DOCSLIB.ORG

The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Rodney D. Britt Jr. Integrated Biomedical Science Program The Ohio State University 2012 Dissertation Committee: Dr. Lynette K. Rogers, PhD (Advisor) Dr. Mark Hall, MD Dr. Leif D. Nelin, MD Dr. Douglas Kniss, PhD Copyright by Rodney D. Britt Jr. 2012 Abstract Development of respiratory distress syndrome (RDS) adversely affects patient populations in neonatal and pediatric intensive care units. Patients with RDS require ventilation and oxygen therapy to maintain adequate tissue oxygenation. Preterm infants who develop RDS are at risk of developing the chronic lung disease, bronchopulmonary dysplasia (BPD). Lung ventilation and exposure to supraphysiological concentrations of oxygen contribute to the risk of developing BPD. Preterm infants with BPD have reduced alveolar and vascular development. Survivors of BPD have diminished lung function and are at risk of developing additional lung diseases such as asthma. Dysregulation of the inflammatory response is a significant contributing factor to BPD. Previous studies showed that cyclooxygenase-2 (COX-2) expression and leukocyte infiltration are increased in the lung during newborn hyperoxic exposure in mice. To determine the role of COX-2 in newborn hyperoxic lung injury, newborn pups were injected with aspirin (non-selective COX -2 inhibitor) and celecoxib (selective COX-2 inhibitor) during exposure to hyperoxia. We tested the hypothesis that COX-2 inhibition would (1) reduce macrophage infiltration and chemokine expression, (2) improve lung alveolarization, and (3) improve lung function in newborn mice exposed to hyperoxia. Our data suggest that COX-2 has a pro-inflammatory role in macrophage infiltration but is not involved in lung alveolarization during hyperoxic lung injury. Understanding the ii role of COX-2 in the developing lung during hyperoxic exposure may lead to therapeutic strategies to improve clinical outcomes and prevent development of BPD. The role of nonciliated airway epithelial cells, or Clara cells, during inflammation remains poorly understood. Studies have suggested that Clara cells are critical for regeneration of the airway epithelium and produce mediators which regulate inflammation. Through immuohistochemical analysis, we have found that Clara cells express COX-2. Mouse transformed Clara cells (MTCC) were utilized as an in vitro model to assess Clara cell responses to pro-inflammatory stimuli. We tested the hypothesis that lipopolysaccharide (LPS) would increase COX-2 and chemokine expression in MTCC. Our data show that LPS stimulation increases COX-2 and chemokine mRNA and protein expression, while increasing prostanoid levels. LPS also stimulates phosphorylation of mitogen activating protein kinases: p38, JNK, and ERK. Our data suggest that Clara cells may produce prostaglandins and chemotactic factors during inflammation. We speculate that Clara cells produce mediators to modulate leukocyte infiltration and the progression of inflammation during the pathogenesis of acute lung injury. Further characterization of Clara cell function may help identify therapeutic strategies to enhance regeneration of the airway epithelium in patients with chronic inflammatory lung diseases. iii This is dedicated to my great grandparents, grandparents, and parents, living and deceased. Thank you for the sacrifices you made to allow me to have an opportunity to pursue biomedical research. iv Acknowledgments There are many people who have significantly contributed to my development into a biomedical scientist. This process has been long and difficult but the support from family and friends have helped me achieve something that I never thought would be possible. First and foremost, I would like to thank Dr. Lynette K. Rogers for the opportunity to become her first graduate student. Under her guidance I have discovered a passion for science and developed a curiosity that will drive my future research efforts. I would also like to thank my family: my grandparents, parents, brother, cousins, aunts, uncles, and friends for their continuous support and encouragement. The faculty at Ohio State who have helped me grow as a scientist including my committee members. Finally, I would like to thank the classmates who helped me make it through my first year and beyond at The Ohio State University. v Vita May 2001………………………..Atholton High School, Columbia MD May 2006………………………..B.S. Chemistry, North Carolina A&T State University 2007 to Present…………………..Graduate Research Associate, College of Medicine, The Ohio State University Publications Rogers LK, Tipple TE, Britt RD, Welty SE. Hyperoxia Exposure Alters Hepatic Eicosanoid Metabolism in Newborn Mice. Pediatric Research, Feb;67(2):144-9, 2010. Rogers LK, Valentine CJ, Pennell M, Velten M, Britt RD, Dingess K, Zhao X, Welty SE, Tipple TE. Maternal DHA Supplementation Decreases Lung Inflammation in Hyperoxia-Exposed Newborn Mice. Journal of Nutrition, Feb;141(2):214-22, 2010. Britt RD Jr, Locy ML, Tipple TE, Nelin LD, Rogers LK. Lipopolysaccharide-induced Cyclooxygenase-2 Expression in Mouse Transformed Clara Cells. Cellular Physiology and Biochemistry, 29(1-2):213-22, 2012. Velten M, Britt RD Jr, Heyob KM, Welty SE, Tipple TE, Rogers LK. Perinatal Inflammation Exacerbates Hyperoxia Induced Functional and Structural Changes in Adult Mice. Am. J. Physiol Regul Integr Comp Physiol, Aug;303(3):R279-90, 2012. Fields of Study Major Field: Integrated Biomedical Science Program Area of Emphasis: Molecular Basis of Disease vi Table of Contents Abstract ............................................................................................................................... ii Acknowledgments............................................................................................................... v Vita ..................................................................................................................................... vi Publications ........................................................................................................................ vi Fields of Study ................................................................................................................... vi Table of Contents .............................................................................................................. vii List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii Chapter 1: Introduction ...................................................................................................... 1 Chronic lung disease in preterm infants .......................................................................... 1 Definition, Pathology, and Characteristics ................................................................. 1 Inflammation ................................................................................................................ 2 Lung Function.............................................................................................................. 4 Oxidative Stress during BPD ....................................................................................... 5 Therapeutic Strategies ................................................................................................. 6 Newborn Hyperoxic Lung Injury .................................................................................... 7 vii Leukocyte Infiltration and Inflammatory Mediators ................................................... 9 Alveolarization and Lung Function ........................................................................... 10 Role of Cyclooxygenase-2 (COX-2) during Lung injury ............................................. 12 COX-2 Expression and Activity ................................................................................. 12 Role of COX-2 during lung inflammation ................................................................. 14 Aspirin and its effect on inflammation .......................................................................... 15 COX-2 acetylation ..................................................................................................... 16 Lipoxins, Resolvins, and Protectins ........................................................................... 16 COX-independent effects of Salicylate and Aspirin .................................................. 19 Specific Aims, Objectives, and Rationale......................................................................... 20 Chapter 2: Role of COX-2 in >95% O2 mouse model of newborn hyperoxia ................. 22 Introduction ................................................................................................................... 22 Materials and Methods .................................................................................................. 24 Results ........................................................................................................................... 28 COX-2 Protein Expression ........................................................................................ 28 Aspirin and salicylic acid plasma levels...................................................................
Load more

Recommended publications
  • Stroke Prevention in Chronic Kidney Disease Disclosures
    5/18/2020 Controversies: Stroke Prevention in Chronic Kidney Disease Wei Ling Lau, MD FASN FAHA FACP Assistant Professor, Nephrology University of California, Irvine Visiting Fellow at OptumLabsCOPY Disclosures • Prior or current research funding from NIH, AHA, Sanofi, ZS Pharma, and Hub Therapeutics. • Associate Medical Director for home peritoneal dialysis at Fresenius University Dialysis Center of Orange. • Has beenNOT on Fresenius medical advisory board for Velphoro. • No conflicts of interest relevant to the current talk. Controversies: Stroke prevention in CKD Wei Ling Lau, MD DO 1 5/18/2020 Stroke Prevention in CKD • Blood pressure targets • Antiplatelet agents • Statins • Anticoagulation Controversies: Stroke prevention in CKD Wei Ling Lau, MD COPY BP TARGETS Data is limited, as patients with CKD were historically excluded from clinical trials NOT Whelton 2017 ACC/AHA hypertension guidelines [Hypertension 2018] Controversies: Stroke prevention in CKD Wei Ling Lau, MD DO 2 5/18/2020 Systolic Blood Pressure Intervention Trial SPRINT: BP lowering to <120 vs <140 mmHg significantly lowered rate of CVD composite primary outcome; no clear effect on stroke Controversies: Stroke prevention in CKD The SPRINT Research Group. N Engl J Med 2015 p2103 Wei Ling Lau, MD COPY SPRINT subgroup analysis: CKD • Patients with CKD stage 3‐4 (eGFR of 20 to <60) comprised 28% of the SPRINT study population • Intensive BP management seemed to provide the same benefits for reduction in the CVD composite primary outcomeNOT – but did not impact stroke Controversies: Stroke prevention in CKD Cheung 2017 J Am Soc Nephrol p2812 Wei Ling Lau, MD DO 3 5/18/2020 The hazard of incident stroke associated with systolic BP (SBP) and chronic kidney disease (CKD)BP using and an unadjusted stroke model risk: that contained J‐shaped dummy variables association for CKD and BP groups (A) and a fully adjusted model that contained dummy variables for CKD and BP grou..
