Skip to main content
SpringerLink
Log in
Book cover

Antithrombotics pp 367–396Cite as

Oral Thrombin Inhibitors: Challenges and Progress

  • Chapter

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 132))

Abstract

The effective modulation of coagulation would significantly improve the treatment of cardiovascular problems secondary to imbalances in the equilibrium between hemostasis and fibrinolysis. These problems include venous and arterial thrombosis, atrial fibrillation, stroke, restenosis, and recurrent myocardial infarction. The central position of thrombin in hemostasis and thrombosis makes it a compelling target for drug discovery. The discovery and development of oral thrombin inhibitors therefore presents a notable medical opportunity for improving the treatment of these cardiovascular disorders and currently represents a major challenge for pharmaceutical researchers.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Ackermann J (1993) Guanidine derivatives compositions and use. US patent 5,260,307

    Google Scholar 

  • Ackermann J (1995a) Guanidine derivatives. US patent 5,393,760

    Google Scholar 

  • Ackermann J (1995b) Sulfonamidacarboxamides. US patent 5,405,854

    Google Scholar 

  • Agnola D, Guiomard A (1995) Anticoagulant therapy (heparins and oral vitamin K antagonists) in 1994. What’s new? Sem Hop 71:413–422

    Google Scholar 

  • Antman EM (1994) Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation 90:1624–1630

    PubMed  CAS  Google Scholar 

  • Antman EM (1996) Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 94:911–921

    PubMed  CAS  Google Scholar 

  • Bacher P, Walenga JM, Igbal O, Bajusz S, Breddin K, Fareed J (1993) The antithrombotic and anticoagulant effects of a synthetic tripeptide and recombinant hirudin in various animal models. Thromb Res 71:251–263

    PubMed  CAS  Google Scholar 

  • Bagdy D, Barabas E, Bajusz S, Szell E (1992a) In vitro inhibition of blood coagulation by tripeptide aldehydes - a retrospective screening study focused on the stable DMePhe- Pro-Arg-H.H2S04. Thromb Haemost 67:325–330

    PubMed  CAS  Google Scholar 

  • Bagdy D, Barabas E, Szabo G, Bajusz S, Szell E (1992b) In vivo anticoagulant and antiplatelet effect of D-Phe-Pro-Arg-H and D-MePhe-Pro-Arg-H. Thromb Haemost 67:357–365

    PubMed  CAS  Google Scholar 

  • Bajusz S (1992)Thromb Hemost 67:357–365

    Google Scholar 

  • Bajusz S, Szell E, Barabas E, Bagdy D (1982) Novel peptidyl-arginine aldehyde derivatives and process for the preparation thereof. US patent 4,316,889

    Google Scholar 

  • Bajusz S, Szell E, Bagdy D, Barabas E, Dioszegi M, Fittler Z et al (1987) Peptidesaldehydes, process for the preparation thereof and pharmaceutical compositions containing the same. US patent 4,703,036

    Google Scholar 

  • Bajusz S, Bagdy D, Barabas E, Feher A, Szabo G, Szell G et al (1993) New anticoagulant peptide derivatives and pharmaceutical compositions containing the same as well as a process for the preparation thereof. WO patent 9318060

    Google Scholar 

  • Bakonyi A, Kavocs L, Duong HT, Aranyi P (1994) Biochemical effect and kinetics of thrombin inhibition by GYKI-14766. Acta Physiol Hung 82:29–36

    PubMed  CAS  Google Scholar 

  • Banner DW, Hadvary P (1991) Crystallographic analysis at 3.0-C resolution of the binding to human thrombin of four active site-directed inhibitors. J Biol Chem 266:20085–20093

    PubMed  CAS  Google Scholar 

  • Banner D, Ackermann J, Gast A, Gubernator K, Hadvary P, Hilpert K et al (1993) Serine proteases: 3D structures, mechanisms of action and inhibitors. In: Testa B, Kyburz E, Fuhrer W, Giger R (eds) Perspectives in medicinal chemistry. Helvetica Chimica Acta, Basel, pp 27-43

    Google Scholar 

  • Beaufils P (1995)What do cardiologists want from anticoagulant treatments? Sem Hop 71:409–412

    Google Scholar 

  • Bendetowicz AV, Beguin S, Caplain H, Hemker HC (1994) Pharmacokinetics and pharmacodynamics of a low molecular-weight heparin (Enoxaparin) after subcutaneous injection, comparison with unfractionated heparin - a three way cross over study in human volunteers. Thromb Haemost 71:305–313

    PubMed  CAS  Google Scholar 

  • Bergmann JF, Neuhart E (1996) A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. The Enoxaparin in Medicine Study Group. Thromb Haemost 76:529–534

    CAS  Google Scholar 

  • Bern MM (1992) Considerations for using lower doses of warfarin. Hematol Oncol Clin North Am 6:1105–1114

    PubMed  CAS  Google Scholar 

  • Bernard JM, Black JR, Kokseng CU, Covey DF (1992) Warfarin sodium: practitioner beware. J Am Pediatr Med Assoc 82:345–351

    CAS  Google Scholar 

  • Berry CN, Girard D, Lochot S, Lecoffre C (1994a) Antithrombotic actions of argatroban in rat models of venous, “mixed” and arterial thrombosis, and its effects on the tail transection bleeding time. Br J Pharmacol 113:1209–1214

    PubMed  CAS  Google Scholar 

  • Berry CN, Girardot C, Lecoffre C, Lunven C (1994b) Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant hirudin. Thromb Haemost 72:381–386

    PubMed  CAS  Google Scholar 

  • Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, DeRonde H et al (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369:64–67

    PubMed  CAS  Google Scholar 

  • Beutler E, Lichtman MA, Coller BS, Kipps TJ (1995) Williams hematology, 5th edn. McGraw-Hill, New York Bone RF, Soli RM, Illig CR, Lu T, Subasinghe NL (1996) Thrombin inhibitors. WO 9640118

