isomers or the racemic mixture, and pharmacokinetic parameters were calculated. Results demonstrated significantly higher AUClast values for the S-enantiomer compared to the R-enantiomer. Unidirectional enantiomeric inversion from R-IBU to S-IBU was observed in all tested species (rats, mice, and guinea pigs), with no reverse conversion detected. Notably, this study is the first to confirm strictly unidirectional enantiomeric inversion of IBU in guinea pigs. Conversion rates calculated from R-IBU and S-IBU concentrations following racemic IBU administration exhibited significant interspecies differences: 54.9 ± 5.6% (rats), 76.6 ± 5.3% (mice), and 65.6 ± 6.7% (guinea pigs). In contrast, no significant species differences were observed when conversion rates were derived from S-IBU concentrations after administration of individual enantiomers (R-IBU and S-IBU), yielding values of 65.9 ± 6.5%, 76.8 ± 21.2%, and 66.3 ± 14.4% for rats, mice, and guinea pigs, respectively.

ObjectiveSymptomatic treatment for osteoarthritis (OA) remains a major unmet need. This trial evaluated XG005, a novel, non-opioid, dual-mechanism agent targeting both inflammatory and neuropathic pathways in patients with knee OA.DesignThis randomized, double-blind, placebo-controlled study enrolled 318 patients with moderate-to-severe knee OA pain to receive XG005 750 mg, 500 mg, or placebo twice daily for 4 weeks. Efficacy measures included weekly average of daily walking pain (WADWP), Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), Patient Global Impression of Change (PGIC), Sleep Interference Score (SIS), and Short-Form-12 Health Survey (SF-12).ResultsThe primary efficacy endpoint of improvement from baseline in WADWP at week 4 was statistically greater for the 750 mg group than placebo with least squares mean difference (LSMD) (95 % CI) of −0.55 (−0.94, −0.16). Key secondary endpoints were significantly improved for high- and low-dose XG005 compared to placebo at week 4, with LSMD (95 % CI) of −0.43 (−0.74, −0.13) and −0.4 (−0.78, −0.02) in WOMAC pain, and 5.56 (2.69, 8.42) and 3.74 (0.17, 7.31) in KOOS pain. WOMAC and KOOS stiffness and function, PGIC, SIS and SF-12 mental and general health showed statistically significant improvements over placebo. Patients with neuropathic pain had approximately 2-3-fold greater symptom improvements than patients with nociceptive pain. Mild dizziness and somnolence were most seen in XG005 groups.ConclusionXG005 demonstrated consistent efficacy in improving OA symptoms with acceptable tolerability. Additional studies in OA patients with neuropathic pain are needed to confirm its dual mechanism advantages.Clinical trial registrationCTR20222406.

<sec><strong>Introduction</strong> Diabetic foot infections impose a substantial economic burden globally, particularly in developing countries such as China. This study evaluated the cost-effectiveness of Fufang Huangbai fluid (FHF) compared with Suprasorb® A + Ag antimicrobial calcium alginate wound dressing (SAAAD) for treating grade 1–2 diabetic foot ulcers (DFUs) (graded according to the International Working Group on the Diabetic Foot/the Infectious Diseases Society of America [IWGDF/IDSA]). </sec><sec><strong>Methods</strong> A cost-effectiveness analysis was conducted using 2 weeks of randomized controlled trial data (<i>n</i> = 176) using Chinese healthcare system costs and service fees. Quality-adjusted life years (QALYs) served as the primary health outcome, and costs included drug expenses and dressing services. Both deterministic and probabilistic sensitivity analyses were performed. </sec><sec><strong>Results</strong> Compared with the SAAAD group, the FHF group saved CNY 300.64 and gained an incremental 0.0013 QALYs, making it a dominant approach with a net monetary benefit of CNY 325.86. Sensitivity analysis indicated that the unit price of SAAAD had the greatest impact on the results. At a willingness-to-pay threshold of CNY 20 000 per QALY, the probability of FHF being cost-effective was 70.65%. </sec><sec><strong>Conclusion</strong> FHF is economically advantageous compared with SAAAD for the treatment of DFUs of IWGDF/IDSA grade 1–2. </sec>