Small-molecule antiviral treatments for COVID-19: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to explore the efficacy and safety of small-molecule antivirals for treating coronavirus disease 2019 (COVID-19). METHODS: Seven databases were searched from their inception to 01 June 2023. The risk of bias in randomised controlled trials and retrospective studies was evaluated individually using the Cochrane risk-of-bias tool and Newcastle Ottawa Scale. RESULTS: In total, 160 studies involving 933 409 COVID-19 patients were evaluated. Compared with placebo or standard of care, proxalutamide demonstrated remarkable efficacy in reducing mortality rates, hospitalisation rates, serious adverse events, and the need for mechanical ventilation. Furthermore, it significantly enhanced both the rate of clinical improvement and expedited the duration of clinical recovery when compared with control groups. In patients with mild-to-moderate COVID-19, proxalutamide exhibited the above advantages, except for mortality reduction. Triazavirin was the most effective treatment for reducing the time required for viral clearance and improving the discharge rate. Leritrelvir and VV116 were ranked first in terms of enhancing the viral clearance rate on days 7 and 14, respectively. Molnupiravir was the most effective treatment for reducing the need for oxygen support. Overall, these findings remained consistent across the various subgroups. CONCLUSIONS: A thorough evaluation of effectiveness, applicable to both mild-to-moderate and unstratified populations, highlights the specific advantages of proxalutamide, nirmatrelvir/ritonavir, triazavirin, azvudine, molnupiravir, and VV116 in combating COVID-19. Additional clinical data are required to confirm the efficacy and safety of simnotrelvir/ritonavir and leritrelvir. The safety profiles of these antivirals were deemed acceptable.

Quercetin improves the protection of hydroxysafflor yellow a against cerebral ischemic injury by modulating of blood-brain barrier and src-p-gp-mmp-9 signalling.

Protection of the structural and functional integrity of the blood-brain barrier (BBB) is crucial for treating ischemic stroke (IS). Hydroxysafflor yellow A (HSYA) and quercetin (Quer), two main active components in the edible and medicinal plant Carthamus tinctorius L., have been reported to exhibit neuroprotective effects. We investigated the anti-IS and BBB-protective properties of HSYA and Quer and the underlying mechanisms. They decreased neurological deficits in middle cerebral artery occlusion (MCAO) mice, while their combination showed better effects. Importantly, HSYA and Quer ameliorated BBB permeability. Their effects on reduction of both EB leakage and infarct volume were similar, which may contribute to improved locomotor activities. Moreover, HSYA and Quer showed protective effects for hCMEC/D3 monolayer against oxygen-glucose deprivation. Src, p-Src, MMP-9, and P-gp were associated with ingredients treatments. Furthermore, molecular docking and molecular dynamics simulations revealed stable and tight binding modes of ingredients with Src and P-gp. The current study supports the potential role of HSYA, Quer, and their combination in the treatment of IS by regulating BBB integrity.

A novel score for early prediction of urinary tract infection risk in patients with acute ischemic stroke: a nomogram-based retrospective cohort study.

This study aimed to construct and externally validate a user-friendly nomogram-based scoring model for predicting the risk of urinary tract infections (UTIs) in patients with acute ischemic stroke (AIS). A retrospective real-world cohort study was conducted on 1748 consecutive hospitalized patients with AIS. Out of these patients, a total of 1132 participants were ultimately included in the final analysis, with 817 used for model construction and 315 utilized for external validation. Multivariate regression analysis was applied to develop the model. The discriminative capacity, calibration ability, and clinical effectiveness of the model were evaluated. The overall incidence of UTIs was 8.13% (92/1132), with Escherichia coli being the most prevalent causative pathogen in patients with AIS. After multivariable analysis, advanced age, female gender, National Institute of Health Stroke Scale (NIHSS) score ≥ 5, and use of urinary catheters were identified as independent risk factors for UTIs. A nomogram-based SUNA model was constructed using these four factors (Area under the receiver operating characteristic curve (AUC) = 0.810), which showed good discrimination (AUC = 0.788), calibration, and clinical utility in the external validation cohort. Based on four simple and readily available factors, we derived and externally validated a novel and user-friendly nomogram-based scoring model (SUNA score) to predict the risk of UTIs in patients with AIS. The model has a good predictive value and provides valuable information for timely intervention in patients with AIS to reduce the occurrence of UTIs.

