Real-world effectiveness and safety of oral Azvudine versus Paxlovid for COVID-19 in patients with kidney disease: a multicenter, retrospective, cohort study

BMC Infectious Diseases, Journal Year: 2025, Volume and Issue: 25(1)

Published: Feb. 25, 2025

Patients with kidney disease (KD) are at high risk of contracting COVID-19 and developing severe disease. There is still a lack guidance regarding the treatment in patients KD. The safety effectiveness Azvudine treating KD remain unknown. This study included 32,864 from nine centers Henan Province, China. After applying exclusion criteria 2:1 propensity score matching, 438 219 participants Paxlovid groups, respectively, were subjected to analysis. Kaplan–Meier analysis revealed no significant differences all-cause death or composite progression between groups (all p values > 0.05). same results obtained Cox regression after baseline characteristics adjustment. Three different sensitivity analyses contributed robustness these findings. Subgroup that treated had lower than did among moderate (p = 0.016, HR: 0.51, 95% CI: 0.27–0.96). Safety data indicated there was difference incidence most adverse events. Compared group, group hypophosphatemia 0.008) PLT count 0.045). Moreover, during 15-day follow-up since drug administration, higher concentrations lymphocytes detected group. first report not inferior those provides additional options for

Language: Английский

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Decoding the selective chemical modulation of CYP3A4

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 10, 2025

Drug-drug interactions associate with concurrent uses of multiple medications. Cytochrome P450 (CYP) 3A4 metabolizes a large portion marketed drugs. To maintain the efficacy drugs metabolized by CYP3A4, pan-CYP3A inhibitors such as ritonavir are often co-administered. Although selective CYP3A4 have greater therapeutic benefits they avoid inhibiting unintended CYPs and undesirable clinical consequences, high homology between CYP3A5 has hampered development inhibitors. Here, we report series scaffolds identified high-throughput screening. Structural, functional, computational analyses reveal that differential C-terminal loop conformations two distinct ligand binding surfaces disfavor to CYP3A5. Structure-guided design compounds validates model yields analogs for versus other major CYPs. These findings demonstrate feasibility selectively inhibit provide guidance designing better

Language: Английский

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Role of HNF4A-AS1/HNRNPC-mediated HNF4A Ubiquitination Protection against Ritonavir-induced Hepatotoxicity

Molecular Pharmacology, Journal Year: 2025, Volume and Issue: 107(3), P. 100021 - 100021

Published: Feb. 7, 2025

Ritonavir (RTV) is an important drug for anti-human immunodeficiency virus treatment and mainly metabolized by cytochrome P450 (CYP) 3A4. Clinically, the most common side effect of RTV hepatoxicity. We previously showed that long noncoding RNA hepatocyte nuclear factor 4 alpha (HNF4A) antisense 1 (HNF4A-AS1) negatively regulated CYP3A4 expression participated in RTV-induced hepatotoxicity vitro, but mechanism has not been well understood. In this study, similar results were observed mouse, where liver-specific knockdown Hnf4aos (homolog human HNF4A-AS1) led to increased serum aspartate (∼1.8-fold) alanine transaminase (∼2.4-fold) levels enlarged degenerated hepatocytes 24 hours after administration. Meanwhile, endoplasmic reticulum stress markers GRP78, PDI, XBP-1 about 2.4-fold, 2.1-fold, 2.7-fold, respectively. The aggravated liver injury correlated with knockdown, attributable heightened Cyp3a11 CYP3A4) (mRNA protein 1.8-fold 2.5-fold, respectively). Importantly, vitro studies revealed underlying HNF4A-AS1 mediated interaction between heterogeneous ribonucleoprotein C HNF4A, whereas promoted HNF4A degradation through ubiquitination pathway, thereby decreasing alleviating injury. Overall, our findings unveil a novel which regulates influence SIGNIFICANCE STATEMENT: CYP3A4, whose overexpression highly ritonavir (RTV)-induced role was confirmed mice. found HNRNPC form complex facilitate protein, hepatotoxicity.

Language: Английский

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Activation of pregnane X receptor sensitizes alcoholic steatohepatitis by transactivating fatty acid binding protein 4

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(11), P. 4776 - 4788

Published: Sept. 2, 2024

Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the tissue as result excessive alcohol consumption. Pregnane X receptor (PXR) xenobiotic nuclear best known for its function in transcriptional regulation drug metabolism disposition. Clinical reports suggested that antibiotic rifampicin, potent human PXR activator, contraindication alcoholics, but mechanism was unclear. In this study, we showed hepatic expression fatty acid binding protein 4 (FABP4) uniquely elevated ASH patients mouse model ASH. Pharmacological inhibiting FABP4 attenuated mice. Furthermore, treatment mice with agonist pregnenolon-16

Language: Английский

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