    [Show full text]
  • Toward an in Vitro Bioequivalence Test
    TOWARD AN IN VITRO BIOEQUIVALENCE TEST by Jie Sheng A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmaceutical Sciences) In The University of Michigan 2007 Doctoral Committee: Professor Gordon L. Amidon, Chair Professor Henry Y. Wang Associate Professor Nair Rodriguez-Hornedo Associate Professor Steven P. Schwendeman Jie Sheng © 2007 All Rights Reserved To Kurt Q. Zhu, my husband and my very best friend, and to Diana S. Zhu and Brandon D. Zhu, my lovely children. ii Acknowledgements Most of all, I thank Prof. Gordon L. Amidon, for his support, guidance, and inspiration during my graduate studies at the University of Michigan. Being his student is the best step happened in my career. I am always amazed by his vision, energy, patience and dedication to the research and his students. He trained me to grow as a scientist and as a person. I also wish to thank all of my committee members, Professors David Fleisher, Nair Rodriguez-Hornedo, Steven Schwendeman and Henry Wang, for their very insightful and constructive suggestions to my research. It took all their efforts to raise me as a professional scientist in pharmaceutical field. They all contributed significantly to development and improvement of my graduate work. Especially, Prof. Wang has also guided me in thinking of career development as if 20-year later. I felt to be his student in many ways. I thank mentors, colleagues and friends, Prof. John Yu from Ohio State University, Paul Sirois from Eli Lilly, Kurt Seefeldt, Chet Provoda, Jonathan Miller, John Chung, Chris Landoswki, Haili Ping and Yasuhiro Tsume from College of Pharmacy, for many interesting discussions throughout the graduate program.
    [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]
  • Salts of Menantine and Cox-Inhibitors and Their Crystal Form in The
    (19) & (11) EP 2 098 500 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 09.09.2009 Bulletin 2009/37 C07C 57/40 (2006.01) C07C 63/70 (2006.01) C07C 65/01 (2006.01) C07C 211/38 (2006.01) (2006.01) (2006.01) (21) Application number: 08384002.5 A61K 31/13 A61K 31/192 A61P 25/02 (2006.01) A61P 29/00 (2006.01) (2006.01) (22) Date of filing: 07.03.2008 A61P 25/28 (84) Designated Contracting States: • Tesson, Nicolas AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 08028 Barcelona (ES) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Farran, Joan RO SE SI SK TR 08028 Barcelona (ES) Designated Extension States: • Rafecas, Llorenc AL BA MK RS 08028 Barcelona (ES) (71) Applicant: Laboratorios Del. Dr. Esteve, S.A. (74) Representative: Peters, Hajo et al 08041 Barcelona (ES) Graf von Stosch Patentanwaltsgesellschaft mbH (72) Inventors: Prinzregentenstrasse 22 • Buschmann, Helmut, Heinrich, Dr. 80538 München (DE) 52076 Aachen (Walheim) (DE) (54) Salts of menantine and cox-inhibitors and their crystal form in the treatment of pain (57) The present invention relates to salts of Memantine and COX-INHIBITORs, their crystal form, the processes for preparation of the same and their uses as medicaments, more particularly for the treatment of pain. EP 2 098 500 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 098 500 A1 Description [0001] The present invention relates to salts of Memantine and COX-INHIBITORs, their crystal from, and their specific polymorphs, the processes for preparation of the same and their uses as medicaments, more particularly for the treatment 5 of pain.