    Google Scholar 

  • Boneu B (1994)Low molecular weight heparin therapy: is monitoring needed? Thromb Haemost 72:330–334

    CAS  Google Scholar 

  • Bourdon P, Jablonski JA, Chao BH (1991) Structure-function relationships of Hirulog peptide interactions with thrombin. FEBS Lett 294:163–166

    PubMed  CAS  Google Scholar 

  • Bush LR (1991) Argatroban, a selective, potent thrombin inhibitor. Cardiovasc Drug Rev 9:247–263

    CAS  Google Scholar 

  • Callas DD, Fareed J (1995) Direct inhibition of protein Ca by site directed thrombin inhibitors: implications in anticoagulant and thrombolytic therapy. Thromb Res 78:457–460

    PubMed  CAS  Google Scholar 

  • Callas D, Bacher P, Igbal O, Hoppensteadt D, Fareed J (1994) Fibrinolytic compromise by simultaneous administration of site-directed inhibitors of thrombin. Thromb Res 74:193–205

    PubMed  CAS  Google Scholar 

  • Cannon CP, Maraganore JM, Loscalzo J, McAllister A, Eddings K, George D (1993) Anticoagulant effects of Hirulog, a novel thrombin inhibitor, in patients with coronary artery disease. Am J Cardiol 71:778–782

    PubMed  CAS  Google Scholar 

  • Claeson G (1994) Synthetic peptides and peptidomimetics as substrates and inhibitors of thrombin and other proteases in the blood coagulation system. Blood Coagul Fibrinolysis 5:411–436

    PubMed  CAS  Google Scholar 

  • Clarke RJ, Mayo G, FitzGerald GA, Fitzgerald DJ (1991) Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 83:1510–1518

    PubMed  CAS  Google Scholar 

  • Cole MS, Minifee PK, Wolma FJ (1988) Coumarin necrosis - a review of the literature. Surgery 103:271–277

    PubMed  CAS  Google Scholar 

  • Colman RW, Hirsh J, Marder VJ, Salzman EW (1987) Hemostasis and thrombosis: basic principles and clinical practice, 2nd edn. Lippincott, Philadelphia

    Google Scholar 

  • Crenshaw BS, Becker RC, Granger CB, Tracy RP, Lambrew CT, Ross AM (1995) Thrombin activity, but not generation, is inhibited by intravenous heparin following thrombolysis: results from the GUSTO hemostasis substudy. J Am Coll Cardiol [Spec Issue ]309A-310A

    Google Scholar 

  • Cushner F, Friedman RJ (1988) Economic impact of total hip arthroplasty. South Med J 81:1379–1381

    PubMed  CAS  Google Scholar 

  • Dahlbäck B (1995) The protein C anticoagulant system: inherited defects as basis for venous thrombosis. Thromb Res 77:1–43

    PubMed  Google Scholar 

  • Das J, Kimball SD (1995) Thrombin active site inhibitors. Bioorg Med Chem 3:999–1007

    PubMed  CAS  Google Scholar 

  • Davie EW, Fujikawa K, Kisiel W (1991) The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30:10363–10370

    PubMed  CAS  Google Scholar 

  • Disch DL, Greenberg ML, Molzberger PT, Malenka DJ, Birkmeyer JD (1994) Managing chronic atrial fibrillation: a Markov decision analysis comparing warfarin, quinidine, and low-dose amiodarone. Ann Intern Med 120:449–457

    PubMed  CAS  Google Scholar 

  • Diuguid D (1997) Oral anticoagulant therapy for venous thromboembolism. N Engl J Med 336:433–434

    PubMed  CAS  Google Scholar 

  • Eichinger S, Wolzt M, Nieszpaur-Los M, Schneider B, Lechner K, Eichter HG (1994) Effects of a low molecular weight heparin (Fragmin) and of unfractionated heparin on coagulation activation at the site of plug formation in vivo. Thromb Haemost 72:831–835

    PubMed  CAS  Google Scholar 

  • Eriksson UG, Renberg L, Vedin C, Strimfors M (1995) Pharmacokinetics of inogatran, a new low molecular weight thrombin inhibitor, in rats and dogs. Thromb Haemost 73:1318

    Google Scholar 

  • Esmon CT (1993) Molecular events that control the protein C anticoagulant pathway. Thromb Haemost 70:29–35

    PubMed  CAS  Google Scholar 

  • Falk E, Fernandez-Ortiz A (1995) Role of thrombosis in atherosclerosis and its complications. Am J Cardiol 75:5B–11B

    CAS  Google Scholar 

  • Fauno P, Suomalalen O, Rehnberg V, Hansen TB, Kronerk, Sojmakallio S et al (1994) Prophylaxis for the prevention of venous thromboembolism after total knee arthroplasty. A comparison between unfractionated and low-molecular-weight heparin. J Bone Joint Surg A 76:1814–1818

    CAS  Google Scholar 

  • Fenton JW II (1986) Thrombin. Ann Acad of Sci 485:5–15

    Google Scholar 

  • Fenton JW II (1992) Coagulation disorders I. Hematology/Oncology Clinics, vol 6, pp 1121–1129

    PubMed  Google Scholar 

  • Fenton JW II, Wittig JI, Bourdon P, Maraganore JM (1990) Thrombin-specific inhibition of a novel hirudin analog. Circulation 82:111–659

    Google Scholar 

  • Fenton JW II, Ni F, Witting JI, Brezniak DV, Andersen TT, Malik AB (1993) The rational design of thrombin-directed antithrombotics. Adv Exp Med Biol 340:1–13

    PubMed  CAS  Google Scholar 

  • Fevig JM, Kettner CA, Lee SO, Carini DJ (1994) Amido and guanidino substituted boronic acid inhibitors of trypsin-like enzymes. WO patent 9425049

    Google Scholar 

  • Fevig JM, Buriak J, Cacciola J, Alexander RS, Kettner CA, Knabb RM, Pruitt JR, Thoolen MJ, Weber PC, Wexler RR (1996) Rational design of boropeptide thrombin inhibitors with greater selectivity over complement factor I. Book of abstracts, 212th ACS National Meeting, Orlando, FL, August 25-26, 1996. MEDI-127. American Chemical Society, Washington, DC

    Google Scholar 

  • Fiore L, Deykin D (1995) Anticoagulant therapy. In: Williams hematology, 5th edn. McGraw-Hill, New York

    Google Scholar 

  • Fitzgerald DJ, FitzGerald GA (1989) Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator. Proc Natl Acad Sci USA 86:7585–7589

    PubMed  CAS  Google Scholar 

  • Fox I, Dawson A, Loynds P, Eisner J, Findlen K, Levin E (1993) Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost 69:157–163

    PubMed  CAS  Google Scholar 

  • Francis CW, Marder VJ, Evarts CM, Yaukoolbodi S (1983) Two-step warfarin therapy. Prevention of postoperative venous thrombosis without excessive bleeding. JAMA 249:374–378

    CAS  Google Scholar 

  • Freedman MD (1992) Oral anticoagulants: pharmacodynamics, clinical indications and adverse effects. J Clin Pharmacol 32:196–209

    PubMed  CAS  Google Scholar 

  • Fuji H, Kurasako N, Takebayashi T, Tanaka T, Sakano S, Kosogabe Y et al (1996) Argatroban, a selective thrombin inhibitor, for anticoagulant therapy during and following vascular surgery (in Japanese). Masui 45:1289–1292

    PubMed  CAS  Google Scholar 

  • Garabedian HD, Gold HK, Hagstrom JN, Collen D, Bovill EG (1993) Accelerated thrombin generation accompanying specific thrombin inhibition in unstable angina patients. Circulation 88:1–264

    Google Scholar 

  • Gast A, Hadvary P, Schmid G, Hilpert K, Ackermann J, Tschopp TB (1993) A novel, synthetic, competitive inhibitor of thrombin inhibits thrombin generation in plasma more potently than heparin and recombinant hirudin. Thromb Haemost 69:1298

    Google Scholar 

  • Gast A, Tschopp TB, Schmid G, Hilpert K, Ackermann J (1994) Inhibition of clotbound and free (fluid-phase thrombin) by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma. Blood Coagul Fibrinolysis 5:879–887

    PubMed  CAS  Google Scholar 

  • Ginsberg JS, Nurmohamed MT, Gent M, MacKinnon B, Sicurella J, Brill-Edwards P (1994) Use of Hirulog in the prevention of venous thrombosis after major hip or knee surgery. Circulation 90:2385–2389

    PubMed  CAS  Google Scholar 

  • Gold HK, Torres FW, Garabedian HD, Werner W, Jang IK, Khan A et al (1993) Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 21:1039–1047

    PubMed  CAS  Google Scholar 

  • Granger CB, Miller JM, Bovill EG, Gruber A, Tracy RP, Krucoff MW (1995) Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation 91:1929–1935

    PubMed  CAS  Google Scholar 

  • Grip L, Wallentin M, Dellborg P, Grande M, Halinen E, Mybre L et al (1996) Thrombin inhibition in myocardial ischaemia: low molecular weight thrombin inhibitor inogatran versus heparin for unstable angina and non-Q-wave myocardial infarction. Eur Heart J 17 [Suppl] :121

    Google Scholar 

  • Griitter MG, Priestle J, Rahuel J, Grossenbacher H, Bode W, Hofsteenge J et al (1990) Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBOJ 9:2361–2365

    Google Scholar 

  • Gustafsson D, Elg M, Lenfors S, Borjesson I, Teger-Nilsson A-C (1995) Effects of inogatran, a new low molecular weight thrombin inhibitor, on rat models of thrombosis. Thromb Haemost 73:1319

    Google Scholar 

  • Hamelink JK, Tang DB, Barr CF, Jackson MR, Reid TJ, Gomez ER et al (1995) Inhibition of platelet deposition by combined Hirulog and aspirin in a rat carotid endarterectomy model. J Vase Surg 21:492–498

    CAS  Google Scholar 

  • Harpel PC (1987) Blood proteolytic enzyme inhibitors: their role in modulating blood coagulation and fibrinolytic enzyme pathways. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds) Hemostasis and thrombosis: basic principles and clinical practice, 2nd edn. Lippincott, Philadelphia

    Google Scholar 

  • Harker L (1990) Potent antithrombotic effects of a novel hybrid antithrombin peptide in vivo. Circulation 82:603

    Google Scholar 

  • Harker LA (1991) Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 77:1006–1012

    PubMed  Google Scholar 

  • Harker LA (1994) Strategies for inhibiting the effects of thrombin. Blood Coagul Fibrinolysis 5:S47–S58

    PubMed  CAS  Google Scholar 

  • Harker LA, Hanson SR, Runge MS (1995) Thrombin hypothesis of thrombus generation and vascular lesion formation. Am J Cardiol 75:12B–17B

    PubMed  CAS  Google Scholar 

  • Harris N (1994) Schering-Plough is creating a cardiovascular alliance. Philadelphia Inquirer 12/20/94

    Google Scholar 

  • Hauptmann J, Markwardt F (1992) Pharmacologic aspects of the development of selective synthetic thrombin inhibitors as anticoagulants. Semin Thromb Hemost 18:200–217

    PubMed  CAS  Google Scholar 

  • Heras M, Chesebro JH, Webster MWI, Mruk JS, Grill DE, Penny WJ et al (1990) Hirudin, heparin, and placebo during deep arterial injury in the pig. The in vivo role of thrombin in platelet-mediated thrombosis. Circulation 82:1476–1484

