DOCSLIB.ORG

1628.Full-Text.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1628.Full-Text.Pdf Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities This information is current as David M. Aronoff, Camila M. Peres, Carlos H. Serezani, of October 2, 2021. Megan N. Ballinger, Jennifer K. Carstens, Nicole Coleman, Bethany B. Moore, R. Stokes Peebles, Lucia H. Faccioli and Marc Peters-Golden J Immunol 2007; 178:1628-1634; ; doi: 10.4049/jimmunol.178.3.1628 http://www.jimmunol.org/content/178/3/1628 Downloaded from References This article cites 39 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/178/3/1628.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities1 David M. Aronoff,2,3* Camila M. Peres,2†‡ Carlos H. Serezani,† Megan N. Ballinger,† Jennifer K. Carstens,* Nicole Coleman,* Bethany B. Moore,† R. Stokes Peebles,§ Lucia H. Faccioli,‡ and Marc Peters-Golden† PGI2 (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI2, in the regulation of both innate and acquired immunity. As PGI2 is unstable, we sought to define the effects of various PGI2 analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, car- baprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were Downloaded from determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the G␣s protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI2 analogs and more closely resembled the effects of PGE2. Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies http://www.jimmunol.org/ differences in immunoregulatory properties of clinically administered PGI2 analogs. These studies are the first to explore the capacity of PGI2 to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents. The Journal of Immunology, 2007, 178: 1628–1634. rostaglandin I2 (prostacyclin; epoprostenol) is an oxygen- In light of its potent vasodilatory properties, PGI2 has been ex- ated metabolite of arachidonic acid formed enzymatically ploited as a pharmacological agent in the treatment of vasocon- P by the sequential activities of cyclooxygenase and PGI strictive/ischemic diseases such as peripheral vascular arterial oc- synthase enzymes (1). It is produced constitutively by vascular clusive disease, cerebrovascular ischemia, and pulmonary arterial by guest on October 2, 2021 endothelial and smooth muscle cells (2) and is induced under in- hypertension (PAH) (1). Although native PGI2 is inherently un- flammatory conditions in vascular cells (3) and macrophages (4). stable at room temperature with a t1/2 of seconds to minutes (6), PGI2 is a potent vasodilator and antithrombotic agent (1) whose continuous infusions of a highly alkaline solution (pH 10.2 to 10.8) effects result from binding to a unique heptahelical G protein-cou- are approved by the U.S. Food and Drug Administration (FDA) in pled receptor termed the I prostanoid (IP)4 receptor (5). This re- the treatment of PAH. To combat the technical difficulties associ- ated with administering epoprostenol, more stable synthetic ana- ceptor is G␣s-coupled and activates adenylate cyclase, resulting in an acute burst of intracellular cAMP. logs of PGI2 have been developed and approved for use in PAH. The compound treprostinil (UT-15, Uniprost), which has a half- life of several hours and is stable at room temperature, was ap- proved by the FDA for continuous s.c. infusion. Treprostinil is a *Division of Infectious Diseases and †Division of Pulmonary and Critical Care Med- potent IP receptor agonist (7), although its specificity for this re- icine, Department of Internal Medicine, University of Michigan Health Systems, Ann ceptor is unknown. Iloprost (8) is an inhaled prostacyclin analog Arbor, MI 48109; ‡Departamento de Ana´lises Clı´nicas, Toxicolo´gicas e Bromato- lo´gicas, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o Preto, Universidade de Sa˜o with a half-life between those of epoprostenol and treprostinil that Paulo, Ribeira˜o Preto, Sa˜o Paulo, Brazil; and §Division of Allergy, Pulmonary, and was also approved by the FDA for use in PAH. Though iloprost is Critical Care Medicine, Vanderbilt University, Nashville, TN 37232 a potent IP receptor agonist that is commonly used in vitro, it also Received for publication September 27, 2006. Accepted for publication November demonstrates significant binding to two of the four E prostanoid 7, 2006. (EP) receptors, namely the G␣q-coupled EP1 and the G␣i-coupled The costs of publication of this article