    [Show full text]
  • Antithrombotic Treatment After Stroke Due to Intracerebral Haemorrhage (Review)
    Cochrane Database of Systematic Reviews Antithrombotic treatment after stroke due to intracerebral haemorrhage (Review) Perry LA, Berge E, Bowditch J, Forfang E, Rønning OM, Hankey GJ, Villanueva E, Al-Shahi Salman R Perry LA, Berge E, Bowditch J, Forfang E, Rønning OM, Hankey GJ, Villanueva E, Al-Shahi Salman R. Antithrombotic treatment after stroke due to intracerebral haemorrhage. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: CD012144. DOI: 10.1002/14651858.CD012144.pub2. www.cochranelibrary.com Antithrombotic treatment after stroke due to intracerebral haemorrhage (Review) Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 3 BACKGROUND .................................... 5 OBJECTIVES ..................................... 5 METHODS ...................................... 6 RESULTS....................................... 8 Figure1. ..................................... 9 Figure2. ..................................... 11 Figure3. ..................................... 12 DISCUSSION ..................................... 14 AUTHORS’CONCLUSIONS . 15 ACKNOWLEDGEMENTS . 15 REFERENCES ..................................... 15 CHARACTERISTICSOFSTUDIES . 18 DATAANDANALYSES. 31 Analysis 1.2. Comparison 1 Short-term antithrombotic treatment, Outcome 2 Death. 31 Analysis 1.6. Comparison 1 Short-term antithrombotic
    [Show full text]
  • Antiplatelet Regimens in the Long-Term Secondary Prevention of Transient Ischaemic Attack and Ischaemic Stroke: an Updated Network Meta-Analysis
    Open Access Research BMJ Open: first published as 10.1136/bmjopen-2015-009013 on 17 March 2016. Downloaded from Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis Peng-Peng Niu, Zhen-Ni Guo, Hang Jin, Ying-Qi Xing, Yi Yang To cite: Niu P-P, Guo Z-N, ABSTRACT et al Strengths and limitations of this study Jin H, . Antiplatelet Objective: To examine the comparative efficacy and regimens in the long-term safety of different antiplatelet regimens in patients with ▪ secondary prevention of Since the dose of aspirin ranged from 30 to prior non-cardioembolic ischaemic stroke or transient transient ischaemic attack 1500 mg daily, treatment with aspirin was and ischaemic stroke: an ischaemic attack. divided into four different regimens and treat- updated network meta- Design: Systematic review and network meta-analysis. ment with aspirin plus dipyridamole was divided analysis. BMJ Open 2016;6: Data sources: As on 31 March 2015, all randomised into two different regimens. e009013. doi:10.1136/ controlled trials that investigated the effects of ▪ Duration of follow-up was included in the model bmjopen-2015-009013 antiplatelet agents in the long-term (≥3 months) to perform the network meta-analysis. secondary prevention of non-cardioembolic transient ▪ Estimates from sensitivity analyses were compat- ▸ Prepublication history and ischaemic attack or ischaemic stroke were searched ible with the main analysis, except that cilostazol additional material is and identified. was not significantly more effective than clopido- available. To view please visit Outcome measures: The primary outcome measure grel and triflusal in preventing serious vascular the journal (http://dx.doi.org/ of efficacy was serious vascular events (non-fatal events when setting the prior on the variance 10.1136/bmjopen-2015- stroke, non-fatal myocardial infarction and vascular equal to a uniform (0, 1000).
    [Show full text]
  • Digital Ischemic Events Related to Gemcitabine: Report of Two Cases and a Systematic Review
    257 case report Digital ischemic events related to gemcitabine: Report of two cases and a systematic review Cvetka Grasic Kuhar, Tanja Mesti, Branko Zakotnik Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia Received 1 February 2010 Accepted 1 March 2010 Correspondence to: Cvetka Grasič Kuhar, MD. PhD, Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška c. 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 5879282; Fax: +386 1 5879305; E-mail: [email protected] Disclosure: No potential conflicts of interest were disclosed. Background. Gemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported. Case report. We report two cases of gemcitabine related digital ischemic events. Case 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m2) he presented with Raynaud’s like phenom- enon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion. Case 2. A 77-year-old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m2) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preex- isting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits.
    [Show full text]
  • Study Protocol
    Protocol 3-001 Confidential 28APRIL2017 Version 4.1 Asahi Kasei Pharma America Corporation Synopsis Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects with Severe Sepsis and Coagulopathy Name of Sponsor/Company: Asahi Kasei Pharma America Corporation Name of Investigational Product: ART-123 Name of Active Ingredient: thrombomodulin alpha Objectives Primary: x To evaluate whether ART-123, when administered to subjects with bacterial infection complicated by at least one organ dysfunction and coagulopathy, can reduce mortality. x To evaluate the safety of ART-123 in this population. Secondary: x Assessment of the efficacy of ART-123 in resolution of organ dysfunction in this population. x Assessment of anti-drug antibody development in subjects with coagulopathy due to bacterial infection treated with ART-123. Study Center(s): Phase of Development: Global study, up to 350 study centers Phase 3 Study Period: Estimated time of first subject enrollment: 3Q 2012 Estimated time of last subject enrollment: 3Q 2018 Number of Subjects (planned): Approximately 800 randomized subjects. Page 2 of 116 Protocol 3-001 Confidential 28APRIL2017 Version 4.1 Asahi Kasei Pharma America Corporation Diagnosis and Main Criteria for Inclusion of Study Subjects: This study targets critically ill subjects with severe sepsis requiring the level of care that is normally associated with treatment in an intensive care unit (ICU) setting. The inclusion criteria for organ dysfunction and coagulopathy must be met within a 24 hour period. 1. Subjects must be receiving treatment in an ICU or in an acute care setting (e.g., Emergency Room, Recovery Room).