    CAS  Google Scholar 

  • Hijikata-Okunomiya A, Okamoto S (1992) A strategy for a rational approach to designing synthetic selective inhibitors. Semin Thromb Hemost 18:135–149

    PubMed  CAS  Google Scholar 

  • Hilpert K, Ackermann J, Banner DW, Gast A, Gubernator K, Hadvary P et al (1994) Design and synthesis of potent and highly selective thrombin inhibitors. J Med Chem 37:3889–3901

    PubMed  CAS  Google Scholar 

  • Hirsh J (1991) Oral anticoagulant drugs. N Engl J Med 324:1865–1875

    PubMed  CAS  Google Scholar 

  • Hirsh J (1993) Low molecular weight heparin. Thromb Haemost 70:204–207

    PubMed  CAS  Google Scholar 

  • Holland AE, Linker S, Bardsley WT, Kopecky S, Litin SC, Meissner I et al (1994) Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 343:687–691

    Google Scholar 

  • Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D et al (1979) Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 301:855–858

    PubMed  CAS  Google Scholar 

  • Hyers TM, Hull RD, Weg JG (1992) Antithrombotic therapy for venous thromboembolic disease. Chest 102:408S–425S

    PubMed  CAS  Google Scholar 

  • Ikoma H, Ohtsu K, Tamao Y, Kikumoto R, Okamoto S (1982) Effect of a potent thrombin inhibitor, MCI-9038, on novel experimental arterial thrombosis (in Japanese). Ketsueki to Myakkan 13:72–77

    CAS  Google Scholar 

  • Illig CR, Soil RM, Salvino JM, Tomczvk BE, Lu T, Subasinghe NL (1996) Arylsulphonylaminobenzene derivatives and the use thereof as factor Xa inhibitors. WO patent 9640100

    Google Scholar 

  • Jackson CM (1987) Mechanisms of prothrombin activation. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds) Hemostasis and thrombosis: basic principles and clinical practice, 2nd edn. Lippincott, Philadelphia

    Google Scholar 

  • Jackson CM, Nemerson Y (1980) Blood coagulation. Annu Rev Biochem 49:765–811

    PubMed  CAS  Google Scholar 

  • Jackson CV, Growe VG, Frank JD, Wilson HC, Coffman WJ, Utterback BG et al (1992) Pharmacological assessment of the antithrombotic activity of the peptide thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766), in a canine model of coronary artery thrombosis. J Pharmacol Exp Ther 261:546–552

    CAS  Google Scholar 

  • Jackson CV, Wilson HC, Growe VG, Shuman RT, Gesellchen PD (1993) Reversible tripeptide thrombin inhibitors as adjunctive agents to coronary thrombolysis a comparison with heparin in a canine model of coronary artery thrombosis. J Cardiovasc Pharmacol 21:587–594

    PubMed  CAS  Google Scholar 

  • Jafri SM, Gheorghiade M, Goldstein S (1992) Oral anticoagulation for secondary prevention after myocardial infarction with special reference to the warfarin reinfarction study. Prog Cardiovasc Dis 34:317–322

    PubMed  CAS  Google Scholar 

  • Jang IK, Gold HK, Ziskind AA, Leinbach RC, Fallon JT, Collen D (1990) Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition. Circulation 81:219–225

    PubMed  CAS  Google Scholar 

  • Jang IK, Gold HK, Leinbach RC, Rivera AG, Fallon JT, Bunting S et al (1992) Persistent inhibition of arterial thrombosis by a 1-hour intravenous infusion of argatroban, a selective thrombin inhibitor. Coron Artery Dis 3:407–414

    Google Scholar 

  • Johnson PH (1994) Hirudin: clinical potential of a thrombin inhibitor. Annu Rev Med 45:165–177

    PubMed  CAS  Google Scholar 

  • Jones KC, Mann KG (1995) A model for the tissue factor pathway to thrombin. II.A mathematical simulation. J Biol Chem 269:23367–23373

    Google Scholar 

  • Kaiser B, Hauptmann J (1992) Pharmacology of synthetic thrombin inhibitors of the tripeptide type. Cardiovasc Drug Rev 10:71–87

    CAS  Google Scholar 

  • Kaiser B, Simon A, Markwardt F (1990) Antithrombotic effects of recombinant hirudin in experimental angioplasty and intravascular thrombolysis. Thromb Haemost 63:44–47

    PubMed  CAS  Google Scholar 

  • Kakkar VV, Boeckl O, Boneu B, Bordenave L, Brehm OA, Brucke P et al (1997) Efficacy and safety of a low-molecular-weight heparin and standard unfractionated heparin for prophylaxis of postoperative venous thromboembolism: European multicenter trial. World J Surg 21:2–8

    PubMed  CAS  Google Scholar 

  • Kalafatis M, Bertina RM, Rand MD, Mann KG (1995) Characterization of the molecular defect in factor V-R506Q.J Biol Chem 270:4053–4057

    PubMed  CAS  Google Scholar 

  • Kearon C, Hirsh J (1995) Starting prophylaxis for venous thromboembolism postoperatively. Arch Intern Med 155:366–372

    PubMed  CAS  Google Scholar 

  • Kelly A, Marzec U, Hanson S, Chao B, Maraganore J, Harker L (1990) Potent antithrombotic effects of a novel hybrid antithrombin peptide in vivo. Circulation 82:111–603

    Google Scholar 

  • Kelly AB, Marzec UM, Krupski W, Bass A, Cadroy Y, Hanson SR et al (1991) Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 77:1006–1012

    PubMed  CAS  Google Scholar 

  • Kettner CA (1991a) In vivo characterization of DuP 714, a new synthetic thrombin inhibitor. Thromb Hem 65:775

    Google Scholar 

  • Kettner CA (1991b) Thrombin inhibition with DuP 714 accelerates reperfusion and delays reocclusion in dogs. Circulation 84:11–467

