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In Vivo Turnover of Tau and APP Metabolites in the Brains of Wild-Type and Tg2576 Mice: Greater Stability of sAPP in the β-Amyloid Depositing Mice  [PDF]
Jose Morales-Corraliza, Matthew J. Mazzella, Jason D. Berger, Nicole S. Diaz, Jennifer H. K. Choi, Efrat Levy, Yasuji Matsuoka, Emmanuel Planel, Paul M. Mathews
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007134
Abstract: The metabolism of the amyloid precursor protein (APP) and tau are central to the pathobiology of Alzheimer's disease (AD). We have examined the in vivo turnover of APP, secreted APP (sAPP), Aβ and tau in the wild-type and Tg2576 mouse brain using cycloheximide to block protein synthesis. In spite of overexpression of APP in the Tg2576 mouse, APP is rapidly degraded, similar to the rapid turnover of the endogenous protein in the wild-type mouse. sAPP is cleared from the brain more slowly, particularly in the Tg2576 model where the half-life of both the endogenous murine and transgene-derived human sAPP is nearly doubled compared to wild-type mice. The important Aβ degrading enzymes neprilysin and IDE were found to be highly stable in the brain, and soluble Aβ40 and Aβ42 levels in both wild-type and Tg2576 mice rapidly declined following the depletion of APP. The cytoskeletal-associated protein tau was found to be highly stable in both wild-type and Tg2576 mice. Our findings unexpectedly show that of these various AD-relevant protein metabolites, sAPP turnover in the brain is the most different when comparing a wild-type mouse and a β-amyloid depositing, APP overexpressing transgenic model. Given the neurotrophic roles attributed to sAPP, the enhanced stability of sAPP in the β-amyloid depositing Tg2576 mice may represent a neuroprotective response.
Randomized, Blinded Trial Comparing Enoxaparin with Unfractionated Heparin in Patients Undergoing Contemporary Percutaneous Coronary Intervention
Hosein Vakili,Ali Mir,Mohammad Hasan Namazi,Habibollahe Saadat
Journal of Tehran University Heart Center , 2007,
Abstract: Background: This study was designed to examine a unique and low dose use of intravenous enoxaparin in elective percutaneous coronary intervention (PCI) that would be applicable to an unselected population regardless of age, weight, and renal function. There is limited experience in anticoagulation using intravenous low-molecular-weight heparin in PCI. Methods: A total of 100 consecutive patients undergoing elective PCI were treated with a single IV bolus of enoxaparin (0.5mg/kg) in group A of patients (n=50) or with unfractionated heparin in group B of patients (n=50). Sheaths were removed immediately after the procedure in patients treated with enoxaparin and some hours later in those treated with unfractionated heparin. Results: In group A, ACT was 124.6±9.3 before PCI and 149.2±17.1 after that (P<0.05). In group B, one patient (2.9%) developed groin hematoma. No deaths, MI, or urgent target vessel revascularization were reported. Conclusion: Low- dose (0.5 mg/kg) IV enoxaparin allows a target level of anticoagulation in patients undergoing PCI, appears to be safe and effective, allows immediate sheath removal, and does not require dose adjustment.
The economic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients  [cached]
Pineo GF,Lin J,Annemans L
ClinicoEconomics and Outcomes Research , 2012,
Abstract: Graham F Pineo1, Jay Lin2, Lieven Annemans31Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 2Novosys Health, Flemington, NJ; 3Department of Medicine, Ghent University, Ghent and Brussels University, Brussels, BelgiumAbstract: Venous thromboembolism (VTE) is a common complication after acute ischemic stroke that can be prevented by the use of anticoagulants. Current guidelines from the American College of Chest Physicians recommend that patients with acute ischemic stroke and restricted mobility receive prophylactic low-dose unfractionated heparin or a low-molecular-weight heparin. Results from clinical studies, most recently from PREVAIL (PREvention of Venous Thromboembolism After Acute Ischemic Stroke with LMWH and unfractionated heparin), suggest that the low-molecular-weight heparin, enoxaparin, is preferable to unfractionated heparin for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility. This is due to a better clinical benefit-to-risk ratio, with the added convenience of once-daily administration. In line with findings from modeling studies and real-world data in acutely ill medical patients, recent economic data indicate that the higher drug cost of enoxaparin is offset by the reduction in clinical events as compared with the use of unfractionated heparin for the prevention of VTE after acute ischemic stroke, particularly in patients with severe stroke. With national performance measures highlighting the need for hospitals to examine their VTE practices, the relative costs of different regimens are of particular importance to health care decision-makers. The data reviewed here suggest that preferential use of enoxaparin over unfractionated heparin for the prevention of VTE after acute ischemic stroke may lead to reduced VTE rates and concomitant cost savings in clinical practice.Keywords: acute ischemic stroke, cost savings, enoxaparin, unfractionated heparin, venous thromboembolism
The economic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients
Pineo GF, Lin J, Annemans L