were defrayed in part by the payment of page EP3 subtypes (9). charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Cyclic AMP is the quintessential intracellular second messenger 1 This work was supported by the National Institutes of Health Grants AI054660, that amplifies extracellular signals following the binding of G␣s- HL069949, HL078727, HL071586, and HL058897; the American Lung Association coupled receptors by appropriate ligands. Acute increases in Grant RG-8909-N; and Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nı´vel Supe- cAMP have profound anti-inflammatory effects on a number of rior (Capes-Brazil). different cell types involved in both innate and acquired immunity 2 D.M.A. and C.M.P. contributed equally to this work. (10). Our laboratory has studied the effects of cAMP-elevating 3 Address correspondence and reprint requests to Dr. David M. Aronoff, University of Michigan Health System, 5220-D Medical Sciences Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0640. E-mail address: tyl-1-methylxantine; KO, knockout; PAH, pulmonary arterial hypertension; PGI2, [email protected] prostacyclin/epoprostenol; PPAR␤, peroxisome proliferator-activated receptor ␤. 4 Abbreviations used in this paper: IP, G protein-coupled I prostanoid receptor; AM, alveolar macrophage; EP, G protein-coupled E prostanoid receptor; IBMX, 3-isobu- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 www.jimmunol.org The Journal of Immunology 1629 compounds on the innate immune system, particularly in the lung Tetrazolium dye reduction assay of bacterial killing (11–13). Recent work demonstrated that PGE2 suppressed critical The ability of bacteria to survive within the macrophages was quantified antimicrobial defense functions of alveolar macrophages (AMs), using a tetrazolium dye reduction assay as described elsewhere (18, 19) and including phagocytosis, bacterial killing, and inflammatory medi- results are expressed as the percentage of survival of phagocytosed ator production, all in a cAMP-dependent manner, mediated via bacteria. the G␣s-coupled EP2 and EP4 receptors (11, 12). Animal models Cytokine measurement in cell culture supernatants have identified important roles for endogenously produced PGE2 in regulating pulmonary host defense (14). Given this ability to Rat or murine macrophages were harvested as described, and the ability of these cells to produce IL-6 and TNF-␣ was assessed by ELISA. Cells were stimulate cAMP production through the IP receptor, we hypothe- treated according to a previously published protocol (13), including a 60- sized that PGI2 analogs might inhibit pulmonary innate immunity min preincubation (37°C with 5% CO2) with compounds of interest in serum-free medium followed by incubation (37°C with 5% CO ) for an in a manner analogous to PGE2. This is particularly relevant given 2 that: 1) PGI analogs are prescribed for PAH; and 2) there are additional 16 h in the presence of LPS 100 ng/ml (or vehicle) and 1% FCS. 2 After this time, cell-free supernatants were collected and analyzed
Load more

Recommended publications
  • VTE) Cindy Ward, DNP, RN-BC, CMSRN, ACNS-BC
    Chronic Complications of Venous Thromboembolism (VTE) Cindy Ward, DNP, RN-BC, CMSRN, ACNS-BC Roanoke, VA Disclosure • The speaker has no conflicts of interest to disclose. Carilion Roanoke Memorial Hospital • 3 time Magnet® designated • Flagship of Carilion Clinic, a 7 hospital system • Region’s only Level 1 Trauma Center • 703-bed academic medical center • System-wide, serves nearly 1 million patients across Virginia, West Virginia and North Carolina Objectives At the conclusion of this education activity, the learner will be able to: • recall VTE risk factors and prevention • describe post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension (CTEPH) • identify nursing implications of caring for patients with post-thrombotic syndrome and CTEPH What is VTE? Pulmonary Embolus Deep Vein (PE) Thrombosis (DVT) Signs/Symptoms of DVT • Swelling • Erythema • Pain • Warmth1 Signs/Symptoms of PE 1 • Sudden onset of dyspnea • Tachycardia • Irregular heartbeat • Chest pain, worse with deep breath • Hemoptysis • Low blood pressure, light-headedness or syncope • 350,000 – 900,000 people per year are affected by VTE1, 2 • VTE is the leading cause of preventable hospital death in the US2 • VTE can occur without symptoms (silent)3 Quick Facts • Patients with DVT who are untreated have a 37% incidence of PE that is fatal4 • Combined mortality from PE (initial and recurrence) is 73%4 Quick Facts • 1 in 20 hospitalized patients will suffer a fatal PE if they have not received adequate VTE prophylaxis5 • For 25% of patients with PE, the first