    Google Scholar 

  • Kettner CA, Shenvi AB (1988) U.S. Patent 5,187,157

    Google Scholar 

  • Kettner CA, Shenvi AB (1992) U.S. Patent 5,242,904

    Google Scholar 

  • Kettner CA, Shenvi AB (1993a) Peptide boronic acid inhibitors of trypsin-like proteases. US patent 5,187,157

    Google Scholar 

  • Kettner CA, Shenvi AB (1993b) Peptide boronic acid inhibitors of trypsin-like proteases. US patent 5,242,904

    Google Scholar 

  • Kettner C, Mersinger L, Knabb R (1990) The selective inhibition of thrombin by peptides of boroarginine. J Biol Chem 265:18289–18297

    PubMed  CAS  Google Scholar 

  • Kikumoto R, Tamao Y, Ohkubo K, Tezuka T, Tonomura S, Okamoto S et al (1980a) Thrombin inhibitors. 2. Amide derivatives of Na-substituted L-arginine. J Med Chem 23:830–836

    CAS  Google Scholar 

  • Kikumoto R, Tamao Y, Ohkubo K, Tezuka T, Tonomura S, Okamoto S et al (1980b) Thrombin Inhibitors. 3. Carboxyl-containing amide derivatives of N’-substituted- 1-arginine. J Med Chem 23:1293–1299

    PubMed  CAS  Google Scholar 

  • Kikumoto R, Tamao Y, Tezuka T, Tonomura S, Hara H, Ninomiya K et al (1984) Selective inhibition of thrombin by (2R,4R)-4-methyl-l-[N2-[(3-methyl-l,2,3,4- tetrahydro-8-quinolinyl) + + + sulfonyl]-L-arginyl)]-2-piperidinecarboxylic acid. Biochemistry 23:85–90

    PubMed  CAS  Google Scholar 

  • Kimball SD (1995a) Challenges in the development of orally bioavailable thrombin active site inhibitors. Blood Coagul Fibrinolysis 6:511–519

    PubMed  CAS  Google Scholar 

  • Kimball SD (1995b) Thrombin active site inhibitors. Curr Pharm Design 1:441–468

    CAS  Google Scholar 

  • Knabb RM, Timmermans PBMWM, Kettner CA, Reilly TM (1991) In vivo characterization of DuP 714, a new synthetic thrombin inhibitor. Thromb Haemost 65:775

    Google Scholar 

  • Koopman MM, Buller HR, Tencate JW (1995) Diagnosis of recurrent deep vein thrombosis. Haemostasis 25:49–57

    PubMed  CAS  Google Scholar 

  • Lawson JH, Kalafatis M, Stram S, Mann KG (1994) A model for the tissue factor pathway to thrombin. I. An empirical study. J Biol Chem 269:23357–23366

    CAS  Google Scholar 

  • Lefkovits J, Topol EJ (1994) Direct thrombin inhibitors in cardiovascular medicine. Circulation 90:1522–1536

    PubMed  CAS  Google Scholar 

  • Lengfelder W (1995) Current status of antithrombotic therapy. Dtsch Med Wochenschr 120:105–110

    PubMed  CAS  Google Scholar 

  • Lidon RM, Theroux P, Lesperance J, Adelman B, Bonan R, Duval D et al (1994) A pilot, early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction. Circulation 89:1567–1572

    PubMed  CAS  Google Scholar 

  • Lindmarker P, Holmstrom M (1996) Use of low molecular weight heparin (dalteparin), once daily, for the treatment of deep vein thrombosis. A feasibility and health economic study in an outpatient setting. Swedish Venous Thrombosis Dalteparin Trial Group. J Int Med 240:395–401

    CAS  Google Scholar 

  • Litin SC, Gastineau DA (1995) Current concepts in anticoagulant therapy. Mayo Clin Proc 70:266–272

    PubMed  CAS  Google Scholar 

  • Lorand L, Radek JT (1992) Activation of human plasma factor XIII by thrombin. In: Berliner LJ (ed) Thrombin: structure and function. Plenum, New York, pp 257–271

    Google Scholar 

  • Lowe GDO, Greer IA, Cooke TG, Dewar EP, Evans MJ, Forbes CD et al (1992) Risk of and prophylaxis for venous thromboembolism in hospital patients. Br Med J 305:567–574

    Google Scholar 

  • Lumma WC, Freidinger RM, Brady S, Sanderson PE, Feng DM (1995) Thrombin inhibitors. WO patent 9603374

    Google Scholar 

  • Lyle TA (1994) Small-molecule inhibitors of thrombin. Perspect Drug Discov Des 1:453–460

    CAS  Google Scholar 

  • Maffrand JP (1992) Direct thrombin inhibitors. Nouv Rev Fr Hematologic 34:405–419

    CAS  Google Scholar 

  • Maraganore JM (1993a) Hirudin and hirulog: advances in antithrombotic therapy. Perspect Drug Discov Des 1:461–478

    Google Scholar 

  • Maraganore JM (1993b) Pre-clinical and clinical studies on hirulog: a potent and specific direct thrombin inhibitor. Adv Exp Med Biol 340:227–236

    PubMed  CAS  Google Scholar 

  • Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW II (1990) Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 29:7095–7101

    PubMed  CAS  Google Scholar 

  • Maraganore JM, Oshima T, Asai F, Sugitachi A (1991a) Comparison of anticoagulant and antithrombotic activities of Hirulog-1 and argatroban (MD-805). Thromb Haemost 65:651

    Google Scholar 

  • Maraganore JM, Chao BH, Weitz JI, Hirsh J (1991b) Comparison of antithrombin activities of heparin and Hirulog-1: basis for improved antithrombotic properties of direct thrombin inhibitors. Thromb Haemost 65:829