ClinicoEconomics and Outcomes Research , 2012, DOI: http://dx.doi.org/10.2147/CEOR.S30857
Abstract: onomic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients Review (1937) Total Article Views Authors: Pineo GF, Lin J, Annemans L Published Date April 2012 Volume 2012:4 Pages 99 - 107 DOI: http://dx.doi.org/10.2147/CEOR.S30857 Received: 14 February 2012 Accepted: 15 March 2012 Published: 23 April 2012 Graham F Pineo1, Jay Lin2, Lieven Annemans3 1Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 2Novosys Health, Flemington, NJ; 3Department of Medicine, Ghent University, Ghent and Brussels University, Brussels, Belgium Abstract: Venous thromboembolism (VTE) is a common complication after acute ischemic stroke that can be prevented by the use of anticoagulants. Current guidelines from the American College of Chest Physicians recommend that patients with acute ischemic stroke and restricted mobility receive prophylactic low-dose unfractionated heparin or a low-molecular-weight heparin. Results from clinical studies, most recently from PREVAIL (PREvention of Venous Thromboembolism After Acute Ischemic Stroke with LMWH and unfractionated heparin), suggest that the low-molecular-weight heparin, enoxaparin, is preferable to unfractionated heparin for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility. This is due to a better clinical benefit-to-risk ratio, with the added convenience of once-daily administration. In line with findings from modeling studies and real-world data in acutely ill medical patients, recent economic data indicate that the higher drug cost of enoxaparin is offset by the reduction in clinical events as compared with the use of unfractionated heparin for the prevention of VTE after acute ischemic stroke, particularly in patients with severe stroke. With national performance measures highlighting the need for hospitals to examine their VTE practices, the relative costs of different regimens are of particular importance to health care decision-makers. The data reviewed here suggest that preferential use of enoxaparin over unfractionated heparin for the prevention of VTE after acute ischemic stroke may lead to reduced VTE rates and concomitant cost savings in clinical practice.
Outcomes of thromboprophylaxis with enoxaparin vs. unfractionated heparin in medical inpatients
Lisa J McGarry, Michael E Stokes, David Thompson
Thrombosis Journal , 2006, DOI: 10.1186/1477-9560-4-17
Abstract: To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice.Using a large, multi-hospital, US database, we identified persons aged ≥40 years hospitalized for ≥6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs. RESULTS: 479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups.We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.Acutely-ill medical inpatients – such as those hospitalized for congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), acute infections, or cancer – often have prolonged hospital stays with periods of immobility that place them at increased risk of venous thromboembolism (VTE) [1]. Because these patients frequently have additional risk factors (e.g., history of VTE, advanced age, obesity, varicose veins, estrogen use), the potential benefits of thromboprophylaxis in this pop
Cost-utility of enoxaparin compared with unfractionated heparin in unstable coronary artery disease
Tricia Nicholson, Alistair McGuire, Ruairidh Milne
BMC Cardiovascular Disorders , 2001, DOI: 10.1186/1471-2261-1-2
Abstract: We found no relevant published full economic evaluations, only cost studies, one of which was conducted in the UK. The other studies, from the US, Canada and France, are difficult to interpret since their resource use and costs may not reflect UK practice.We aimed to compare the benefits and costs of short-term treatment (two to eight days) with enoxaparin and unfractionated heparin in unstable coronary artery disease. We used published data sources to estimate the incremental cost per quality adjusted life year (QALY), adopting a NHS perspective and using 1998 prices.The base case was a 0.013 QALY gain and net cost saving of £317 per person treated with enoxaparin instead of unfractionated heparin. All but one sensitivity analysis showed net savings and QALY gains, the exception (the worst case) being a cost per QALY of £3,305. Best cases were a £495 saving and 0.013 QALY gain, or a £317 saving and 0.014 QALY gain per person.Enoxaparin appears cost saving compared with unfractionated heparin in patients with unstable coronary artery disease. However, cost implications depend on local revascularisation practice.Advantages of low molecular weight heparins over unfractionated heparin include convenience of administration, higher bioavailability and the lack of need for monitoring. Some varieties are now used in the treatment of unstable angina and non-Q wave myocardial infarction (henceforth referred to as unstable coronary artery disease). These conditions are common in hospital and may be increasing. Incidence of unstable angina ranges from 99 to 246 per 100,000[1,2] and approximately 20–38% of myocardial infarctions are non-Q-wave [3].A recent meta-analysis [4] compared low molecular weight heparins (enoxaparin, dalteparin and nadroparin) with unfractionated heparin in unstable coronary artery disease. The short-term treatment comparison combined the results from 5 randomised controlled trials (12,169 patients). The overall result suggested that the low molecular v
