Objective:To evaluate the efficacy and outcomes of early removal of lumen-apposing metal stent (LAMS) in the treatment of pancreatic wall-off necrosis (WON).Methods:A retrospective analysis was performed on 51 patients with WON who underwent endoscopic ultrasound (EUS)-guided transluminal drainage (ETD) and direct endoscopic necrosectomy (DEN) using LAMS at Nanjing Drum Tower Hospital from January 2018 to December 2022. Patients were divided into the early removal group (within two weeks, n=24) and the traditional removal group (after two weeks, n=27) based on the timing of LAMS removal. The short-term effects, safety and long-term outcomes of WON were compared between the two groups. Results:The technical success rate of LAMS placement in 51 patients reached 100%, and all patients underwent ETD and DEN. The median number of necrosectomy sessions in the early removal group was significantly lower than in the traditional removal group, 2.0 sessions vs 3.0 sessions and the difference was statistically significant ( P<0.05). Postoperatively, 15.7% of patients required percutaneous catheter drainage (PCD) and 5.9% required surgery, with no significant difference between the two groups. The clinical success rate and mortality rate in the early removal group were 79.2% and 8.3%, respectively, compared to 81.5% and 3.7% in the traditional removal group, with no statistically significant difference. In terms of safety, the early removal group exhibited a significantly lower rate of adverse events during stent retention with statistically significant difference (12.5% vs 37.0%, P<0.05) compared to the traditional removal group. A total of 46 patients were followed up for six months. In the early removal group, the rates of disease recurrence, need for endoscopic reintervention and occurrence of long-term complications were 20.0%, 10.0% and 20.0%, respectively. These rates did not show a significant increase compared to the traditional removal group, which were 7.7%, 3.8% and 38.5%, respectively, without significant differences between the groups. Conclusions:In the treatment of WON, early removal of LAMS is safe and effective to a certain extent. In comparison to the traditional practice of removing LAMS after two weeks, early removal does not reduce clinical success rates, nor does it increase the rates of disease-related mortality, recurrence, or long-term complications. On the contrary, it may reduce the occurrence of adverse events during stent retention and decrease the number of necrosectomy procedures subsequently.

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.