    Google Scholar 

  • Maraganore JM, Yao SK, McNatt J, Eidt J, Cui K, Buja LM et al (1991c) Hirudinbased peptides accelerate thrombolysis and delay reocclusion after treatment with recombinant tissue-type plasminogen activator. Thromb Haemost 65:1188

    Google Scholar 

  • Maraganore JM, Fenton JW, Kline T, Bourdon P, Wittig J, Jablonski J et al (1991d) Modifications in Hirulog peptides yielding improved antithrombin activities. Thromb Haemost 65:830

    Google Scholar 

  • Marki WE, Wallis RB (1990) The anticoagulant and antithrombotic properties of hirudins. Thromb Haemost 64:344–348

    PubMed  CAS  Google Scholar 

  • Markwardt F (1957) Die Isolierung und chemische Charakterisierung des Hirudins. Hoppe Seyler Z Physiol Chem 308:147–156

    PubMed  CAS  Google Scholar 

  • Maryanoff BE, Qui X, Padmanabhan KP, Tulinsky A, Almond HR Jr, Andrade- Gordon P et al (1993) Molecular basis for the inhibition of human a-thrombin by the macrocyclic peptide cyclotheonamide A. Proc Natl Acad Sci USA 90:8048–8052

    PubMed  CAS  Google Scholar 

  • McBride R et al (1994) Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 343:687–691

    Google Scholar 

  • McDonagh J (1987) Structure and function of factor XIII. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds) Hemostasis and thrombosis: basic principles and clinical practice, 2nd edn. Lippincott, Philadelphia

    Google Scholar 

  • Meade TW, Miller GJ (1995) Combined use of aspirin and warfarin in primary prevention of ischemic heart disease in men at high risk. Am J Cardiol 75:23B–26B

    PubMed  CAS  Google Scholar 

  • Mellot MJ, Connolly TM, York SJ, Bush LR (1990) Prevention of reocclusion by MCI- 9038, a thrombin inhibitor, following t-PA-induced thrombolysis in a canine model of femoral arterial thrombosis. Thromb Haemost 64:526–534

    Google Scholar 

  • Merli GJ (1993) Update. Deep vein thrombosis and pulmonary embolism prophylaxis in orthopedic surgery. Med Clin North Am 77:397–411

    PubMed  CAS  Google Scholar 

  • Mosesson MW, Siebenlist KR, Amrani DL, DiOrio JP (1989) Identification of covalently linked trimeric and tetrameric D domains in crosslinked fibrin. Proc Natl Acad Sci USA 86:1113–1117

    PubMed  CAS  Google Scholar 

  • Naski MC, Shafer JA (1991) A kinetic model for the a-thrombin catalyzed conversion of plasma levels of fibrinogen to fibrin in the presence of antithrombin III.J Biol Chem 266:13003–13010

    PubMed  CAS  Google Scholar 

  • Naski MC, Shafer JA (1993) a-Thrombin within fibrin clots: inactivation of thrombin by antithrombin-III. Thromb Res 69:453–465

    PubMed  CAS  Google Scholar 

  • Neuhaus KL, von Essen R, Tebbe U, Jessel A, Heinrichs H, Maurer W et al (1994) Safety observations: a study of the Arbeitsgemeinschaft Leitender KardiologischerKrankenhausarzte (ALKK). From the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. Circulation 90:1638–1642

    PubMed  CAS  Google Scholar 

  • Nurmohamed MT, Rosendaal FR, Buller HR, Dekker E, Hommes DW, Vandenbroucke JP et al (1992)Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 340:152–156

    PubMed  CAS  Google Scholar 

  • Okamoto S, Hijikata A, Kikumoto R, Tamao Y, Ohkubo K, Tezuka T et al (1978) N2- Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof. US patent 4,117,127

    Google Scholar 

  • Okamoto S, Kinjo K, Hijikata A, Kikumoto R, Tamao Y, Ohkubo K et al (1980) Thrombin inhibitors. 1. Ester derivatives of Na-(arylsulfonyl)-L-arginine. J Med Chem 23:827–830

    PubMed  CAS  Google Scholar 

  • Okamoto S, Hijikata A, Kikumoto R, Tamao Y, Ohkubo K, Tezuka T et al (1981) N2- arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof. US patent 4,258,192

    Google Scholar 

  • Parry MA, Maraganore JM, Stone SR (1994) Kinetic mechanism for the interaction of Hirulog with thrombin. Biochemistry 33:14807–14814

    PubMed  CAS  Google Scholar 

  • Pearson DA et al (1993) Internation Patent Application 93/15756

    Google Scholar 

  • Peters RF, Lees CM, Mitchell KA, Tweed MF, Talbot MD, Wallis RB (1991) The characterisation of thrombus development in an improved model of arteriovenous shunt thrombosis in the rat and the effects of recombinant desulphatohirudin (CGP 39393), heparin, and iloprost. Thromb Haemost 65:268–274

    PubMed  CAS  Google Scholar 

  • Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B et al (1989) Placebocontrolled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1:175–179

    CAS  Google Scholar 

  • Philippides GJ, Loscalzo J (1996) Potential advantages of direct-acting thrombin inhibitors. Coron Artery Dis 7:497–507

    PubMed  CAS  Google Scholar 

  • Pinede L, Ninet J, Boissel JP, Pasquier J (1994) Anticoagulant therapy for venous thromboembolic disease: optimal duration of oral anti vitamin K therapy. Review of the literature. Presse Med 23:1817–1820

    CAS  Google Scholar 

  • Poller L, Samama M (1994) Laboratory monitoring of oral anticoagulant therapy. Clin Lab Med 14:813–823

    PubMed  CAS  Google Scholar 

  • Poller L, McKernan A, Thomson JM, Elstein M, Hirsch PJ, Jones JB (1987) Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery. Med J Clin Res Ed 295:1309–1312

    CAS  Google Scholar 

  • Richard BM, Nolan TG, Tran HS, Mille MM, Nutt RG, Vlasuk GP (1994) Bioavailability of a novel direct thrombin inhibitor in non-human primates following oral administration. Circulation 90:1–180

    Google Scholar 

  • Rote WE, Dempsey EM, Oldeschulte GL, Ardecky RJ, Tamura SY, Nutt RF et al (1994) Evaluation of a novel orally active direct inhibitor of thrombin in animal models of thrombosis. Circulation 90:1–344

    Google Scholar 

  • Rupin A, Mennecier P, de Nanteuil G, Laubie M, Verbeuren TJ (1995) A screening procedure to evaluate the anticoagulant activity and the kinetic behaviour of direct thrombin inhibitors. Thromb Res 78:217–225

    PubMed  CAS  Google Scholar 

  • Ruterbories KJ, Hanssen BR, Lindstrom TD (1992) ISSX proceedings, 4th North American ISSX meeting, p 204

    Google Scholar 

  • Rydel TJ, Ravichandran KO, Tulinsky A, Bode W, Huber R, Roitsche C et al (1990) The structure of a complex of recombinant hirudin and human a-thrombin. Science 249:277–280

    PubMed  CAS  Google Scholar 

  • Rydel TJ, Tulinsky A, Bode W, Huber R (1991) Refined structure of the hirudinthrombin complex. J Mol Biol 221:583–601

    PubMed  CAS  Google Scholar 

  • Schulman S, Granquist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P et al (1997) The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 336:393–398

    CAS  Google Scholar 

  • Schumacher WA, Steinbacher TE, Heran CL, Seiler SM, Michel IM, Ogletree ML (1993a) Comparison of thrombin active site and exosite inhibitors and heparin in experimental models of arterial and venous thrombosis and bleeding. J Pharmacol Exp Ther 267:1237–1242

    PubMed  CAS  Google Scholar 

  • Schumacher WA, Steinbacher TE, Heran CL, Megill JR, Durham SK (1993b) Effects of antithrombotic drugs in a rat model of aspirin-insensitive arterial thrombosis. Thromb Haemost 69:509–514

    PubMed  CAS  Google Scholar 

  • Schumacher WA, Balasubramanian N, St. Laurent DR, Seiler SM (1994) Effect of a novel thrombin active-site inhibitor on arterial and venous thrombosis. Eur J Pharmacol 259:165–171

    PubMed  CAS  Google Scholar 

  • Schumacher WA, Heran CL, Steinbacher TE (1996) Low-molecular-weight heparin (fragmin) and thrombin active-site inhibitor (argatroban) compared in experimental arterial and venous thrombosis and bleeding time. J Cardiovase Pharmacol 28:19–25

    CAS  Google Scholar 

  • Scrip (1996) Novastan promising in acute MI. 2177:21

    Google Scholar 

  • Scrip (1997) Schering-Plough further extends Corvas alliance. 2199:21

    Google Scholar 

  • Scully MF (1992) The biochemistry of blood clotting: the digestion of a liquid to form a solid. Essays Biochem 27:17–36

    PubMed  CAS  Google Scholar 

  • Serlin MJ, Breckenridge AM (1983) Drug interactions with warfarin. Drugs 25:610–620

    PubMed  CAS  Google Scholar 

  • Sharma GV, Lapsley D, Vita JA, Sharma S, Coccio E, Adelman B et al (1993) Usefulness and tolerability of Hirulog, a direct thrombin-inhibitor, in unstable angina pectoris. Am J Cardiol 72:1357–1360

    PubMed  CAS  Google Scholar 

  • Shetty HG, Fennerty AG, Routledge PA (1989) Clinical pharmacokinetic considerations in the control of oral anticoagulant therapy. Clin Pharmacokinet 16:238–253

    PubMed  CAS  Google Scholar 

  • Siebenlist KR, Diorio JP, Budzynski AZ, Mosesson MW (1990) The polymerization and thrombin-binding properties of des-(Bβl-42)-fibrin. J Biol Chem 265:18650–18655

    PubMed  CAS  Google Scholar 

  • Simoons M, Lenderin KT, Scheffer M, Stoel I, de Milliano P, Remme W (1994) Efegatran, a new direct thrombin inhibitor: safety and dose response in patients with unstable angina. Circulation 90:1–231

    Google Scholar 

  • Sixma JJ, de Groot PG (1992) The ideal anti-thrombotic drug. Thromb Res 68:507–512

    PubMed  CAS  Google Scholar 

  • Smith AJ, Holt RE, Fitzpatrick JB, Palacios IF, Gold HK, Werner W et al (1996) Transient thrombotic state after abrupt discontinuation of heparin in percutaneous coronary angioplasty. Am Heart J 131:434–439

    PubMed  CAS  Google Scholar 

  • Smith P, Arnesen H, Holme I (1990) The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 323:147–152

    PubMed  CAS  Google Scholar 

  • Stone SR, Tapparelli C (1995) Thrombin inhibitors as antithrombotic agents: the importance of rapid inhibition. J Enzym Inhib 9:3–15

    PubMed  CAS  Google Scholar 

  • Stone SR, Dennis S, Wallace A, Hofsteenge J (1990) Use of protein chemistry and molecular biology to determine interaction areas between proteases and their inhibitors: the thrombin-hirudin interaction as an example. In: Festoff BW (ed) Serine proteases and their serpin inhibitors in the nervous system: regulation in development and in degenerative and malignant disease. Plenum, New York, pp 115–135

    Google Scholar 

  • Tamaki T, Aoki N (1982) Cross-linking of 2-plasmin inhibitor to fibrin catalyzed by activated fibrin-stabilizing factor. J Biol Chem 257:14767–14772

    PubMed  CAS  Google Scholar 

  • Tapparelli C, Metternich R, Ehrhardt C, Zurini M, Claeson G, Scully MF et al (1993a) In vitro and in vivo characterization of a neutral boron-containing thrombin inhibitor. J Biol Chem 268:4734–4741

