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(12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao Et Al
USOO9498481 B2 (12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao et al. (45) Date of Patent: *Nov. 22, 2016 (54) CYCLOPROPYL MODULATORS OF P2Y12 WO WO95/26325 10, 1995 RECEPTOR WO WO99/O5142 2, 1999 WO WOOO/34283 6, 2000 WO WO O1/92262 12/2001 (71) Applicant: Apharaceuticals. Inc., La WO WO O1/922.63 12/2001 olla, CA (US) WO WO 2011/O17108 2, 2011 (72) Inventors: Tadimeti Rao, San Diego, CA (US); Chengzhi Zhang, San Diego, CA (US) OTHER PUBLICATIONS Drugs of the Future 32(10), 845-853 (2007).* (73) Assignee: Auspex Pharmaceuticals, Inc., LaJolla, Tantry et al. in Expert Opin. Invest. Drugs (2007) 16(2):225-229.* CA (US) Wallentin et al. in the New England Journal of Medicine, 361 (11), 1045-1057 (2009).* (*) Notice: Subject to any disclaimer, the term of this Husted et al. in The European Heart Journal 27, 1038-1047 (2006).* patent is extended or adjusted under 35 Auspex in www.businesswire.com/news/home/20081023005201/ U.S.C. 154(b) by Od en/Auspex-Pharmaceuticals-Announces-Positive-Results-Clinical M YW- (b) by ayS. Study (published: Oct. 23, 2008).* This patent is Subject to a terminal dis- Concert In www.concertpharma. com/news/ claimer ConcertPresentsPreclinicalResultsNAMS.htm (published: Sep. 25. 2008).* Concert2 in Expert Rev. Anti Infect. Ther. 6(6), 782 (2008).* (21) Appl. No.: 14/977,056 Springthorpe et al. in Bioorganic & Medicinal Chemistry Letters 17. 6013-6018 (2007).* (22) Filed: Dec. 21, 2015 Leis et al. in Current Organic Chemistry 2, 131-144 (1998).* Angiolillo et al., Pharmacology of emerging novel platelet inhibi (65) Prior Publication Data tors, American Heart Journal, 2008, 156(2) Supp. -
Specifications of Approved Drug Compound Library
Annexure-I : Specifications of Approved drug compound library The compounds should be structurally diverse, medicinally active, and cell permeable Compounds should have rich documentation with structure, Target, Activity and IC50 should be known Compounds which are supplied should have been validated by NMR and HPLC to ensure high purity Each compound should be supplied as 10mM solution in DMSO and at least 100µl of each compound should be supplied. Compounds should be supplied in screw capped vial arranged as 96 well plate format. -
Occurrence, Elimination, and Risk of Anticoagulant Rodenticides in Wastewater and Sludge
Occurrence, elimination, and risk of anticoagulant rodenticides in wastewater and sludge Silvia Lacorte, Cristian Gómez- Canela Department of Environmental Chemistry, IDAEA-CSIC, Jordi Girona 18-26, 08034 Barcelona Rats and super-rats Neverending story 1967 Coumachlor 1 tn rodenticides /city per campaign “It will be the LAST ONE” Rodenticides Biocides: use regulated according to EU. Used mainly as bait formulations. First generation: multiple feedings, less persistent in tissues, commensal and outdoor use. Second generation: single feeding (more toxic), more persistent in tissue, commensal use only. Toxic: vitamin K antagonists that cause mortality by blocking an animal’s ability to produce several key blood clotting factors. High oral, dermal and inhalation toxicity. Origin and fate of rodenticides Study site: Catalonia (7.5 M inhabitants) 1693 km of sewage corridor 13 fluvial tanks (70.000 m3) 130,000,000 € / 8 YEARS 32,000 km2 378,742 kg/y AI 2,077,000 € Objectives 1. To develop an analytical method to determine most widely used rodenticides in wastewater and sludge. 2. To monitor the presence of rodenticides within 9 WWTP receiving urban and agricultural waters. 3. To evaluate the risk of rodenticides using Daphnia magna as aquatic toxicological model. 4. To study the accumulation of rodenticides in sludge. Compounds studied Coumachlor* Pindone C19H15ClO4 C14H14O3 Dicoumarol Warfarin C19H12O6 C19H16O4 Coumatetralyl Ferulenol FGARs C19H16O3 C24H30O3 Acenocoumarol Chlorophacinone • Solubility C19H15NO6 C23H15ClO3 0.001-128 mg/L • pKa 3.4-6.6 Flocoumafen Bromadiolone C H F O C H BrO 33 25 3 40 30 23 4 • Log P 1.92-8.5 Brodifacoum Fluindione C H BrO 31 23 3 C15H9FO2 SGARs Difenacoum Fenindione C31H24O3 C15H10O2 1. -
Wastewater-Borne Exposure of Limnic Fish to Anticoagulant Rodenticides
