39 research outputs found
Valproate Protein Binding Is Highly Variable in ICU Patients and Not Predicted by Total Serum Concentrations: A Case Series and Literature Review
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/1/phar1912-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/2/phar1912_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/3/phar1912.pd
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Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy
Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy
Retinal Expression of Wnt-Pathway Mediated Genes in Low-Density Lipoprotein Receptor-Related Protein 5 (Lrp5) Knockout Mice
Mutations in low-density lipoprotein receptor-related protein 5 (Lrp5) impair retinal angiogenesis in patients with familial exudative vitreoretinopathy (FEVR), a rare type of blinding vascular eye disease. The defective retinal vasculature phenotype in human FEVR patients is recapitulated in Lrp5 knockout mouse with delayed and incomplete development of retinal vessels. In this study we examined gene expression changes in the developing mouse retina to gain insight into the molecular mechanisms that underlie the pathology of FEVR in humans. Gene expression levels were assessed with an Illumina microarray on total RNA from and WT retinas isolated on postnatal day (P) 8. Regulated genes were confirmed using RT-qPCR analysis. Consistent with a role in vascular development, we identified expression changes in genes involved in cell-cell adhesion, blood vessel morphogenesis and membrane transport in retina compared to WT retina. In particular, tight junction protein claudin5 and amino acid transporter slc38a5 are both highly down-regulated in retina. Similarly, several Wnt ligands including Wnt7b show decreased expression levels. Plasmalemma vesicle associated protein (plvap), an endothelial permeability marker, in contrast, is up-regulated consistent with increased permeability in retinas. Together these data suggest that Lrp5 regulates multiple groups of genes that influence retinal angiogenesis and may contribute to the pathogenesis of FEVR
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Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy
Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy
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Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1
Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine1. Current dogma suggests that high-energy–consuming photoreceptors depend on glucose2, 3. Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors4 and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid5, 6. In the retinas of Vldlr−/− mice with low fatty acid uptake6 but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr−/− photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr−/− retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD)7, which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases
Valproate protein binding is highly variable in ICU patients and not predicted by total serum concentrations: a case series and literature review.
STUDY OBJECTIVE: The free fraction of valproate (the pharmacologically active moiety, normally 5-10%) may vary significantly in critically ill patients, but this topic is understudied, with only four prior intensive care unit (ICU) case reports. The objective of this study was to evaluate the range of valproate plasma protein binding in ICU patients.
DESIGN: Observational study of consecutive ICU patients.
SETTING: Neurocritical and medical critical care services in a nonuniversity academic medical center.
PATIENTS: Consecutive ICU patients treated with valproate with serum albumin less than 4 g/dl.
MEASUREMENTS AND MAIN RESULTS: Simultaneous total and free trough serum valproate concentrations were measured as were serum creatinine, blood urea nitrogen, albumin, platelets, and transaminase values. The reference concentration range was 50-125 mg/L (total) and 5-17 mg/L (free). Valproate concentrations were categorized as within reference range, low, or high, and as concordant if both concentrations were in the same category. Data are reported as median (interquartile range). Fifteen patients (nine men) were evaluated. The median age was 63 (34-70) years. The valproate dose was 3 g/day (35 mg/kg/day). No patient had a valproate free fraction of 5-10%; the median was 48%, and the range was 15-89%. Total and free concentrations showed poor correlation (0.43) and were concordant in only two patients (both in the reference range). Free valproate concentration was poorly predicted by an equation correcting for albumin (r = 0.45). Suspected adverse drug events occurred in 10 patients: hyperammonemia in 7 of 12 tested (58%), elevated transaminases in 2 of 15 (13%), and thrombocytopenia in 5 of 15 (33%).
CONCLUSIONS: Protein binding of valproate was highly inconsistent in this cohort of ICU patients, and total valproate concentrations did not predict free concentrations, even when correcting for albumin. Additional research to define best practice for dosing and monitoring valproate and the relationship between free valproate concentrations and clinical or adverse effects in ICU patients is needed
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Emergency Department-based Intensive Care Unit Use Peaks Near Emergency Department Shift Turnover
Introduction: The Emergency Critical Care Center (EC3) is an emergency department-based intensive care unit (ED-ICU) designed to improve timely access to critical care for ED patients. ED patients requiring intensive care are initially evaluated and managed in the main ED prior to transfer to a separate group of ED-ICU clinicians. The timing of patient transfers to the ED-ICU may decrease the number of handoffs between main ED teams and have an impact on both patient outcomes and optimal provider staffing models, but has not previously been studied. We aimed to analyze patterns of transfer to the ED-ICU and the relationship with shift turnover times in the main ED. We hypothesized that the number of transfers to the ED-ICU increases near main ED shift turnover times.Methods: An electronic health record search identified all patients managed in the ED and ED-ICU in 2016 and 2017. We analyzed the number of ED arrivals per hour, the number of ED-ICU consults per hour, the time interval from ED arrival to ED-ICU consult, the distribution throughout the day, and the relationship with shift turnover times in the main ED.Results: A total of 160,198 ED visits were queried, of which 5308 (3.3%) were managed in the ED-ICU. ED shift turnover times were 7 am, 3 pm, and 11 pm. The mean number of ED-ICU consults placed per hour was 221 (85 standard deviation), with relative maximums occurring near ED turnover times: 10:31 pm -11:30 pm (372) and 2:31 pm -3:30 pm (365). The minimum was placed between 7:31 am – 8:30 am (88), shortly after the morning ED turnover time. The median interval from ED arrival time to ED-ICU consult order was 161 minutes (range 6-1,434; interquartile range 144-174). Relative minimums were observed for patients arriving shortly prior to ED turnover times: 4:31 am - 5:30 am (120 minutes [min]), 12:31 pm - 1:30 pm (145 min), and 9:31 pm - 10:30 pm (135 min). Relative maximums were observed for patients arriving shortly after ED turnover times: 7:31 am - 8:30 am (177 min), 4:31 pm - 5:30 pm (218 min), and 11:31 pm - 12:30 am (179 min).Conclusion: ED-ICU utilization was highest near ED shift turnover times, and utilization was dissimilar to overall ED arrival patterns. Patients arriving immediately prior to ED shift turnover received earlier consults to the ED-ICU, suggesting these patients may have been preferentially transferred to the ED-ICU rather than signed out to the next team of emergency clinicians. These findings may guide operational planning, staffing models, and timing of shift turnover for other institutions implementing ED-ICUs. Future studies could investigate whether an ED-ICU model improves critically ill patients’ outcomes by minimizing ED provider handoffs
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Propranolol Inhibition of β-Adrenergic Receptor Does Not Suppress Pathologic Neovascularization in Oxygen-Induced Retinopathy
Purpose.: Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects.
Methods.: Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups.
Results.: None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor.
Conclusions.: Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP