tbuckley/cabot-search huggingface dataset:
Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease
Authors: David Valdés-Arias, Elyana V. T. Locatelli, Paula A. Sepulveda-Beltran, Simran Mangwani-Mordani, Juan Carlos Navia, Anat Galor
Journal: Drugs (2024)

Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual's well-being. This cumulative impact of DED on an individual's activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.
Abstract 5784: Altered Receptor Distribution and Expression Causing Vascular Myocytes Insensitivity to <i>α</i> <sub>1</sub> Adrenergic Activation
Authors: Shuang Ren, Linlin Fan, Hong Zhou, Junqi He, Dali Luo
Journal: Circulation (2009)

Alpha 1D -adrenergic receptor ( α 1D -AR) plays a critical role in controlling peripheral vascular resistance and blood pressure. However, unlike α 1A - and α 1B -AR subtypes that primarily locate at the plasma membrane and function efficiently, α 1D -ARs are accumulated within intracellular compartments and poorly functioned in vitro. Using fluo4, BODIPY prazosin and subtype-specific antibodies to evaluate the native α 1 AR regulated Ca 2+ signaling and their subcellular distribution in rat aortic and cardiac myocytes, we tested the hypothesis that α 1D -ARs are altered during cell isolation or/and culturing procedures, causing the responding discordance between tissue and cells. In aortic rings and freshly isolated myocytes α 1 AR agonist phenylephrine (PE, 10 −5 M) induced vasoconstriction, and intracellular Ca 2+ increase and cell shortening, which could be abolished by a specific antagonist of α 1D -AR BMY7378 (10 −6 M), respectively. The cellular response to PE, however, was decreased to 55.2±4.9% in 1-day-and 0% in ≥2-day-cultured aortic myocytes (n= 40, and 238), but remained in all the cultured neonatal rat cardiomyocytes (n= 267). Similarly as the α 1A -ARs in cultured cardiomyocytes, α 1D -ARs distributed both intracellularly and at the cell membrane in freshly dispersed aortic myocytes, but mostly redistributed intracellularly in cultured aortic myocytes. Treating the culture medium with 2% charcoal/dextran (C/D) for 48 h caused restorations of the cell surface α 1D -AR distribution in 34.67±4.1% (n=84) and partial Ca 2+ signaling response to PE in 29.5±0.2% (n=81, p&lt;0.05 vs. no C/D) cultured cells, suggesting an essential requirement for membrane expressed α 1 ARs for their efficient intracellular coupling. Additionally, the α 1D -AR expression in the cultured aortic myocytes was reduced relative to the tissue. These results indicate that α 1D -ARs can primarily express at the cell membrane in native system but occur internalized into the cytoplasm and declined in expression in culture condition, resulting in the intracellular uncoupling to α 1 adrenergic activation in vitro. Charcoal/dextran in culture medium partially prevents this receptor subtype redistribution.
Abstract 5786: Prostaglandin E <sub>2</sub> and EP3 Activation Potentiate Human Platelet Responsiveness
Authors: Bianca Rocca, Giovanna Petrucci, Carlo Patrono
Journal: Circulation (2009)

Activated human platelets synthesize prostaglandin (PG) E 2 , although at much lower rates than thromboxane A 2 . PGE 2 binds different receptors (EP1–4). EP3-deleted mice displayed lower platelet response to sub-threshold concentrations of agonists and less susceptibility to experimental thrombosis than wild type mice. However, the role of PGE 2 in human platelet function remains poorly characterized. We investigated the effect of PGE 2 and EP-agonists on human platelet responsiveness to other agonists. Platelets were incubated with increasing concentrations of PGE 2 or different EP agonists, and stimulated by aggregating doses of adenosine diphosphate (ADP), collagen or arachidonic acid (AA). Aggregation was measured by the optical method. EP expression was studied by immunohistochemistry in platelets and bone marrow megakaryocytes. PGE 2 in the microM range (1–200 microM) dose-dependently inhibited 10microM ADP-induced aggregation. However nanoM PGE 2 concentrations (2–200 nanoM), dose-dependently increased the slope (velocity) of the secondary wave of 8 microM ADP-induced platelet aggregation, with an EC 50 of 25±6 nanoM (n=15), without affecting maximal aggregation. At lower (4 microM) ADP concentration, PGE 2 reverted the reversible aggregation, with an EC 50 of 29±10 nanoM (n=6). In in vitro aspirinated platelets, 200 nanoM PGE 2 in part counteracted the effect of aspirin in abolishing the secondary wave of 8 microM ADP-induced aggregation. In addition, PGE 2 dose-dependently abolished shape change caused by 10 microg/ml collagen and 50 microg/ml AA, with an IC 50 of 157±4 nanoM. The EP3 agonist, 11-deoxy-16,16-dimetyl PGE 2 , mimicked the PGE 2 effect on the secondary wave of ADP-induced aggregation, with an EC 50 58±1 nanoM (n=10), while the EP2 agonist butaprost was ineffective. The EP3 agonist at microM concentrations, dose-dependently induced spontaneous platelet aggregation with an EC 50 of 5.5±1 microM. Immunostains revealed EP3 expression in human platelets and megakaryocytes. We conclude that PGE 2 -EP3 interaction potentiates human platelet response to physiological concentrations of common agonists. EP3 might represent a novel pharmacological target for inhibiting platelet responsiveness in atherothrombotic diseases.
Abstract 5758: The Anti-Angiogenic Activity of rPAI-1 <sub>23</sub> Promotes Vasa Vasorum Regression in Atherogenic Mice Through a Plasmin-Dependent Mechanism
Authors: Mary Mulligan Kehoe
Journal: Circulation (2009)

Introduction : Angiogenic vasa vasorum is considered the conduit for nutrient supplies to atherosclerotic plaque and its inhibition is associated with reduced plaque progression. We reported that the anti-angiogenic activity of rPAI-1 23 , a truncated PAI-1 protein, stimulates a highly significant decrease in vasa vasorum vessel area and length, plaque area and plaque cholesterol in the descending aorta in atherogenic mice. High levels of FGF-2 associated with adventitial vascular structures of saline treated mice appear to stimulate tube formation and vessel guidance, which is inhibited by rPAI-1 23 . Objective : In this study we investigated the mechanism of angiogenic vasa vasorum regression in atherogenic mice treated with rPAI-1 23 . Methods and results : Plasma from female LDLR −/− /ApoB-100 mice fed Paigen’s diet without cholate for 20 weeks while receiving rPAI-1 23 treatment (n = 21) for the last six weeks was compared to control mice treated with saline (n= 16). The rPAI-1 23 treated mice have significantly elevated plasmin, MMP-3 and MMP-2 activities accompanied by increased fibrinogen breakdown. Protease activities correspond with basement membrane breakdown visualized in confocal microscopy images of nidogen-probed adventitia. Immunoprecipitation of descending aorta adventitial protein pulls down a fibrinogen• FGF-2 complex in both treatment groups, but FGF-2 and fibrinogen levels are significantly less in rPAI-1 23 treated mice. In vitro studies show that FGF-2• fibrinogen complexes increase endothelial cell permeability and tube formation by 3- and 4-fold, respectively; rPAI-1 23 inhibits both angiogenic processes. Conclusion : In conclusion, rPAI-1 23 promotes vasa vasorum regression in atherogenic female LDLR −/− /ApoB-100 mice through a plasmin-dependent mechanism that negatively regulates the fibrinogenic and angiogenic pathways. Enhanced plasmin activity, in response to rPAI-1 23 , stimulates activation of MMPs known to degrade basement membrane and fibrinogen, thus leading to vessel collapse. Fibrinogen degradation inhibits the angiogenic potential of the fibrinogen•FGF-2 complex.
Abstract 5766: Reduction of Oxidized Stress by High-Dose N-Acetylcysteine versus Placebo in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Holger Thiele, Ingo Eitel, Georg Fuernau, Volker Adams, Matthias Gutberlet, Gerhard Schuler
Journal: Circulation (2009)

Background STEMI patients undergoing primary PCI develop oxidative stress which might have an impact on reperfusion injury. High-dose N-Acetylcysteine (N-ACC) might prevent oxidative stress with subsequent reduction of reperfusion injury and also the incidence of contrast-induced nephropathy (CIN). Aim of this randomized, controlled, single-blind trial was to assess the effects of N-ACC on oxidative stress, reperfusion injury and CIN in patients undergoing primary PCI. Methods Two hundred-fifty patients undergoing primary PCI were randomized to either N-ACC (2×1200 mg/d for 48 hours) or placebo plus optimal hydration. The two primary endpoints were: occurrence of CIN defined as an increase in the serum creatinine concentration of &gt;25% from the baseline value within 72 h; Myocardial salvage measured by T2-weighted STIR-images and delayed enhancement MRI at day 2–4 after primary PCI. Secondary endpoints were oxidative stress, infarct size, microvascular obstruction, ST-resolution at 90 minutes and occurrence of MACE at 30 day follow-up. Results The median volume of contrast agent during PCI was 190 ml (IQR 130, 250 ml) in the N-ACC and 180 (IQR 143; 228 ml) in the placebo group (p= n.s.). Baseline creatinine and creatinine clearance were 88 vs 86 μ mol/l and 90 vs 95 ml/min, respectively. Oxidized low-density lipoprotein and advance oxidative protein products as marker for oxidative stress were reduced by 20% in the N-ACC group (p&lt;0.05), whereas no change was evident in placebo. The primary endpoint CIN occurred in 14% in the N-ACC group and in 18% in the placebo group (p=n.s.). The primary endpoint reperfusion injury measured by myocardial salvage was also not different between both treatment groups (25.4%; IQR 14.1; 38.1 versus 22.5%; IQR 16.8; 36.5; p=n.s.). In addition, no differences in infarct size and microvascular obstruction as well as in ST-segment resolution were observed. The MACE rate after N-ACC was similar to placebo (19.4% versus 19.4%, p=n.s.). Conclusion High-dose N-ACC reduces oxidative stress. However, it does not provide an additional clinical benefit to placebo with respect to CIN and prevention of myocardial reperfusion injury in patients undergoing primary PCI with moderate doses of contrast medium and optimal hydration.
Abstract 5757: RAGE in Bone Marrow Derived Cells Blunts Restoration of Blood Flow in Mice Subjected to Femoral Artery Ligation
Authors: Xiaoping Shen, Fei Song, Rosa Rosario, Alfredo Morales, Yu Shan Zou, Ann Marie Schmidt, Shi Fang Yan
Journal: Circulation (2009)

Receptor for Advanced Glycation Endproducts (RAGE) plays central roles in the injury response to global hypoxia and ischemia/reperfusion (I/R) injury. Our previous data revealed that diabetic (D) and non-diabetic (ND) homozygous RAGE null mice subjected to hind limb ischemia displayed improvement in angiogenesis and restoration of blood flow. Here, we tested the hypothesis that endogenous RAGE expression in bone marrow (BM)-derived cells may contribute to impaired angiogenesis and blunted restoration of blood flow after femoral artery (FA) ligation. Wild type (WT) mice were rendered diabetic (D) with streptozotocin (stz); non-diabetic (ND) cohorts were treated with buffer alone. N D or D WT mice were used as recipient mice in BM transplantation. Rosa +/− transgenic mice containing a lacZ reporter gene were used as an indicator of transplantation of RAGE +/+ or RAGE −/− BM, therefore, the chimerical mice containing RAGE +/+ /Rosa +/− or RAGE −/− /Rosa +/− were generated as donor strains for BM transplantation. Immunostaining with anti- β -galactosidase IgG demonstrated that BM transplantation was successful from donors to recipients by localization of the expression of LacZ gene in the muscle tissues. FA ligation was performed on 13-week old ND or D WT recipient mice. Both ND and D WT recipient mice with transplantation of RAGE −/− /Rosa +/− BM displayed significantly improved blood flow ratios (injured/contralateral leg) by laser Doppler analysis on day 28 after FA ligation compared to ND or D WT recipient mice with transplantation of RAGE +/+ /Rosa +/− BM (Table ). Our data suggested that RAGE expression in the bone marrow contributes to impairment in blood flow recovery after acute arterial injury, irrespective of the state of glycemia. Table. Doppler data of Blood Flow Ratios (BRF, %)
Use of Contraindicated Anti-Thrombotics in Dialysis Patients Undergoing Percutaneous Coronary Interventions: Insights From the NCDR Cath-PCI Registry
Authors: Thomas T Tsai
Journal: Circulation (2009)

Abstract #895 Thomas T Tsai, Thomas M Maddox, Denver VA Medical Ctr/Univ of Colorado Denver, Denver, CO; Matthew T Roe, David Dai, Karen P Alexander, Duke Univ Medical Ctr, Durham, NC; P, Michael Ho, Denver VA Medical Ctr/Univ of Colorado Denver, Denver, CO; John C. Messenger, Univ of Colorado Denver, Denver, CO; Brahmajee K Nallamothu, Univ of Michigan Hosp, Ann Arbor, MI; Eric D Peterson, Duke Univ Medical Ctr, Durham, NC; John S. Rumsfeld, Denver VA Medical Ctr/Univ of Colorado Denver, Denver, CO Thomas T Tsai, 2009 Finalist and Presenting Author
Abstract 5768: The Effect of Ticagrelor on Cardiopulmonary Function in Patients With Stable Coronary Artery Disease
Authors: Robert F Storey, Kevin Bliden, Shankar B Patil, Arun Karunakaran, Rosemary Ecob, Kathleen Butler, Renli Teng, Paul Gurbel
Journal: Circulation (2009)

Background: A higher incidence of dyspnea has been observed in patients treated with ticagrelor (T) versus clopidogrel (C). As part of a multicenter, randomized, double-blind, parallel-group study (the ONSET-OFFSET study) in patients with stable coronary artery disease (CAD), we investigated whether T treatment is associated with any change in cardiopulmonary function. Methods: A total of 123 stable aspirin-treated CAD patients were randomized to T (180 mg load then 90 mg bid [n=57]), C (600 mg load then 75 mg qd [n=54]), or placebo (n=12) for 6 weeks. Echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements, and comprehensive pulmonary function tests were performed prior to (baseline) and 6 weeks after drug administration and/or following development of dyspnea. ANCOVA was used to analyze cardiopulmonary function changes from baseline. Results: The incidence of new-onset dyspnea following randomization was 24.6%, 5.6%, and 0% in the T, C, and placebo groups, respectively. The majority of instances were mild and/or lasted less than 24 h, although 3 patients on T versus 0 on C or placebo discontinued due to dyspnea. Seven of 16 and 8/16 patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, there were no significant changes between baseline and 6 weeks in any of the cardiopulmonary function parameters (Table ). Subgroup analysis of patients experiencing dyspnea also showed no significant changes in these parameters. C max and AUC 0-inf were similar between T-treated patients who experienced dyspnea and those who did not. Conclusions: Ticagrelor treatment had no effect on cardiopulmonary function in stable CAD patients. Dyspnea occurred with a higher frequency with ticagrelor versus clopidogrel but was not accompanied by any significant change in cardiopulmonary function.
Abstract 5791: A New Score to Improve the Detection of Peripheral Artery Disease
Authors: Susan Duval, Michael R Jaff, William E Boden, Mark J Alberts, Robert M Califf, Kim A Eagle, Ralph B D’Agostino, Joseph M Massaro, Alison Pedley, P. Gabriel Steg, Deepak L Bhatt, Alan T Hirsch
Journal: Circulation (2009)

Background: Detection of peripheral artery disease (PAD) typically entails noninvasive imaging or population screening, but whether a risk factor-based model has clinical utility is unclear. Our objective was to derive and internally validate a new score for estimating the probability of PAD utilizing the large US REACH Registry dataset. Methods: Analyses were conducted on 23,395 US REACH Registry outpatients with a complete baseline risk factor profile. PAD presence was determined by previous or current intermittent claudication associated with an ankle-brachial index &lt;0.9 or previous lower extremity intervention. Multivariable stepwise logistic regression identified cross-sectional correlates of PAD from demographic, clinical, and laboratory variables. Model performance was assessed internally using 10-fold cross validation, and effect estimates were used to generate the PAD score. Results: Overall PAD prevalence was 9.1% (n=2135), with a mean age of 70 years. Age, smoking, history of congestive heart failure, diabetes, coronary artery disease (CAD), cerebrovascular disease (CVD), BMI, sex, and hypertension stage were predictive of PAD (Table 1 ). The model had reasonable discrimination on derivation and internal validation (c-index = 0.61 and 0.60, respectively). The model-estimated PAD prevalence varied more than 3-fold from lowest to highest decile (range 4.8% to 16.4%) and corresponded closely with the actual PAD prevalence observed in each. Conclusions: This new PAD detection score uses easily available clinical variables to estimate the probability of disease prevalence. While the predictive power of the model may be limited, its use should nevertheless improve PAD detection in vulnerable, at-risk populations. These data should provide clinicians and patients with a simple risk-based tool to estimate the probability of PAD prevalence across a wide range of patients with atherothrombosis. Table 1: Factors related to PAD
Abstract 5809: Recombinant HSP27 Therapy Reduces Serum Cholesterol Levels and Experimental Atherogenesis
Authors: Yong-Xiang Chen, Xiaoling Zhao, Melissa McNulty, Edward R O’Brien
Journal: Circulation (2009)

Introduction: Recently we demonstrated that Heat Shock Protein 27 (HSP27) is a biomarker of atherosclerosis and apoE −/− mice that over-express HSP27 show a marked attenuation of aortic lesion size compared to apoE −/− mice (ATVB 20005; Circ Res 2008). Moreover, serum HSP27 levels are inversely related to atherosclerotic burden, estrogens mediate the release of HSP27 from cells and extracellular HSP27 binds to Scavenger Receptor-A where competitively inhibits acLDL uptake. Purpose/Methods: The goal of this study was to determine if recombinant HSP27 (rHSP27) administered to apoE −/− mice can attenuate atherogenesis. rHSP27 was produced in E.coli; (endotoxin concentration &lt;8EU/mg). In vitro aggregation and refolding assays revealed appropriate rHSP27 function. In vivo a series of subcutaneous dosing schedules were explored. Herein we report the results obtained for ApoE −/− mice maintained on a high fat diet and randomized to rHSP27 (100 μ g) vs. phosphate buffered saline (PBS) twice a day for 3 weeks. Results: All mice survived the study period without changes in body weight or adverse events. Total serum cholesterol levels were approximately 40% lower in rHSP27 treated mice. The aortic lesion areas were reduced by approximately 30% and 25% for en face and sinus cross-sectional analyses. In rHSP27 treated mice the abundance of aortic sinus lesion macrophages and apoptotic macrophages were reduced by approximately 45% and 80%, respectively. Conclusions: rHSP27 is a promising new therapeutic modality for reducing serum cholesterol levels as well as atherogenesis. Moreover, the lesions that form in mice treated with rHSP27 contain fewer inflammatory cells and undergo less apoptosis. Studies are ongoing to optimize the dose, schedule and form of rHSP27 that might be used not only for the prevention of atherogenesis but also regression of existing lesions.
Abstract 5811: Dual Function of Bone Morphogenetic Protein-2 in the Progression of Atherosclerotic Lesion and Atherosclerotic Intimal Calcification in vivo
Authors: Yusuke Nakagawa, Koji Ikeda, Ritsuko Nakano, Maki Uraoka, Masahiro Koide, Yoshiki Akakabe, Hiroaki Matsubara
Journal: Circulation (2009)

Vascular calcification is one of the most important risk factor for the cardiovascular diseases as well as a predictor of all-cause death. Recent findings suggest that bone calcification regulatory factors, locally expressed in blood vessels, play unique roles in the formation of vascular calcification. However, detailed molecular mechanisms, that regulate the intimal calcification associated with atherosclerosis, remain unclear. We first investigated the potential role of de-differentiated VSMCs in the formation of atherosclerotic intimal calcification. In vitro studies revealed that bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblastic differentiation was markedly up-regulated in the de-differentiated VSMCs comparing to the differentiated VSMCs. We therefore generated the BMP-2 transgenic mice in which BMP-2 expression was driven by α SMA-promoter, and mated them with ApoE-knockout mice to obtained BMP-2-Tg/ApoE-KO mice. After 8 weeks of high fat diet, atherosclerotic intimal calcification was not detectable even in BMP-2-Tg/ApoE-KO mice. Somewhat unexpectedly, atherosclerosis was significantly attenuated in BMP-2-Tg/ApoE-KO mice as compared to ApoE-KO mice. The number of α SMA-positive VSMCs and macrophages in the atherosclerotic intima was significantly reduced in BMP-2-Tg/ApoE-KO. Also, we found that BMP-2 inhibits the uptake of acetylated LDL in macrophage, and protects endothelial cells from apoptosis in vitro. Of note, when fed with high fat diet for 30 weeks, atherosclerotic intimal calcification was greater in BMP-2-Tg/ApoE-KO than in ApoE-KO mice, whereas the size of atherosclerotic lesion was not different between them. In conclusion, we revealed the dual function of BMP-2 in the atherosclerosis anti-atherogenic function in the early atherosclerotic lesion, presumably through reducing the proliferation of VSMCs inhibiting the lipid-uptake in macrophage protecting endothelial cells from apoptosis, and pro-calcification function in the advanced atherosclerotic intima.