Is Azvudine Comparable to Nirmatrelvir-Ritonavir in Real-World Efficacy and Safety for Hospitalized Patients with COVID-19? A Retrospective Cohort Study.

INTRODUCTION: Azvudine and nirmatrelvir-ritonavir are more extensively used to treat COVID-19 in China due to their earlier approval by the National Medical Products Administration. However, there has been a scarcity of research directly comparing the clinical outcomes between azvudine and nirmatrelvir-ritonavir till now. We aimed to make a head-to-head comparison of the efficacy and safety of azvudine or nirmatrelvir-ritonavir in hospitalized patients with COVID-19 in China. METHODS: This retrospective cohort study was conducted using data collected from Tongde Hospital of Zhejiang Province between December 2022 and January 2023. All-cause mortality, risk of progressing to a critical condition, proportion with nucleic-acid negative conversion (PNANC), time to first nucleic-acid negative conversion (TFNANC), length of hospital stay and incidence of adverse events were systematically assessed as outcomes. Multi-model regression analysis, propensity-score-matching analysis, subgroup analysis and several sensitivity analyses were applied to compare these outcomes. RESULTS: This study included a total of 1571 hospitalized patients with COVID-19, among whom 272 received nirmatrelvir-ritonavir and 156 received azvudine. We found no significant differences in all-cause mortality (HR 1.41; 95% CI 0.56-3.56; P = 0.471), risk of progressing to critical COVID-19 (HR 1.67; 95% CI 0.78-3.60; P = 0.189), PNANC (HR 0.87; 95% CI 0.69-1.09; P = 0.220), length of stay (ß - 0.82; 95% CI - 2.78 to 1.15; P = 0.414) and adverse event rate (3.21% vs. 4.41%, P = 0.538) between the two groups, although azvudine was slightly less effective than nirmatrelvir-ritonavir. Meanwhile, the azvudine group exhibited a significantly longer TFNANC (ß 2.53; 95% CI 0.76-4.29; P = 0.005) than the nirmatrelvir-ritonavir group. Results were similar for propensity-score matching and multiple sensitivity analyses. CONCLUSION: Azvudine probably possessed comparable efficacy and safety to nirmatrelvir-ritonavir, although it was less effective than nirmatrelvir-ritonavir for some outcomes.

A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy.

BACKGROUND: Butylphthalide (NBP), approved by the China National Medical Products Administration (NMPA) for the treatment of ischemic stroke (IS), showed pleiotropic potentials against central nervous system (CNS) diseases, including neuroprotection and cognitive deficits improvement. However, the effects and corresponding modes of action were not fully explored. This study was designed to investigate the potential of NBP against IS-associated CNS diseases based on network pharmacology (NP) and molecular docking (MD). METHODS: IS was inputted as the index disease to retrieve the "associated diseases" in DisGeNET. Three-database-based IS genes were obtained and integrated (DisGeNET, Malacards, and OMIM). Then, IS-associated genes were identified by combining these genes. Meanwhile, PubMed references and online databases were applied to identify NBP target genes. The IS-related disease-disease association (DDA) network and NBP-disease regulation network were constructed and analyzed in Cytoscape. In silico MD and references were used to validate the binding affinity of NBP with critical targets and the potential of NBP against certain IS-related CNS disease regulation. RESULTS: 175 NBP target genes were obtained, while 312 IS-related disease genes were identified. 36 NBP target genes were predicted to be associated with IS-related CNS diseases, including Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), amyotrophic lateral sclerosis (ALS), and dementia. Six target genes (i.e., GRIN1, PTGIS, PTGES, ADRA1A, CDK5, and SULT1E1) indicating disease specificity index (DSI) >0.5 showed certain to good degree binding affinity with NBP, ranging from -9.2 to -6.7 kcal/mol. And the binding modes may be mainly related to hydrogen bonds and hydrophobic "bonds." Further literature validations inferred that these critical NBP targets had a tight association with AD, epilepsy, ALS, and depression. CONCLUSIONS: Our study proposed a drug-target-disease integrated method to predict the drug repurposing potentials to associated diseases by application of NP and MD, which could be an attractive alternative to facilitate the development of CNS disease therapies. NBP may be promising and showed potentials to be repurposed for treatments for AD, epilepsy, ALS, and depression, and further investigations are warranted to be carefully designed and conducted.