    [Show full text]
  • CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene and Pathophysiological Conditions
    Review CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene and Pathophysiological Conditions Rossana Roncato 1,*,†, Jacopo Angelini 2,†, Arianna Pani 2,3,†, Erika Cecchin 1, Andrea Sartore-Bianchi 2,4, Salvatore Siena 2,4, Elena De Mattia 1, Francesco Scaglione 2,3,‡ and Giuseppe Toffoli 1,‡ 1 1 Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy; [email protected] (E.C.); [email protected] (E.D.M.); [email protected] (G.T.) 2 Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122 Milan, Italy; [email protected] (J.A.); [email protected] (A.P.); [email protected] (A.S-B.); [email protected] (S.S.); [email protected] (F.S.) 3 Clinical Pharmacology Unit, ASST Grande Ospedale Metropolitano Niguarda, Piazza dell'Ospedale Maggiore 3, 20162 Milan, Italy 4 Department of Hematology and Oncology, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy * Correspondence: [email protected]; Tel.:+390434659130 † These authors contributed equally. ‡ These authors share senior authorship. Int. J. Mol. Sci. 2020, 21, x; doi: www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x 2 of 8 Table S1. Co-administered agents categorized according to their potential risk for Drug-Drug interaction (DDI) in combination with CDK4/6 inhibitors (CDKis). Colors suggest the risk of DDI with CDKis: green, low risk DDI; orange, moderate risk DDI; red, high risk DDI. ADME, absorption, distribution, metabolism, and excretion; GI, Gastrointestinal; TdP, Torsades de Pointes; NTI, narrow therapeutic index. * Cardiological toxicity should be considered especially for ribociclib due to the QT prolongation.
    [Show full text]
  • GTH 2021 State of the Art—Cardiac Surgery: the Perioperative Management of Heparin-Induced Thrombocytopenia in Cardiac Surgery
    Review Article 59 GTH 2021 State of the Art—Cardiac Surgery: The Perioperative Management of Heparin-Induced Thrombocytopenia in Cardiac Surgery Laura Ranta1 Emmanuelle Scala1 1 Department of Anesthesiology, Cardiothoracic and Vascular Address for correspondence Emmanuelle Scala, MD, Centre Anesthesia, Lausanne University Hospital (CHUV), Lausanne, Hospitalier Universitaire Vaudois, Rue du Bugnon 46, BH 05/300, 1011 Switzerland Lausanne, Suisse, Switzerland (e-mail: [email protected]). Hämostaseologie 2021;41:59–62. Abstract Heparin-induced thrombocytopenia (HIT) is a severe, immune-mediated, adverse drug Keywords reaction that paradoxically induces a prothrombotic state. Particularly in the setting of ► Heparin-induced cardiac surgery, where full anticoagulation is required during cardiopulmonary bypass, thrombocytopenia the management of HIT can be highly challenging, and requires a multidisciplinary ► cardiac surgery approach. In this short review, the different perioperative strategies to run cardiopul- ► state of the art monary bypass will be summarized. Introduction genicity of the antibodies and is diagnostic for HIT. The administration of heparin to a patient with circulating Heparin-induced thrombocytopenia (HIT) is a severe, im- pathogenic HITabs puts the patient at immediate risk of mune-mediated, adverse drug reaction that paradoxically severe thrombotic complications. induces a prothrombotic state.1,2 Particularly in the setting The time course of HIT can be divided into four distinct of cardiac surgery, where full anticoagulation is required phases.6 Acute HIT is characterized by thrombocytopenia during cardiopulmonary bypass (CPB), the management of and/or thrombosis, the presence of HITabs, and confirma- HIT can be highly challenging, and requires a multidisciplin- tion of their platelet activating capacity by a functional ary approach.
    [Show full text]
  • List of Union Reference Dates A
    Active substance name (INN) EU DLP BfArM / BAH DLP yearly PSUR 6-month-PSUR yearly PSUR bis DLP (List of Union PSUR Submission Reference Dates and Frequency (List of Union Frequency of Reference Dates and submission of Periodic Frequency of submission of Safety Update Reports, Periodic Safety Update 30 Nov. 2012) Reports, 30 Nov.
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • Ventavis, INN-Iloprost
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Ventavis 10 microgram/ml nebuliser solution Ventavis 20 microgram/ml nebuliser solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Ventavis 10 microgram/ml nebuliser solution 1 ml solution contains 10 microgram iloprost (as iloprost trometamol). Each ampoule with 1 ml solution contains 10 microgram iloprost. Each ampoule with 2 ml solution contains 20 microgram iloprost. Ventavis 20 microgram/ml nebuliser solution 1 ml solution contains 20 microgram iloprost (as iloprost trometamol). Each ampoule with 1 ml solution contains 20 microgram iloprost. Excipient with known effect • Ventavis 10 microgram/ml: Each ml contains 0.81 mg ethanol 96% (equivalent to 0.75 mg ethanol) • Ventavis 20 microgram/ml: Each ml contains 1.62 mg ethanol 96% (equivalent to 1.50 mg ethanol). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Nebuliser solution. Ventavis 10 microgram/ml nebuliser solution Clear, colourless solution. Ventavis 20 microgram/ml nebuliser solution Clear, colourless to slightly yellowish solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of adult patients with primary pulmonary hypertension, classified as NYHA functional class III, to improve exercise capacity and symptoms. 4.2 Posology and method of administration Drug product Suitable inhalation device (nebuliser) to be used Ventavis 10 microgram/ml Breelib I-Neb AAD Venta-Neb Ventavis 20 microgram/ml Breelib I-Neb AAD Ventavis should only be initiated and monitored by a physician experienced in the treatment of pulmonary hypertension. 2 Posology Dose per inhalation session At initiation of Ventavis treatment the first inhaled dose should be 2.5 microgram iloprost as delivered at the mouthpiece of the nebuliser.
    [Show full text]
  • Clinical Trial Protocol: BPS-314D-MR-PAH-302
    Clinical Trial Protocol: BPS-314d-MR-PAH-302 Study Title: A multicenter, double-blind, randomized, placebo-controlled, Phase 3 study to assess the efficacy and safety of oral BPS-314d-MR added-on to treprostinil, inhaled (Tyvaso®) in subjects with pulmonary arterial hypertension Study Number: BPS-314d- MR-PAH-302 Study Phase: 3 Product Name: Beraprost Sodium 314d Modified Release IND Number: 111,729 Indication: Treatment of Pulmonary Arterial Hypertension Investigators: Multicenter Sponsor: Lung Biotechnology Inc. Sponsor Contact: Medical Monitor: Date Original Protocol: 16 April 2013 Amendment 1: 17 December 2013 Amendment 2 15 October 2014 GCP Statement: This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and applicable regulatory requirements. Confidentiality Statement The concepts and information contained herein are confidential and proprietary and shall not be disclosed in whole or part without the express written consent of Lung Biotechnology Inc. © 2014 Lung Biotechnology Inc. Beraprost Sodium 314d Modified Release Lung Biotechnology Inc. Clinical Trial Protocol: BPS-314-d-MR-PAH 302 15 October 2014 LIST OF CONTACTS Study Sponsor: Lung Biotechnology Inc. 1040 Spring Street Silver Spring, Maryland 20910 United States Phone: 301-608-9292 Fax: 301-589-0855 Sponsor Contact: Medical Monitor: SAE Reporting: CONFIDENTIAL Page 2 of 75 Beraprost Sodium 314d Modified Release Lung Biotechnology Inc. Clinical Trial Protocol: BPS-314-d-MR-PAH 302 15 October 2014 SYNOPSIS Sponsor: Lung Biotechnology Inc.
    [Show full text]
  • Evaluation of Low-Dose Aspirin for Primary Prevention of Ischemic
    Kim et al. Diabetology & Metabolic Syndrome (2015) 7:8 DIABETOLOGY & DOI 10.1186/s13098-015-0002-y METABOLIC SYNDROME RESEARCH Open Access Evaluation of low-dose aspirin for primary prevention of ischemic stroke among patients with diabetes: a retrospective cohort study Ye-Jee Kim1†, Nam-Kyong Choi2,3†, Mi-Sook Kim4, Joongyub Lee2, Yoosoo Chang5, Jong-Mi Seong1, Sun-Young Jung1, Ju-Young Shin1, Ji-Eun Park6,7 and Byung-Joo Park1,4,6* Abstract Background: Low-dose aspirin is recommended to reduce the risk of cardiovascular disease. However, the questions with regard to primary prevention have been raised among patients with diabetes. We evaluated low-dose aspirin use for preventing ischemic stroke in patients with diabetes using a national health insurance database. Methods: Using data from the Korean Health Insurance Review and Assessment Service database from January 1, 2005, through December 31, 2009, a population-based retrospective cohort study was conducted with incident patients with diabetes aged 40 to 99 years old with the initial use of low-dose aspirin during the index period from January 1, 2006 to December 31, 2007. We matched each low-dose aspirin user to one non-user using a propensity score. The Cox proportional hazards model was used to compare the risk of hospitalization for ischemic stroke in users and nonusers of low-dose aspirin until December 31, 2009. Results: Out of 261,065 incident patients with diabetes, 15,849 (6.2%) were low-dose aspirin users. Compared to non-users, the adjusted hazard ratio (95% confidence interval) of low-dose aspirin users for hospitalization due to ischemic stroke was 1.73 (95% CI; 1.41-2.12).
    [Show full text]
  • Effect of Prostanoids on Human Platelet Function: an Overview
    International Journal of Molecular Sciences Review Effect of Prostanoids on Human Platelet Function: An Overview Steffen Braune, Jan-Heiner Küpper and Friedrich Jung * Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology, 01968 Senftenberg, Germany; steff[email protected] (S.B.); [email protected] (J.-H.K.) * Correspondence: [email protected] Received: 23 October 2020; Accepted: 23 November 2020; Published: 27 November 2020 Abstract: Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements in thrombosis and hemostasis. The function of platelets is influenced by mediators in the blood and the vascular wall. Activated platelets aggregate and release bioactive substances, thereby activating further neighbored platelets, which finally can lead to the formation of thrombi. Prostanoids regulate the function of blood platelets by both activating or inhibiting and so are involved in hemostasis. Each prostanoid has a unique activity profile and, thus, a specific profile of action. This article reviews the effects of the following prostanoids: prostaglandin-D2 (PGD2), prostaglandin-E1, -E2 and E3 (PGE1, PGE2, PGE3), prostaglandin F2α (PGF2α), prostacyclin (PGI2) and thromboxane-A2 (TXA2) on platelet activation and aggregation via their respective receptors. Keywords: prostacyclin; thromboxane; prostaglandin; platelets 1. Introduction Hemostasis is a complex process that requires the interplay of multiple physiological pathways. Cellular and molecular mechanisms interact to stop bleedings of injured blood vessels or to seal denuded sub-endothelium with localized clot formation (Figure1).
    [Show full text]
  • Treprostinil for Pulmonary Hypertension
    REVIEW Treprostinil for pulmonary hypertension Nika Skoro-Sajer1 Abstract: Treprostinil is a stable, long-acting prostacyclin analogue which can be admin- Irene Lang1 istered as a continuous subcutaneous infusion using a portable miniature delivery system. Robert Naeije2 Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and 1Division of Cardiology, Department of Internal Medicione II, Vienna quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor General Hospital, Medical University prognosis. Side effects include facial fl ush, headache, jaw pain, abdominal cramping, and diar- 2 of Vienna, Austria; Department rhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and of Cardiology, Erasme University Hospital, Brussels, Belgium infusion site pain which may make further treatment impossible in 7%–10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting effi cacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2–3 times those given subcutaneously, appear to be needed to obtain the same effi cacy. Preliminary results of a randomized controlled trial of inhaled treprostinil
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Statistical Analysis Plan – Part 1
    NCT03251482 Janssen Research & Development Statistical Analysis Plan – Part 1 A Randomized, Double-blind, Double-dummy, Multicenter, Adaptive Design, Dose Escalation (Part 1) and Dose-Response (Part 2) Study to Evaluate the Safety and Efficacy of Intravenous JNJ-64179375 Versus Oral Apixaban in Subjects Undergoing Elective Total Knee Replacement Surgery Protocol 64179375THR2001; Phase 2 JNJ-64179375 Status: Approved Date: 18 October 2017 Prepared by: Janssen Research & Development, LLC Document No.: EDMS-ERI-148215770 Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential. 1 Approved, Date: 18 October 2017 JNJ-64179375 NCT03251482 Statistical Analysis Plan - Part 1 64179375THR2001 TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................................... 2 LIST OF IN-TEXT TABLES AND FIGURES ...............................................................................................
    [Show full text]