    PubMed  CAS  Google Scholar 

  • Tapparelli C, Metternich R, Ehrhardt C, Cook NS (1993b) Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile. Trends Pharmacol Sci 14:366–376

    PubMed  CAS  Google Scholar 

  • Teger-Nilsson AC, Bylund R (1993) New peptide derivatives. WO patent 9311152

    Google Scholar 

  • Teger-Nilsson A, Eriksson U, Gustafsson D, Bylund R, Fager G, Meld P et al (1995) Phase I studies on Inogatran, a new selective thrombin inhibitor. J Am Coll Cardiol 117A–118A

    Google Scholar 

  • Theroux P, Waters D, Lam J, Juneau M, McCans J (1992) Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 327:141–145

    PubMed  CAS  Google Scholar 

  • Thomas D (1994) Venous thrombogenesis. Br Med Bull 50:803–812

    PubMed  CAS  Google Scholar 

  • Topol EJ (1995) Novel antithrombotic approaches to coronary artery disease. Am J Cardiol 75:27B–33B

    PubMed  CAS  Google Scholar 

  • Topol EJ (1996) A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 335:775–782

    Google Scholar 

  • Topol EJ, Bonan R, Jewitt D, Sigwart U, Kakkar VV, Rothman M et al (1993) Use of a direct antithrombin Hirulog in place of heparin during coronary angioplasty. Circulation 87:1622–1629

    PubMed  CAS  Google Scholar 

  • Tschopp TB, Ackermann J, Gast A, Hilpert K, Kirchhofer D, Roux S et al (1995) Napsagatran. Drugs Future 20:476–479

    Google Scholar 

  • Vitali J, Martin PD, Malkowski MG, Robertson WD, Lazar JB, Winant RC et al (1992) The structure of a complex of bovine a-thrombin and recombinant hirudin at 2.8 C resolution. J Biol Chem 267:17670–17678

    PubMed  CAS  Google Scholar 

  • Vlasuk GP (1994) Inhibitors of thrombosis. U.S. Patent 5,999,999

    Google Scholar 

  • Vlasuk GP, Webb TA, Pearson DA, Abelman MM (1996) Inhibitors of thrombosis. US 5492895

    Google Scholar 

  • von der Saal W, Heck R, Kucznierz R, Leinert H, Stegmeier K (1996a) Neue 4- Aminopyridazine, Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel. WO patent 9606832

    Google Scholar 

  • von der Saal W, Leinert H, Stegmeier K (1996b) Neue Phosphanoxide, Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel. WO patent 9606849

    Google Scholar 

  • Walenga JM, Fareed J, Pifarre R et al (1991) Current developments in the use of recombinant hirudin as an antithrombotic agent. Curr Opin Therap Pat 1:869

    Google Scholar 

  • Wallentin L (1996) Low molecular weight heparins: a valuable tool in the treatment of acute coronary syndromes. Eur Heart J 17:1470–1476

    PubMed  CAS  Google Scholar 

  • Weinmann EE, Salzman EW (1994) Deep-vein thrombosis. N Engl J Med 331:1630–1641

    PubMed  CAS  Google Scholar 

  • Weitz J (1994) New anticoagulant strategies. Current status and future potential. Drugs 48:485–497

    CAS  Google Scholar 

  • Weitz JI (1995) Activation of blood coagulation by plaque rupture: mechanisms and prevention. Am J Cardiol 75:18B–22B

    PubMed  CAS  Google Scholar 

  • Weitz JI, Hudoba M, Massel P, Maraganore J, Hirsh J (1990) Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 86:385–391

    PubMed  CAS  Google Scholar 

  • Wheeldon NM (1995) Atrial fibrillation and anticoagulant therapy. Eur Heart J 16:302–312

    PubMed  CAS  Google Scholar 

  • Willerson JT, Casscells W (1993) Thrombin inhibitors in unstable angina: rebound or continuation of angina after argatroban withdrawal? J Am Coll Cardiol 21:1048–1051

    PubMed  CAS  Google Scholar 

  • Wiman B, Collen D (1979) On the mechanism of the reaction between human a2- antiplasmin and plasmin. J Biol Chem 254:9291–9297

    PubMed  CAS  Google Scholar 

  • Wittig JI, Bourdon P, Brezniak DV, Maraganore JM, Fenton JW II (1992) Thrombinspecific inhibition by and slow cleavage of Hirulog-1. Biochem J 283:737–743

    Google Scholar 

  • Yasuda T, Gold HK, Yaoita H, Leinbach RC, Guerrero JL, Jang IK et al (1990) Comparative effects of aspirin, a synthetic thrombin inhibitor and a monoclonal antiplatelet glycoprotein Ilb/IIIa antibody on coronary artery reperfusion, reocclusion and bleeding with recombinant tissue-type plasminogen activator in a canine preparation. J Am Coll Cardiol 16:714–722

    PubMed  CAS  Google Scholar 

  • Zeymer U, Neuhaus KL (1995) Hirudin and excess bleeding. Implications for future use. Drug Saf 12:234–239

    CAS  Google Scholar 

  • Zoldhelyi P, Bichler J, Owen WG, Grill DE, Fuster V, Mruk JS et al (1994) Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation 90:2671–2678

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. S. D. Kimball
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Drug Development, Parke-Davis Pharmaceutical Research Division, Warner-lambert Company, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Andrew C. G. Uprichard M.D. (Vice President) (Vice President)

  2. Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA

    Kim P. Gallagher Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kimball, S.D. (1999). Oral Thrombin Inhibitors: Challenges and Progress. In: Uprichard, A.C.G., Gallagher, K.P. (eds) Antithrombotics. Handbook of Experimental Pharmacology, vol 132. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59942-2_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-59942-2_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64190-9

  • Online ISBN: 978-3-642-59942-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation