DOCSLIB.ORG

(10) Patent No.: US 9062298 B2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(10) Patent No.: US 9062298 B2 USOO9062298B2 (12) United States Patent (10) Patent No.: US 9,062,298 B2 Lu et al. (45) Date of Patent: *Jun. 23, 2015 (54) ANTIDOTES FOR FACTOR XA INHIBITORS 5,939,304 A 8, 1999 Suzuki et al. AND METHODS OF USING THE SAME 6,060,300 A 5/2000 Raditsch et al. 6,069,234 A 5, 2000 Chmielewska et al. 6,086,871 A 7/2000 Fischer et al. (71) Applicant: Portola Pharmaceuticals, Inc., South 6,376,515 B2 4/2002 Zhu et al. San Francisco, CA (US) 6,472,562 B1 10/2002 Klingler et al. 6,660,885 B2 12/2003 South et al. (72) Inventors: Genmin Lu, Burlingame, CA (US); 6,835,739 B2 12/2004 Zhu et al. David R. Phillips, San Mateo, CA (US); 3: 538 Night s al. Patrick Andre, San Mateo, CA (US); 7,220,569 B2 5/2007 HimmelspachO. ca. et al. Uma Sinha, San Francisco, CA (US) 7,220,849 B2 5/2007 High et al. 7,247,654 B2 7/2007 Priestley et al. (73) Assignee: Portola Pharmaceuticals, Inc., South 7,598.276 B2 10/2009 Grant et al. San Francisco, CA (US) 8,153,590 B2 4/2012 Lu et al. ..................... 514,144 8,268,783 B2 * 9/2012 Sinha et al. ... 514,144 (*) Notice: Subject to any disclaimer, the term of this 3. R: ck 38. y r 3. patent is extended or adjusted under 35 2003/0064414 A1 4/2003 Benecky et al. U.S.C. 154(b) by 0 days. 2003/02O7796 A1 11/2003 Sinha et al. 2004/O198660 A1 10, 2004 Petersen et al. This patent is Subject to a terminal dis- 2005/00098.95 A1 1/2005 Priestley et al. claimer. 2007/01 12039 A1 5/2007 Grant et al. (21) Appl. No.: 13/889,014 FOREIGN PATENT DOCUMENTS (22) Filed: May 7, 2013 CA 2156991 2, 1996 EP 182O 508 AO 8, 2007 O O WO WO-96.OO577 1, 1996 (65) Prior Publication Data WO WO-98,38317 9, 1998 WO WO-98.38318 AO 9, 1998 US 2014/OO44773 A1 Feb. 13, 2014 WO WO-98.39456 AO 9, 1998 O O WO WO-2007/059513 5/2007 Related U.S. Application Data WO WO-2007/096116 8/2007 (63) Continuation of application No. 13/414,499, filed on W. W323 $392 Mar. 7, 2012, now Pat. No. 8,455,441, which is a inued continuation of application No. 12/239.651, filed on (Continued) Sep. 26, 2008, now Pat. No. 8,153,590. OTHER PUBLICATIONS (60) gal applits C.2. s Sp Morita et al., J Biol Chem. Mar. 25, 1986:261 (9):4015-23.* file d p pp s s Rezaie et al., “Analysis of the Functions of the First Epidermal ed on Aug. 20, 2008. Growth Factor-like Domain of Factor X.” the Journal of Biological Chemistry, Apr. 15, 1993, vol. 268, No. 11, pp. 8176-8180. (51) Int. Cl. Rezaie et al., "Contribution of Residue 192 in Factor Xa to Enzymeym A6 IK39/00 (2006.01) Specificity and Function.” The Journal of Biological Chemistry, Jul. CI2N 9/64 (2006.01) 7, 1995, vol. 270, No. 27, pp. 16176-16181. A6 IK38/48 3:08: Yang et al., “Antibodies Against the Activated Coagulation Factor X A6 IK 47/48 2006.O1 (FXa) in the Antiphospholipid Syndrome that Interfere with the FXa. (52) U.S. Cl. Inactivation by Antithrombin.” J. Immunol. Dec. 1, 2006, vol. 177. CPC .......... CI2N 9/6432 (2013.01); A61K 38/4826 No. 11, pp. 1-17. (2013.01); A61K 38/4833 (2013.01); A61 K (Continued) 38/4846 (2013.01); A61 K38/4853 (2013.01); A61 K 39/00 (2013.01); A61K47/48215 Pri Exami Michael SZperk (2013.01): CI2Y 304/21006 (2013.01) rimary Examiner - Michael Szperka r (58) Field of Classification Search (74) Attorney, Agent, or Firm — Sheppard Mullin Richter & None Hampton LLP S ee appl1cauonlication fileIlle fIor completelet searcnh historv.n1Story (57) ABSTRACT (56) References Cited The present invention relates antidotes to anticoagulants tar geting factor Xa. The antidotes are factor Xa protein deriva U.S. PATENT DOCUMENTS tives that bind to the factor Xa inhibitors thereby substantially 5,278,144 A 1, 1994 Wolf neutralizing them but do not assemble into the prothrombi 5,589,571 A 12/1996 King nase complex. The derivatives describe herein lack or have 5,589,572 A 12/1996 King reduced intrinsic coagulant activity. Disclosed herein are 5,597,799 A 1, 1997 Wolf methods of stopping or preventing bleeding in a patient that is 5,602,233 A 2/1997 King 5,679,639 A 10, 1997 Griffin et al. currently undergoing anticoagulant therapy with a factor Xa 5,770,699 A 6/1998 King inhibitor. 5,795,863 A 8, 1998 Wolf 5,817.309 A 10, 1998 Nowak et al. 18 Claims, 12 Drawing Sheets US 9,062.298 B2 Page 2 (56) References Cited Hylek (2007) "Drug evaluation: DU-176b, an oral, direct factor Xa antagonist”. Curr Opin Invest Drugs 8(9):778-783. Izaguirre et al. "Mechanism by Which Exosites Promote the Inhibi FOREIGN PATENT DOCUMENTS tion of Blood Coagulation Proteases by Heparin-activated WO WO-2010/070137 6/2010 Antithrombin” (2007) J. Boil. Chem. 282,33609-33622. WO WO-2011/008885 1/2011 Jesty et al. (1975) "The activation of coagulation factor X” J. Biol. Chem. 250(12):4497-4504. OTHER PUBLICATIONS Kubitza et al. (2005) “Safety, pharmacodynamics, and U.S. Appl. No 07/808,329 filed Dec. 16, 1991, Wolf. pharmacokinetics of BAY 59-7939—an oral, direct factor Xa inhibi Agnelli et al. (2007) "A phase II study of the oral factor Xa inhibitor tor—after multiple dosing in healthy male subjects' Eur, J. Clin. LY517717 for the prevention of venous thromboembolism after hip or knee replacement” J. Thromb. Haemost. 5(4):746-753. Pharmacol. 61:873-880. Ansell et al. (2004) “The Pharmacology and Management of the Larson et al. (1998) "Structure/Function analysis of recombinant Vitamin K Antagonists: The Seventh ACCP Conference on variants of human factor Xa. Factor Xa incorporation into Antithrombotic and Thrombolytic Therapy” Chest 126:204-233. Prothrombinase on the thrombin-activated platelet surface is not Bajajetal. (1982) "Decarboxylation of?-carboxyglutamic acid resi mimicked by synthetic phospholipid vesicles' Biochem. 37:5029 dues in human prothrombin” J. Biol. Chem. 257(7):3726-3731. 5038. Betz et al. (1999) “Inhibition of factor Xa by a peptidyl-a- Lauritzen et al. 2005 "Recombinant human FVlla reduces heparin ketothiazole involves two steps. Evidence for a stabilizing and low molecular weight heparin (LMWH)-induced in rats' Blood conformational change” Biochem. 38(44): 14582-14591. 106:607A-608A: Abstract No. 2149. Bijsterveld et al. (2002) "Ability of recombinant factor Vilato reverse Levi et al. (2004) “Recombinant factor VIIa as an antidote for the anticoagulant effect of the pentasaccharide fondaparinux in anticoagulant treatment” Seminars in Hematology 41(1):(Supp. 1) healthy volunteers' Circulation 106:2550-2554. 65-69. Bijsterveld etal. (2002) "Neutralization of the anticoagulant effect of Leytus et al. (1986) “Gene for human factor X: A blood coagulation fondaparinux by recombinant activated factor VII in healthy male factor shoes gene organization is essentially identical with that of volunteers' European Heart Journal 23:725: Abstract No. P3701. factor IX and Protein C” Biochemistry 25:5098-5102. Brandstetter, Hetal. (1996)"X-ray Structure of Active Site-inhibited Lin PH. et al. (1997) “Reversible Acylation of Factor Xa as a Poten clotting Factor Xa” J. Bio. Chem. 271 (47): 29988-29992. tial therapy for Hemophilia” Thrombosis Res. 88(4):365-372. Camire (2002) "Protothrombinase assembly and S1 site occupation Lisman et al. (2003) "Recombinant factor VIIa reverses the in vitro restore the catalytic site of FXa impaired by mutation at the sodium and ex vivo anticoagulant and profibinolytic effects of fondaparinux s binding site” Journal of Biological Chemistry 277(40):37863-37870. Journal of Thrombosis and Haemostasis 1:2368-22373. Camire et al. (2000)"Enhance?-carboxylation of recombinant factor Lu, G. et al., “Recombinant Antidote for Reversal of Anticoagulation X using a chimeric construct containing the prothrombin propeptide' by Factor Xa. Inhibitors”, BLOOD, vol. 112, No. 11, p. 362 (2008). Biochem. 39:14322-14329. Luettgen et al. (2006) In vitro evaluation of apixoban, a novel, potent, Chang et al. (2001) "Low molecular weight protamine as nontoxic selective and orally bioavailable factor Xa inhibitor Blood 108(11): heparin/low molecular weight heparin antidote (III): Preliminary in abstract 4130 Retrieved online from http://abstracts. vivo evaluation of efficacy and toxicity using a canine model” AAPS hematologylibrary.org/cgi/content/abstract/108/11/ Pharmsci. 3(2):1-8: Article 19. 4130Pmaxtoshow =&HITS=10&hits=10&RESULTFORMAT= DE 4430205 (English abstract). &fulltext-Evaluation+of+Apixaban&searchid=1 Elget al. (2001) “Effects of agents, used to treat bleeding disorders, &FIRSTINDEX=0&volume=108&issue=11 on bleeding time prolonged by a very high dose of a direct thrombin &resourcetype=HWCIT). inhibitor in anesthesized rats and rabbits' Thrombosis Research Mann et al. (1990) "Surface-Dependent reactions of the Vitamin 101:159-170. K-Dependent Enzyme Complexes” Blood 76(1):1-16. Eriksson et. al. (2005) “YM150, an oral direct factor Xa inhibitor, as Mann, Kget al. (1990) "Surface-Dependent reactions of the Vitamin prophylaxis for venous thrombeombolism in patients with elective K-Dependent Enzyme Complexes” Blood 76(1):1-16. primary hip replacement sturgery. A dose escalation study.” Blood Morita et al. (1986) “Preparation and properties of derivatives of 106(11), Abstract 1865; Retrieved online from http://abstracts. bovine factor X and Factor Xa from which the ?-Carboxyglutamic hematologylibrary.org/cgi/content/abstract/106/11/ acid containing domain has been removed' J.
Load more

Recommended publications
  • Coagulation Factors Directly Cleave SARS-Cov-2 Spike and Enhance Viral Entry
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.31.437960; this version posted April 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry. Edward R. Kastenhuber1, Javier A. Jaimes2, Jared L. Johnson1, Marisa Mercadante1, Frauke Muecksch3, Yiska Weisblum3, Yaron Bram4, Robert E. Schwartz4,5, Gary R. Whittaker2 and Lewis C. Cantley1,* Affiliations 1. Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA. 2. Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA. 3. Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA. 4. Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. 5. Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA. *Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.03.31.437960; this version posted April 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Summary Coagulopathy is recognized as a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. Other host proteases, including TMPRSS2, are recognized to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing viral entry.
    [Show full text]
  • Heparin EDTA Patent Application Publication Feb
    US 20110027771 A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0027771 A1 Deng (43) Pub. Date: Feb. 3, 2011 (54) METHODS AND COMPOSITIONS FORCELL Publication Classification STABILIZATION (51) Int. Cl. (75)75) InventorInventor: tDavid Deng,eng, Mountain rView, V1ew,ar. CA C09KCI2N 5/073IS/00 (2006.01)(2010.01) C7H 2L/04 (2006.01) Correspondence Address: CI2O 1/02 (2006.01) WILSON, SONSINI, GOODRICH & ROSATI GOIN 33/48 (2006.01) 650 PAGE MILL ROAD CI2O I/68 (2006.01) PALO ALTO, CA 94304-1050 (US) CI2M I/24 (2006.01) rsr rr (52) U.S. Cl. ............ 435/2; 435/374; 252/397:536/23.1; (73) Assignee: Arts Health, Inc., San Carlos, 435/29: 436/63; 436/94; 435/6: 435/307.1 (21) Appl. No.: 12/847,876 (57) ABSTRACT Fragile cells have value for use in diagnosing many types of (22) Filed: Jul. 30, 2010 conditions. There is a need for compositions that stabilize fragile cells. The stabilization compositions of the provided Related U.S. Application Data inventionallow for the stabilization, enrichment, and analysis (60) Provisional application No. 61/230,638, filed on Jul. of fragile cells, including fetal cells, circulating tumor cells, 31, 2009. and stem cells. 14 w Heparin EDTA Patent Application Publication Feb. 3, 2011 Sheet 1 of 17 US 2011/0027771 A1 FIG. 1 Heparin EDTA Patent Application Publication Feb. 3, 2011 Sheet 2 of 17 US 2011/0027771 A1 FIG. 2 Cell Equivalent/10 ml blood P=0.282 (n=11) 1 hour 6 hours No Composition C Composition C Patent Application Publication Feb.
    [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]
  • (12) United States Patent (10) Patent No.: US 8,835,407 B2 Mosher Et Al
    US008835407B2 (12) United States Patent (10) Patent No.: US 8,835,407 B2 Mosher et al. (45) Date of Patent: *Sep. 16, 2014 (54) PHARMACEUTICAL COMPOSITIONS 5,324,718 A 6/1994 Loftsson COMPRISING PRASUGREL AND 5,376,645 A 12, 1994 Stella et al. CYCLODEXTRIN DERVATIVES AND 3:3: A .22 seal. METHODS OF MAKING AND USING THE 5576,328 A 1 1/1996 Herbert et al. SAME 5,632,275 A 5/1997 Browne et al. 5,874,418 A 2f1999 Stella et al. (75) Inventors: Gerold L. Mosher, Kansas City, MO 357. A 1 A.28 t al (US), Stephen G. Michatha, Waltham, 6,071,514. A 6/2000 GrinnellCai Ca. et al. MA (US); Daniel J. Cushing, 6,133,248. A 10/2000 Stella Phoenixville, PA (US) 6,153,746 A 1 1/2000 Shah et al. 6,204.256 B1 3/2001 Shalaby et al. (73) Assignee: CyDex Pharmaceuticals, Inc., La Jolla, 6.248,729 B1 6/2001 Coniglio et al. CA (US) 6,294,192 B1 9/2001 Patel et al. 6,383,471 B1 5, 2002 Chen et al. (*) Notice: Subject to any disclaimer, the term of this 6,451,3396,429,210 B2B1 9/20028, 2002 B styletet alal. patent is extended or adjusted under 35 6,504,030 B1 1/2003 Bousquet et al. U.S.C. 154(b) by 0 days. 6,509.348 B1 1/2003 Ogletree 6,569.463 B2 5/2003 Patel et al. This patent is Subject to a terminal dis- 6,573.381 B1 6/2003 Bousquet et al.
    [Show full text]
  • Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation Current Clinical Evidence and Future Developments
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 56, No. 25, 2010 © 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2010.09.017 STATE-OF-THE-ART PAPER Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation Current Clinical Evidence and Future Developments Stephan H. Schirmer, MD, PHD,* Magnus Baumhäkel, MD,* Hans-Ruprecht Neuberger, MD, PHD,* Stefan H. Hohnloser, MD,† Isabelle C. van Gelder, MD, PHD,‡§ Gregory Y. H. Lip, MD,ʈ Michael Böhm, MD* Homburg/Saar and Frankfurt, Germany; Groningen and Utrecht, the Netherlands; and Birmingham, England, United Kingdom Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using aspirin or vitamin K antagonists (VKA) is currently prescribed for prevention for ischemic stroke in patients with AF. A narrow therapeutic range and the need of regular monitoring of its antico- agulatory effect impair effectiveness and safety of VKA, causing a need for alternative anticoagulant drugs. Re- cently developed anticoagulants include direct thrombin antagonists such as dabigatran or factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, and edoxaban. Currently, data from a phase III clinical trial are avail- able for dabigatran only, which show the direct thrombin antagonist to be at least noninferior in efficacy to VKA for the prevention of stroke and systemic embolism in patients with AF. This review focuses on current advances in the development of directly acting oral anticoagulant drugs and their potential to replace the VKA class of drugs in patients with AF.
    [Show full text]
  • (10) Patent No.: US 9034822 B2
    USOO9034822B2 (12) United States Patent (10) Patent No.: US 9,034,822 B2 Van Ryn et al. (45) Date of Patent: *May 19, 2015 (54) METHODS OF USING ANTIBODIES DURING (56) References Cited ANTCOAGULANT THERAPY OF DABGATRAN AND/OR RELATED U.S. PATENT DOCUMENTS COMPOUNDS 6,440,417 B1 8/2002 Thibaudeau et al. 6,469,039 B1 10/2002 Hauel et al. (71) Applicants: Joanne Van Ryn, Warthausen (DE); 8,486,398 B2* 7/2013 Van Ryn et al. ........... 424,133.1 2004/OO97547 A1 5, 2004 Taveras et al. John Edward Park, Warthausen (DE): 2011/0206656 A1 8/2011 Van Ryn et al. Norbert Hauel, Schemmerhofen (DE): 2012fOO27780 A1 2/2012 Van Rynet al. Ulrich Kunz, Biberach an der Riss (DE); Tobias Litzenburger, Mittelbiberach FOREIGN PATENT DOCUMENTS (DE); Keith Canada, Southbury, CT CA 2 277 949 8, 1998 (US); Sanjaya Singh, Sandy Hook, CT CA 2277949 A1 * 8, 1998 (US); Alisa Waterman, Weston, CT WO WO-9837O75 8, 1998 (US) WO WO-2011 O23.653 3, 2011 WO WO-2011 089183 T 2011 (72) Inventors: Joanne Van Ryn, Warthausen (DE); John Edward Park, Warthausen (DE): OTHER PUBLICATIONS Norbert Hauel, Schemmerhofen (DE): Schlaeppi et al., Eur J Biochem. Mar. 10, 1990:188(2):463-70.* Ulrich Kunz, Biberach an der Riss (DE); Herion et al., Blood. May 1985:65(5):1201-7.* Tobias Litzenburger, Mittelbiberach Colburn, W. A., “Specific antibodies and fab fragments to alter the (DE); Keith Canada, Southbury, CT pharmacokinetics and reverse the pharmacologic/toxicologic effects (US); Sanjaya Singh, Sandy Hook, CT of drugs.” Drug Metabolism Reviews, 1980, vol.
    [Show full text]
  • What Is/Are the Best Oral Anticoagulant/S for Primary Prevention, Treatment
    What is/are the best oral anticoagulant/s for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation? Protocol Background and Rationale Importance of the health problem to the NHS Thrombosis followed by embolization to distant organs occurs in both arterial and venous circulation and these conditions can be treated or prevented by oral anticoagulant treatment. Venous thromboembolic disease Venous thromboembolic disease (VTE) (UK annual incidence 183 per 100,000) encompasses clot formation in deep veins of legs or pelvis (deep vein thrombosis (DVT; annual incidence 123 per 100,000), and their displacement to pulmonary arteries (pulmonary embolism (PE; annual incidence 60 per 100,000). Important risk factors for VTE include major surgery, particularly lower limb orthopaedic surgery and surgery for cancer, as well as hospitalization in acutely ill general medical patients (approximate incidence 15%). VTE costs the NHS £640 million and is responsible for approximately 30,000 (10%) deaths each year in hospitals in England. DVT is also an important cause of long-term morbidity, being a major risk factor for chronic leg ulceration. PE may also lead to long- term morbidity due to pulmonary hypertension. There is an approximately 30% risk of recurrence of VTE within 8 years. The risk of VTE during hospitalisation for surgical or medical treatment can be reduced by low molecular weight heparin (LMWH), fonaparinux or unfractionated heparin.1 Warfarin is the most frequently prescribed anticoagulant for the initial treatment and for the long-term secondary prevention of VTE in those deemed to be at high risk of recurrence.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Head Injury Partial Update
    Head Injury partial update Literature search strategies Appendix A: Literature search strategies Contents Introduction Search methodology Section A.1 Population search strategies A.1.1 Head injury A.1.2 General trauma A.1.3 Spinal injury Section A.2 Study filter terms A.2.1 Excluded studies designs and publication types A.2.2 Observational studies A.2.3 Patient views A.2.4 Qualitative studies A.2.5 Predictive rules A.2.6 Triage A.2.7 Economic studies A.2.8 Quality of life Section A.3 Searches for specific questions with intervention A.3.1 Direct transport to hospital A.3.2 Imaging A.3.3 Anticoagulants A.3.4 Biomarkers A.3.5 Cervical spine A.3.6 Patient information Section A.4 Economic searches A.4.1 Economic reviews A.4.2 Quality of Life in anticoagulation patients and cervical spine patients Section A.5 References Search strategies used for the Head Injury guideline are outlined below and were run in accordance with the methodology in the NICE Guidelines Manual 2009.{National Institute for Health and Clinical Excellence, 2009 NICE2009 /id} All searches were run up to 31 May 2013 unless otherwise stated. Any studies added to the databases after this date were not included unless specifically stated in the text. Where possible searches were limited to retrieve material published in English. Searches to update questions covered in the previous NICE guidance on Head injury (reference) were limited to retrieve material published since the date of the original searches for that guideline. The date limitations for each search are indicated with the searches below.
    [Show full text]
  • Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-Cov-2 Into
    Homology modeling of TMPRSS2 yields candidate drugs that may inhibit entry of SARS-CoV-2 into human cells. 1 2 3 4 4 1 Stefano Rensi ,​ Allison Keys ,​ Yu-Chen Lo ,​ Alexander Derry ,​ Greg McInnes ,​ Tianyun Liu ,​ Russ ​ ​ ​ ​ ​ ​ Altman1,2,4,5 ​ 1 D​ epartment of Bioengineering, Stanford University, Stanford, CA, USA 2 D​ epartment of Computer Science, Stanford University, CA, USA 3 P​ ediatrics, Bass Center for Childhood Cancer, Stanford School of Medicine, Stanford, CA, USA. 4 D​ epartment of Biomedical Data Science, Stanford University, Stanford, CA, USA 5 D​ epartments of Genetics, Stanford University, Stanford, CA, USA Correspondence to: [email protected], [email protected] ​ ​ ​ ABSTRACT The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects.