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 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. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] BMJ Open Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and Taiwan Journal: BMJ Open ManuscriptFor ID peerbmjopen-2019-032426 review only Article Type: Research Date Submitted by the 27-Jun-2019 Author: Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department
    [Show full text]
  • Use of Antiplatelet Agents Decreases the Positive Predictive Value of Fecal Immunochemical Tests for Colorectal Cancer but Does Not Affect Their Sensitivity
    Journal of Personalized Medicine Article Use of Antiplatelet Agents Decreases the Positive Predictive Value of Fecal Immunochemical Tests for Colorectal Cancer but Does Not Affect Their Sensitivity Yoonsuk Jung 1,† , Eui Im 2,†, Jinhee Lee 3, Hyeah Lee 4 and Changmo Moon 5,6,* 1 Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Korea; [email protected] 2 Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine and Cardiovascular Center, Yongin Severance Hospital, Yongin 16995, Korea; [email protected] 3 Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Korea; [email protected] 4 Clinical Trial Center, Ewha Womans University Mokdong Hospital, Seoul 07985, Korea; [email protected] 5 Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul 07985, Korea 6 Inflammation-Cancer Microenvironment Research Center, Ewha Womans University, Seoul 07804, Korea * Correspondence: [email protected]; Tel.: +82-2-2650-2945; Fax: +82-2-2650-5936 † These authors contributed equally to this study. Abstract: Previous studies have evaluated the effects of antithrombotic agents on the performance of fecal immunochemical tests (FITs) for the detection of colorectal cancer (CRC), but the results were inconsistent and based on small sample sizes. We studied this topic using a large-scale population- based database. Using the Korean National Cancer Screening Program Database, we compared Citation: Jung, Y.; Im, E.; Lee, J.; Lee, the performance of FITs for CRC detection between users and non-users of antiplatelet agents and H.; Moon, C. Use of Antiplatelet warfarin.
    [Show full text]
  • Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model
    Effect of Argatroban on Microthrombi Formation and Brain Damage in the Rat Middle Cerebral Artery Thrombosis Model Hiroshi Kawai#, Kazuo Umemura and Mitsuyoshi Nakashima Department of Pharmacology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu 431-31, Japan Received May 19, 1995 Accepted July 26, 1995 ABSTRACT-Ischemic cerebral infarcts induce hypercoagulation and microthrombosis in the surrounding region, thus leading to vascular occlusion. We determined whether microthrombi contribute to the spread- ing of ischemic lesions following thrombotic middle cerebral artery (MCA) occlusion and also determined whether argatroban, a selective thrombin inhibitor, reduces the formation of the microthrombi and the area of the ischemic lesions. The rat left MCA was occluded by a platelet-rich thrombus formed following the photochemical reaction between rose bengal and green light. Microthrombi were histologically identified in the left hemisphere. The extent of ischemic lesions and microthrombi containing fibrin increased in a time- dependent manner after MCA occlusion. Argatroban inhibited the formation of microthrombi up to 3 hr after MCA occlusion; beyond 3 hr, it was ineffective. Argatroban also significantly (P<0.01) reduced the size of ischemic cerebral lesions at 6 hr after MCA occlusion. It is concluded that the formation of microthrombi contributes to the progression of ischemic lesions in the early stage. It is likely that thrombin generated following thrombotic MCA occlusion contributes to the progression of ischemic lesions by promoting the formation of microthrombi. Argatroban can reduce the formation of microthrombi and ischemic lesions in the early stage. Keywords: Thrombin, Argatroban, Microthrombosis, Thrombotic middle cerebral artery occlusion The progression of focal cerebral infarction is depend- in the ischemic areas and might contribute to micro- ent on numerous factors (1, 2).
    [Show full text]