Water Research 167 (2019) 115090 Contents lists available at ScienceDirect Water Research journal homepage: www.elsevier.com/locate/watres Wastewater-borne exposure of limnic fish to anticoagulant rodenticides * Julia Regnery a, , Pia Parrhysius a, Robert S. Schulz a, Christel Mohlenkamp€ a, Georgia Buchmeier b, Georg Reifferscheid a, Marvin Brinke a a Department of Biochemistry, Ecotoxicology, Federal Institute of Hydrology, Am Mainzer Tor 1, 56068 Koblenz, Germany b Unit Aquatic Ecotoxicology, Microbial Ecology, Bavarian Environment Agency, Demollstr. 31, 82407 Wielenbach, Germany article info abstract Article history: The recent emergence of second-generation anticoagulant rodenticides (AR) in the aquatic environment Received 18 June 2019 emphasizes the relevance and impact of aquatic exposure pathways during rodent control. Pest control Received in revised form in municipal sewer systems of urban and suburban areas is thought to be an important emission 12 September 2019 pathway for AR to reach wastewater and municipal wastewater treatment plants (WWTP), respectively. Accepted 13 September 2019 To circumstantiate that AR will enter streams via effluent discharges and bioaccumulate in aquatic or- Available online 14 September 2019 ganisms despite very low predicted environmental emissions, we conducted a retrospective biological monitoring of fish tissue samples from different WWTP fish monitoring ponds exclusively fed by Keywords: fl Bioaccumulation municipal ef uents in Bavaria, Germany. At the same time, information about rodent control in asso- Biocides ciated sewer systems was collected by telephone survey to assess relationships between sewer baiting Monitoring and rodenticide residues in fish. In addition, mussel and fish tissue samples from several Bavarian surface PBT-Substances waters with different effluent impact were analyzed to evaluate the prevalence of anticoagulants in Sewer baiting indigenous aquatic organisms. -
(12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 De Juan Et Al
US 200601 10428A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 de Juan et al. (43) Pub. Date: May 25, 2006 (54) METHODS AND DEVICES FOR THE Publication Classification TREATMENT OF OCULAR CONDITIONS (51) Int. Cl. (76) Inventors: Eugene de Juan, LaCanada, CA (US); A6F 2/00 (2006.01) Signe E. Varner, Los Angeles, CA (52) U.S. Cl. .............................................................. 424/427 (US); Laurie R. Lawin, New Brighton, MN (US) (57) ABSTRACT Correspondence Address: Featured is a method for instilling one or more bioactive SCOTT PRIBNOW agents into ocular tissue within an eye of a patient for the Kagan Binder, PLLC treatment of an ocular condition, the method comprising Suite 200 concurrently using at least two of the following bioactive 221 Main Street North agent delivery methods (A)-(C): Stillwater, MN 55082 (US) (A) implanting a Sustained release delivery device com (21) Appl. No.: 11/175,850 prising one or more bioactive agents in a posterior region of the eye so that it delivers the one or more (22) Filed: Jul. 5, 2005 bioactive agents into the vitreous humor of the eye; (B) instilling (e.g., injecting or implanting) one or more Related U.S. Application Data bioactive agents Subretinally; and (60) Provisional application No. 60/585,236, filed on Jul. (C) instilling (e.g., injecting or delivering by ocular ion 2, 2004. Provisional application No. 60/669,701, filed tophoresis) one or more bioactive agents into the Vit on Apr. 8, 2005. reous humor of the eye. Patent Application Publication May 25, 2006 Sheet 1 of 22 US 2006/0110428A1 R 2 2 C.6 Fig. -
Role of Thrombin and Thromboxane A2 in Reocclusion Following Coronary
Proc. Natl. Acad. Sci. USA Vol. 86, pp. 7585-7589, October 1989 Medical Sciences Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator (thrombolytic therapy/coronary thrombosis/platelet activation/reperfusion) DESMOND J. FITZGERALD*I* AND GARRET A. FITZGERALD* Divisions of *Clinical Pharmacology and tCardiology, Vanderbilt University, Nashville, TN 37232 Communicated by Philip Needleman, June 28, 1989 (receivedfor review April 12, 1989) ABSTRACT Reocclusion of the coronary artery occurs against the prothrombinase formed on the platelet surface after thrombolytic therapy of acute myocardlal infarction (13) and the neutralization ofheparin by platelet factor 4 (14) despite routine use of the anticoagulant heparin. However, and thrombospondin (15), proteins released by activated heparin is inhibited by platelet activation, which is greatly platelets. enhanced in this setting. Consequently, it is unclear whether To address the role of thrombin during coronary throm- thrombin induces acute reocclusion. To address this possibility, bolysis, we have examined the effect of a specific thrombin we examined the effect of argatroban {MCI9038, (2R,4R)- inhibitor, argatroban {MCI9038, (2R,4R)-4-methyl-1-[N-(3- 4-methyl-l-[Na-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfo- methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2- nyl)-L-arginyl]-2-piperidinecarboxylic acid}, a specific throm- piperidinecarboxylic acid} on the response to tissue plasmin- bin inhibitor, on the response to tissue-type plasminogen ogen activator (t-PA) in a closed-chest canine model of activator in a dosed-chest canine model of coronary thrombo- coronary thrombosis. MCI9038, an argimine derivative which sis. MCI9038 prolonged the thrombin time and shortened the binds to a hydrophobic pocket close to the active site of time to reperfusion (28 + 2 min vs. -