    [Show full text]
  • Evidence-Based College of Chest Physicians New Antithrombotic Drugs
    New Antithrombotic Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Jeffrey I. Weitz, Jack Hirsh and Meyer M. Samama Chest 2008;133;234-256 DOI 10.1378/chest.08-0673 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.org/cgi/content/abstract/133/6_suppl/234S CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 2007 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder (http://www.chestjournal.org/misc/reprints.shtml). ISSN: 0012-3692. Downloaded from chestjournal.org on June 25, 2008 Copyright © 2008 by American College of Chest Physicians Supplement ANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES New Antithrombotic Drugs* American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition)* Jeffrey I. Weitz, MD, FCCP; Jack Hirsh, MD, FCCP; and Meyer M. Samama, MD This chapter focuses on new antithrombotic drugs that are in phase II or III clinical testing. Development of these new agents was prompted by limitations of existing antiplatelet, anticoag- ulant, or fibrinolytic drugs. Addressing these unmet needs, this chapter (1) outlines the rationale for development of new antithrombotic agents, (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs, and (3) provides clinical perspectives on the opportunities and challenges faced by these novel agents.
    [Show full text]
  • Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs
    Molecules 2016, 21, 75; doi:10.3390/molecules21010075 S1 of S110 Supplementary Materials: Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs Fei Mao 1, Wei Ni 1, Xiang Xu 1, Hui Wang 1, Jing Wang 1, Min Ji 1 and Jian Li * Table S1. Common names, indications, CAS Registry Numbers and molecular formulas of 6891 approved drugs. Common Name Indication CAS Number Oral Molecular Formula Abacavir Antiviral 136470-78-5 Y C14H18N6O Abafungin Antifungal 129639-79-8 C21H22N4OS Abamectin Component B1a Anthelminithic 65195-55-3 C48H72O14 Abamectin Component B1b Anthelminithic 65195-56-4 C47H70O14 Abanoquil Adrenergic 90402-40-7 C22H25N3O4 Abaperidone Antipsychotic 183849-43-6 C25H25FN2O5 Abecarnil Anxiolytic 111841-85-1 Y C24H24N2O4 Abiraterone Antineoplastic 154229-19-3 Y C24H31NO Abitesartan Antihypertensive 137882-98-5 C26H31N5O3 Ablukast Bronchodilator 96566-25-5 C28H34O8 Abunidazole Antifungal 91017-58-2 C15H19N3O4 Acadesine Cardiotonic 2627-69-2 Y C9H14N4O5 Acamprosate Alcohol Deterrant 77337-76-9 Y C5H11NO4S Acaprazine Nootropic 55485-20-6 Y C15H21Cl2N3O Acarbose Antidiabetic 56180-94-0 Y C25H43NO18 Acebrochol Steroid 514-50-1 C29H48Br2O2 Acebutolol Antihypertensive 37517-30-9 Y C18H28N2O4 Acecainide Antiarrhythmic 32795-44-1 Y C15H23N3O2 Acecarbromal Sedative 77-66-7 Y C9H15BrN2O3 Aceclidine Cholinergic 827-61-2 C9H15NO2 Aceclofenac Antiinflammatory 89796-99-6 Y C16H13Cl2NO4 Acedapsone Antibiotic 77-46-3 C16H16N2O4S Acediasulfone Sodium Antibiotic 80-03-5 C14H14N2O4S Acedoben Nootropic 556-08-1 C9H9NO3 Acefluranol Steroid
    [Show full text]