Pharmacology of Recombinant Hirudin

ABSTRACT

Hirudin is the anticoagulative product of the salivary glands of the medical leech Hirudo medicinalis. It is characterized by a direct, bifunctional inhibition mechanism and a high, exclusive specificity and a strong ability to bind to thrombin (tight binding). Further characteristics are the organic-chemical structure of hirudin (peptide), which allows only parenteral administration; the missing metabolism in the organism; and the exclusive glomerular filtration of hirudin in kidneys as the effective elimination mechanism. Recombinant hirudin (r-hirudin) is a product of genetic engineering that is identical to the hirudin found in nature and has the same biochemical and pharmacological characteristics as natural hirudin.

KEYWORDS

r-hirudin - pharmacology - pharmacokinetics - ECT

REFERENCES

• 1 De la Llosa P, Tertrin C, Justisz M. Composition en acides aminés de l'hirudin. Identification du résidu N-terminal.  Bulletin de la Societé de Chimie Biologique . 1963;  45 69-74
• 2 De la Llosa P, Tertrin C, Justisz M. L'enchainemant C-terminal de l'hirudin.  Biochim Biophys Acta . 1964;  93 40-44
• 3 Dodt J, Müller H P, Seemüller U, Chang J Y. The complete amino acid sequence of hirudin, a thrombin specific inhibitor.  FEBS Lett . 1984;  162 180-183
• 4 Johnson P, Sze P, Winant R, Payne P W, Lazar J B. Biochemistry and genetic engineering of hirudin.  Semin Thromb Hemost . 1989;  15 302-315
• 5 Bagdy D, Barabas E, Graf L, Peterson T E, Magnusson S. Hirudin. In: Lorand L, ed. Methods in Enzymology: Proteolytic Enzymes, Vol 19. New York: Academic Press 1976: 924-932
• 6 Scharf M, Engels J, Tripier D. Primary structures of new ``iso-hirudins''.  FEBS Lett . 1989;  225 105-110
• 7 Walsmann P, Markwardt F. Biochemische und pharmakologische Aspekte des Thrombininhibitors Hirudin.  Pharmazie . 1981;  26 653-660
• 8 Rydel T J, Ravichandran K G, Tulinsky A. The structure of a complex of recombinant hirudin and human α-thrombin.  Science . 1990;  249 277-280
• 9 Stone S, Hofsteenge J. The kinetics of the inhibition of thrombin by hirudin.  Biochemistry . 1986;  25 4622-4628
• 10 Nowak G, Markwardt F, Fink E. Pharmacokinetic studies with recombinant hirudin in dogs.  Folia Haematol Leipzig . 1988;  115 70-74
• 11 Markwardt F, Fink G, Kaiser B. Pharmacological survey of recombinant hirudin.  Pharmazie . 1988;  43 202-207
• 12 Markwardt F, Hauptmann J, Nowak G, Klessen C, Walsmann P. Pharmacological studies on the antithrombotic action of hirudin in experimental animals.  Thromb Haemost . 1982;  47 226-229
• 13 Markwardt F, Kaiser B, Nowak G. Studies on antithrombotic effects of recombinant hirudin.  Thromb Res . 1989;  54 377-388
• 14 Lindhoff-Last E, Willeke A, Mosch G. Hirudin treatment in a breastfeeding woman.  Lancet . 2000;  355 467-468
• 15 Markwardt F, Nowak G, Stürzebecher J, Vogel G. Clinico-pharmacological studies with recombinant hirudin.  Thromb Res . 1988;  52 393-400
• 16 Markwardt F, Nowak G, Stürzebecher J. Pharmacokinetics and anticoagulant effect of hirudin in man.  Thromb Haemost . 1984;  52 160-163
• 17 Nowak G, Bucha E, Gööck T, Prasa D, Thieler H. Pharmakokinetik von Hirudin bei gestörter Nierenfunktion.  Hämostaseologie . 1991;  11 152-157
• 18 Nowak G, Bucha E, Gööck T, Thieler M, Markwardt F. Pharmacology of r-hirudin in renal impairment.  Thromb Res . 1992;  66 707-715
• 19 Bucha E, Markwardt F, Nowak G. Hirudin in haemodialysis.  Thromb Res . 1990;  60 445-455
• 20 Nowak G, Bucha E, Brauns I, Czerwinski R. Anticoagulation with r-hirudin in regular haemodialysis with heparin-induced thrombocytopenia (HIT II).  Wien Klin Wochenschr . 1997;  109 354-358
• 21 Markwardt F, Nowak G, Bucha E. Hirudin as anticoagulant in experimental hemodialysis.  Haemostasis . 1991;  21(Suppl 1) 149-155
• 22 Stringer K A, Lindenfield J. Hirudins: antithrombin anticoagulants.  Ann Pharmacother . 1992;  26 1535-1540
• 23 Bucha E, Nowak G, Markwardt F. Prevention of experimental coronary thrombosis by hirudin.  Folia Haematol . 1988;  115 52-58
• 24 Heras M, Chesebro J H, Webster M WI. Hirudin, heparin or placebo during deep arterial injury in the pig: the in vivo role of thrombin in platelet-mediated thrombosis.  Circulation . 1990;  82 1476-1484
• 25 Markwardt F. Past, present and future of hirudin.  Haemostasis . 1991;  21(Suppl 1) 11-26
• 26 Pötzsch B, Iversen S, Riess F C. Recombinant hirudin as an anticoagulant in open-heart surgery: a case report (Abst).  Ann Hematol . 1993;  68(Suppl 2) A46
• 27 Pötzsch B, Madlener K, Seelig C. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass-assessment of the whole blood ecarin clotting time.  Thromb Haemost . 1997;  77 920-925
• 28 Breddin H K, Radziwon P, Eschenfelder V, Müller-Peltzer H, Esslinger H U. PEG-hirudin and acetylsalicylic acid show a strong interaction on bleeding time (Abst).  Ann Haematol . 1996;  72 53
• 29 Meyer B H, Luus H G, Müller F O, Badenhorst P N, Röthig H-J. The pharmacology of recombinant hirudin, a new anticoagulant.  S Afr Med J . 1990;  78 268-270
• 30 Weitz J I, Hudoba M, Massel D, Maragonore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.  J Clin Invest . 1990;  86 385-391
• 31 Antman E M, for the TIMI 9B investigators. Hirudin in acute myocardial infarction. Thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial.  Circulation . 1996;  94 911-921
• 32 Canon C P, McCabe C H, Henry T D, for the TIMI-5 investigators. Hirudin reduces reocclusion compared to heparin following thrombolysis in acute myocardial infarction (Abst).  J Am Coll Cardiol . 1993;  21 136a
• 33 Moia M, Schiele F, Walker M. Treatment of acute deep vein thrombosis (DVT) by subcutaneous r-hirudin (HBW 023): a multicenter study (Abst).  Thromb Haemost . 1995;  73 1456
• 34 Parent F, Bridey F, Dreyfus M. Treatment of severe venous thrombo-embolism with intravenous hirudin (HBW-023). An open pilot study.  Thromb Haemost . 1993;  70 386-388
• 35 Rupprecht H J, Terres W, Özbek C. Recombinant hirudin (HBW 023) prevents troponin release after coronary angioplasty in patients with unstable angina.  J Am Coll Cardiol . 1995;  26 1637-1642
• 36 Hermann J PR, Kutryk M JV, Serruys P W. Clinical trials of direct thrombin inhibitors during invasive procedures.  Thromb Haemost . 1997;  78 367-376
• 37 The Global Use of Strategies To Open occluded coronary arteries (GUSTO) IIb investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996 335: 775-782
• 38 Walenga J M, Pifarré R. Hirudin as an anticoagulant in cardiopulmonary bypass. In: Pifarré R, ed. New Anticoagulants for the Cardiovascular Patient Philadelphia, PA: Hanley & Belfus 1997: 175-186
• 39 Zeymer U, von Essen R, Tebbe U. Frequency of ``optimal anticoagulation'' for acute myocardial infarction after thrombolysis with front-load recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW 023).  Am J Cardiol . 1995;  76 997-1001
• 40 Zoldhelyi P, Webster M WI, Fuster V. Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters.  Circulation . 1993;  88 2015-2022
• 41 Greinacher A. Lepirudin for the treatment of heparin-induced thrombocytopenia: a prospective study (Abst).  Blood . 1998;  92 1490
• 42 Schiele F, Vuillemenot A, Kramarz P. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.  Am J Hematol . 1995;  50 20-25
• 43 Schmidt O H, Lang W. Heparin-induced thrombocytopenia with thromboembolic arterial occlusion treated with recombinant hirudin.  N Engl J Med . 1997;  337 1389
• 44 Agnelli G, Snaglia F. Recombinant hirudin in the prevention of venous thromboembolism in patients undergoing elective hip surgery.  Semin Thromb Hemost . 1997;  22 143-148
• 45 Eriksson B I, Ekman S, Kälebo P. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393.  Lancet . 1996;  347 635-639
• 46 Eriksson B, Kälebo P, Ekman S. Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement.  Thromb Haemost . 1994;  72 227-231
• 47 Buchwald A B, Sandrock D, Unterberg C A. Platelet and fibrin deposition on coronary stents in minipigs: effects of hirudin versus heparin.  J Am Coll Cardiol . 1993;  21 249-254
• 48 Haskel E J, Prager N A, Sobel B E, Abenschein D R. Relative efficacy of antithrombin compared with antiplatelet agents in accelerating coronary thrombolysis and preventing early reocclusion.  Circulation . 1991;  83 1048-1056
• 49 Bichler J, Gemmerli R, Fritz H. Studies for revealing a possible sensitization to hirudin after repeated intravenous injections in baboons.  Thromb Res . 1991;  61 39-51
• 50 Eichler P, Friesen H J, Lubenow N, Jaeger B, Greinacher A. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance.  Blood . 2000;  96 2373-2378
• 51 Brüggener E, Walsmann P, Markwardt F. Neutralization of hirudin anticoagulant action by DIP-thrombin.  Pharmazie . 1989;  44 648-649
• 52 Tripodi A, Chantarangkul V, Arbini A A, Moia M, Manucci P M. Effects of hirudin on activated partial thromboplastin time determined with ten different reagents.  Thromb Haemost . 1993;  70 286-288
• 53 Spinner S, Stöffler G, Fink E. Quantitative enzyme-linked immunosorbent assay (ELISA) for hirudin.  J Immunol Methods . 1988;  87 79-83
• 54 Nowak G. Monitoring of the action of antithrombin agents by ecarin clotting time. In: Pifarré R, ed. New Anticoagulants for the Cardiovascular Patient Philadelphia, PA: Hanley & Belfus 1997: 530-550
• 55 Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids.  Semin Thromb Hemost . 1996;  22 197-202
• 56 Nowak G, Bucha E, Hoffmann J. Verfahren zur Bestimmung von Hirudin und synthetischen Thrombininhibitoren. DPA 4203980.0 Deutsches Patentamt 1992