Characterising the Risk of Major Bleeding in Patients With
EU PE&PV Research Network under the Framework Service Contract (nr. EMA/2015/27/PH) Study Protocol Characterising the risk of major bleeding in patients with Non-Valvular Atrial Fibrillation: non-interventional study of patients taking Direct Oral Anticoagulants in the EU Version 3.0 1 June 2018 EU PAS Register No: 16014 EMA/2015/27/PH EUPAS16014 Version 3.0 1 June 2018 1 TABLE OF CONTENTS 1 Title ........................................................................................................................................... 5 2 Marketing authorization holder ................................................................................................. 5 3 Responsible parties ................................................................................................................... 5 4 Abstract ..................................................................................................................................... 6 5 Amendments and updates ......................................................................................................... 7 6 Milestones ................................................................................................................................. 8 7 Rationale and background ......................................................................................................... 9 8 Research question and objectives .............................................................................................. 9 9 Research methods .................................................................................................................... -
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.. -
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. -
Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-Target Organisms Katherine Horak U.S
University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln USDA National Wildlife Research Center - Staff U.S. Department of Agriculture: Animal and Plant Publications Health Inspection Service 2018 Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms Katherine Horak U.S. Department of Agriculture, [email protected] Penny M. Fisher Landcare Research Brian M. Hopkins Landcare Research Follow this and additional works at: https://digitalcommons.unl.edu/icwdm_usdanwrc Part of the Life Sciences Commons Horak, Katherine; Fisher, Penny M.; and Hopkins, Brian M., "Pharmacokinetics of Anticoagulant Rodenticides in Target and Non- target Organisms" (2018). USDA National Wildlife Research Center - Staff Publications. 2091. https://digitalcommons.unl.edu/icwdm_usdanwrc/2091 This Article is brought to you for free and open access by the U.S. Department of Agriculture: Animal and Plant Health Inspection Service at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in USDA National Wildlife Research Center - Staff ubP lications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Chapter 4 Pharmacokinetics of Anticoagulant Rodenticides in Target and Non-target Organisms Katherine E. Horak, Penny M. Fisher, and Brian Hopkins 1 Introduction The concentration of a compound at the site of action is a determinant of its toxicity. This principle is affected by a variety of factors including the chemical properties of the compound (pKa, lipophilicity, molecular size), receptor binding affinity, route of exposure, and physiological properties of the organism. Many compounds have to undergo chemical changes, biotransformation, into more toxic or less toxic forms. Because of all of these variables, predicting toxic effects and performing risk assess- ments of compounds based solely on dose are less accurate than those that include data on absorption, distribution, metabolism (biotransformation), and excretion of the compound. -
)&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 -
PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 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.