Effect of remimazolam tosilate on the incidence of hypoxemia in elderly patients undergoing gastrointestinal endoscopy: A bi-center, prospective, randomized controlled study.

Background: Remimazolam tosilate is a new ultra-short-acting benzodiazepine sedative medicine. In this study, we evaluated the effect of remimazolam tosilate on the incidence of hypoxemia during sedation in elderly patients undergoing gastrointestinal endoscopy. Methods: Patients in the remimazolam group received an initial dose of 0.1 mg/kg and a bolus dose of 2.5 mg of remimazolam tosilate, whereas patients in the propofol group received an initial dose of 1.5 mg/kg and a bolus dose of 0.5 mg/kg of propofol. Patients received ASA standard monitoring (heart-rate, non-invasive blood pressure, and pulse oxygen saturation) during the entire examination process. The primary outcome was the incidence of moderate hypoxemia (defined as 85%≤ SpO2< 90%, >15s) during the gastrointestinal endoscopy. The secondary outcomes included the incidence of mild hypoxemia (defined as SpO2 90%-94%) and severe hypoxemia (defined as SpO2< 85%, >15s), the lowest pulse oxygen saturation, airway maneuvers used to correct hypoxemia, patient's hemodynamic as well as other adverse events. Results: 107 elderly patients (67.6 ± 5.7 years old) in the remimazolam group and 109 elderly patients (67.5 ± 4.9 years old) in the propofol group were analyzed. The incidence of moderate hypoxemia was 2.8% in the remimazolam group and 17.4% in the propofol group (relative risk [RR] = 0.161; 95% confidence interval [CI], 0.049 to 0.528; p < 0.001). The frequency of mild hypoxemia was less in the remimazolam group, but not statistically significant (9.3% vs. 14.7%; RR = 0.637; 95% CI, 0.303 to 1.339; p = 0.228). There was no significant difference in the incidence of severe hypoxemia between the two groups (4.7% vs. 5.5%; RR = 0.849; 95% CI, 0.267 to 2.698; p = 0.781). The median lowest SpO2 during the examination was 98% (IQR, 96.0%-99.0%) in patients in the remimazolam group, which was significantly higher than in patients in the propofol group (96%, IQR, 92.0%-99.0%, p < 0.001). Patients in the remimazolam group received more drug supplementation during endoscopy than patients in the propofol group (p = 0.014). There was a statistically significant difference in the incidence of hypotension between the two groups (2.8% vs. 12.8%; RR = 0.218; 95% CI, 0.065 to 0.738; p = 0.006). No significant differences were found in the incidence of adverse events such as nausea and vomiting, dizziness, and prolonged sedation. Conclusion: This study explored the safety of remimazolam compared with propofol during gastrointestinal endoscopy in elderly patients. Despite the increased supplemental doses during sedation, remimazolam improved risk of moderate hypoxemia (i.e., 85%≤ SpO2 < 90%) and hypotension in elderly patients.

Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that targets oxysterol-binding protein (OSBP).

Itraconazole (ITZ) is a well-known, FDA-approved antifungal drug that is also in clinical trials for its anticancer activity. ITZ exerts its anticancer activity through several disparate targets and pathways. ITZ inhibits angiogenesis by hampering the functioning of the vascular endothelial growth receptor 2 (VEGFR2) and by indirectly inhibiting mTOR signaling. Furthermore, ITZ directly inhibits the growth of several types of tumor cells by antagonizing Hedgehog signaling. Recently, we reported that ITZ also has broad-spectrum antiviral activity against enteroviruses, cardioviruses and hepatitis C virus, independent of established ITZ-activities but instead via a novel target, oxysterol-binding protein (OSBP), a cellular lipid shuttling protein. In this study, we analyzed which structural features of ITZ are important for the OSBP-mediated antiviral activity. The backbone structure, consisting of five rings, and the sec-butyl chain are important for antiviral activity, whereas the triazole moiety, which is critical for antifungal activity, is not. The features required for OSBP-mediated antiviral activity of ITZ overlap mostly with published features required for inhibition of VEGFR2 trafficking, but not Hh signaling. Furthermore, we use in silico studies to explore how ITZ could bind to OSBP. Our data show that several pharmacological activities of ITZ can be uncoupled, which is a critical step in the development of ITZ-based antiviral compounds with greater specificity and reduced off-target effects.

Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis.

The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis.