Vascular endothelial growth factor (VEGF) increases endothelial barrier permeability, an effect that may contribute to macular edema in diabetic retinopathy. Since vitamin C, or ascorbic acid, can tighten the endothelial permeability barrier, we examined whether it could prevent the increase in permeability due to VEGF in human umbilical vein endothelial cells (HUVECs). As previously observed, VEGF increased HUVEC permeability to radiolabeled inulin within 60 min in a concentration-dependent manner. Loading the cells with increasing concentrations of ascorbate progressively prevented the leakage caused by 100 ng/ml VEGF, with a significant inhibition at 13 μM and complete inhibition at 50 μM. Loading cells with 100 μM ascorbate also decreased basal generation of reactive oxygen species and prevented the increase caused by both 100 ng/ml VEGF. VEGF treatment decreased intracellular ascorbate by 25%, thus linking ascorbate oxidation to its prevention of VEGF-induced barrier leakage. The latter was blocked by treating the cells with 60 μM L-NAME (but not D-NAME) as well as by 30 μM sepiapterin, a precursor of tetrahydrobiopterin that is required for proper function of endothelial nitric oxide synthase (eNOS). These findings suggest that VEGF-induced barrier leakage uncouples eNOS. Ascorbate inhibition of the VEGF effect could thus be due either to scavenging superoxide or to peroxynitrite generated by the uncoupled eNOS, or more likely to its ability to recycle tetrahydrobiopterin, thus avoiding enzyme uncoupling in the first place. Ascorbate prevention of VEGF-induced increases in endothelial permeability opens the possibility that its repletion could benefit diabetic macular edema.
Introduction Nonmedical opioid use (NMOU) in patients with cancer is a term covering a spectrum of nonprescribed opioid use. The extent to which an individual uses opioids in a nonprescribed manner will influence propensity for adverse effects such as neurotoxicity, substance use disorder, overdose, and death. Objectives The objectives of this study were to (A) evaluate current literature regarding management of NMOU in patients with cancer‐related pain; (B) provide best practice recommendations based on evidence; and (C) integrate practices derived from the management of noncancer pain, where clinically appropriate or when the oncology literature is limited. Methods This study is a narrative review. Implications Although harm from NMOU was thought to be rare among oncology patients, about one in five patients with cancer is at risk of adverse outcomes including prolonged opioid use, high opioid doses, and increased health care utilization. The management of NMOU can be challenging because pain is a multidimensional experience encompassing physical, psychological, and spiritual domains. An interdisciplinary team approach is most effective, and management strategies may include (A) education of patients and families; (B) harm reduction, including opioid switching, decreasing the overall daily dose, avoiding concurrent sedative use, and using adjuvant medications for their opioid‐sparing potential; (C) managing psychological and spiritual distress with an interdisciplinary team and techniques such as brief motivational interviewing; and (D) risk mitigation by pill counts, frequent clinic visits, and accessing statewide prescription drug monitoring plans. Conclusion Although many of the management strategies for NMOU in patients with cancer‐related pain are modeled on those for chronic non–cancer‐related pain, there is emerging evidence that education and harm‐reduction initiatives specifically for cancer‐related pain are effective. Implications for Practice Nonmedical opioid use (NMOU) in patients with cancer is a term covering a broad spectrum of nonprescribed opioid use. The extent to which an individual uses opioids in a nonprescribed manner will influence propensity for adverse effects such as neurotoxicity, substance use disorder, overdose, and death. This review evaluates the evidence for best practices in oncology and addresses limitations in the literature with supplemental evidence from noncancer chronic pain. Management recommendations for NMOU are provided, based on a combination of literature‐based evidence and best clinical practice. Effective management of NMOU in oncology has the potential to improve quality of life, decrease health utilization, and improve survival.
Ivermectin has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replication in vitro. It is unknown whether this inhibition of SARS‐CoV‐2 replication correlates with improved clinical outcomes. To assess the effectiveness and safety of ivermectin in hospitalized patients with COVID‐19. A total of 286 patients with COVID‐19 were included in the study. Univariate analysis of the primary mortality outcome and comparisons between treatment groups were determined. Logistic regression and propensity score matching (PSM) was used to adjust for confounders. Patients in the ivermectin group received 2 doses of Ivermectin at 200 μg/kg in addition to usual clinical care on hospital Days 1 and 3. The ivermectin group had a significantly higher length of hospital stay than the control group; however, this significance did not maintain on multivariable logistic regression analysis. The length of intensive care unit (ICU) stay and duration of mechanical ventilation were longer in the control group. However, a mortality benefit was not seen with ivermectin treatment before and after PSM (p values = 0.07 and 0.11, respectively). ICU admission, and intubation rate were not significantly different between the groups (p = 0.49, and p = 1.0, respectively). No differences were found between groups regarding the length of hospital stay, ICU admission, intubation rate, and in‐hospital mortality.
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