Unfractionated heparin and enoxaparin reduce high-stretch ventilation augmented lung injury: a prospective, controlled animal experiment
Li-Fu Li, Chung-Chi Huang, Horng-Chyuan Lin, Ying-Huang Tsai, Deborah A Quinn, Shuen-Kuei Liao
Critical Care , 2009, DOI: 10.1186/cc7949
Abstract: Male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume (30 ml/kg) or low-tidal-volume (6 ml/kg) mechanical ventilation with room air for 1 to 5 hours after 200 IU/kg or 400 IU/kg unfractionated heparin and 4 mg/kg or 8 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet- to dry-weight ratio, histopathologic grading of epithelium, myeloperoxidase, and gene expression of PAI-1 were measured. The expression of PAI-1 was studied by immunohistochemistry.High-tidal-volume ventilation induced increased microvascular permeability, neutrophil influx, PAI-1 mRNA expression, production of PAI-1 protein, and positive staining of PAI-1 in epithelium in a dose-dependent manner. Lung injury induced by high-tidal-volume ventilation was attenuated with PAI-1-deficient mice and pharmacologic inhibition of PAI-1 activity by low-dose unfractionated heparin and enoxaparin.We conclude that high-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx, lung PAI-1 mRNA expression, production of active PAI-1. The deleterious effects were attenuated by low-dose unfractionated heparin or enoxaparin treatment. Understanding the protective mechanism of unfractionated heparin and enoxaparin related to the reduction of PAI-1 may afford further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.Acute respiratory distress syndrome (ARDS) is an inhomogeneous lung disease characterized by neutrophil influx into the lungs, increased expression of inflammatory cytokines or chemokines, loss of epithelial and endothelial integrity, and the development of alveolar and interstitial pulmonary edema [1]. The use of high tidal volume in normal animals mimics this overdistention of the normal lung. Mechanical ventilation with high tidal volumes (VT) causes acute lung injury (VILI, ventilator-induced lung injury) c
Safety of enoxaparin versus unfractioned heparin in patients undergoing percutaneous coronary intervention using drug eluting stents: A pilot study
MJ Zibaeenezhad,H kamfiroozi,K Aghasadeghi
Iranian Cardiovascular Research Journal , 2008,
Abstract: Background: Unfractioned heparin (UFH) is the standard antithrombotic agent in elective percutaneous coronary intervention (PCI), but has its own limitations. Several studies have suggested intravenous enoxaparin as a safe and effective alternative but most of them are uncontrolled. Our main goal was to evaluate the safety of enoxaparin over UFH in PCI patients undergoing coronary stenting by drug eluting stents (DES).Methods: We randomly assigned 195 patients undergoing PCI using DES to receive either 0.75 mg enoxaparin per kilogram of body weight or 10000 IU unfractioned heparin. The primary end point was the incidence of major or minor bleeding . The secondary end point was the incidence of acute coronary events (ST-elevation myocardial infarction, non ST-elevation myocardial infarction,and unstable angina) in the first 24 hours after PCI.Results: The rate of major and minor bleedings was similar in the first 24 hours after procedure between enoxaparin group and UFH group ( P value>0.05). The incidence of acute coronary events and mortality was also similar between two arms.Conclusion: In DES based PCI , a single intravenous bolus of 0.75 mg of enoxaparin per kilogram is associated with similar rate of bleeding as compaired with UFH. Also the rates of ischemic events are not different for enoxaparin and UFH however larger trials are needed for definit conclusion.
Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons  [PDF]
Cristina Ploia,Alessandra Sclip,Alessio Colombo,Mariaelena Repici,Fabrizio Gardoni,Monica Di Luca,Gianluigi Forloni,Xanthi Antoniou,Tiziana Borsello
Pharmaceuticals , 2010, DOI: 10.3390/ph3010042
Abstract: The phosphorylation of Amyloid Precursor Protein (APP) at Thr 668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5) can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM) for 30’-45’ led to an increase of P-APP Thr 668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway.
Changes in expression of GFAP, ApoE and APP mRNA and protein levels in the adult rat brain following cortical injury
Lon?arevi?-Vasiljkovi? Nata?a,Pe?i? Vesna,Tani? N.,Milanovi? Desanka
Archives of Biological Sciences , 2013, DOI: 10.2298/abs1301255l
Abstract: The recovery period following cortical injury (CI) is characterized by a dynamic and highly complex interplay between beneficial and detrimental events. The aim of this study was to examine the expressions of Glial Fibrillary Acidic Protein (GFAP), Apolipoprotein E (ApoE) and Amyloid Precursor Protein (APP), all of which are involved in brain plasticity and neurodegeneration. Our results reveal that CI strongly influenced GFAP, ApoE and APP mRNA expression, as well as GFAP and ApoE protein expression. Considering the pivotal role of these proteins in the brain, the obtained results point to their potential contribution in neurodegeneration and consequent Alzheimer’s disease development. [Projekat Ministarstva nauke Republike Srbije, br. 173056]
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