Download PDF
Hamostaseologie 1991; 11(03): 158-162
DOI: 10.1055/s-0038-1660297
Originalarbeiten
Schattauer GmbH

Toxikologische Aspekte bei der Anwendung von Hirudin

H. P. Klöcking
1   Institut für Pharmakologie und Toxikologie der Medizinischen Akademie Erfurt
› Author Affiliations
Further Information

Publication History

Publication Date:
26 June 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Natives Hirudin und rekombinantes Desulfato-Hirudin wurden bei akuten und subchronischen Toxizitätsstudien in den bisher angewandten Dosisbereichen toleriert. Blutungen als Nebenwirkung traten bei Anwendung antithrombotisch wirksamer Dosierungen nicht auf. Hirudin erwies sich als schwaches Immunogen, so daß bei wiederholter Anwendung therapeutischer Dosen Immunreaktionen nicht zu erwarten sind. Hirudin ließ sich unter In-vivo-Bedingungen antagonisieren bzw. neutralisieren. Die Throm- bogenität von Prothrombinkomplexkonzentraten ließ sich durch Zusatz von Hirudin abschwächen bzw. aufheben. Durch bakterielle Toxine verursachte Hämostasestörungen konnten durch prophylaktische Gabe von Hirudin verhindert werden.

 

  • LITERATUR

  • 1 Bergmann C, Dodt J, Köhler S, Fink E, Gassen HG. Chemical synthesis and expression of a gene coding for hirudin, the thrombin specific inhibitor from the leech Hirudo medicinalis. Biol Chem 1986; 367: 731-40.
    PubMedGoogle Scholar
  • 2 Bichler J, Fichtl B, Siebeck M, Fritz H. Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration. Arzneimittelforschung 1988; 38: 704-10.
    PubMedGoogle Scholar
  • 3 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.
    PubMedGoogle Scholar
  • 4 Bichler J, Siebeck M, Maschler R, Pelzer H, Fritz H. Determination of thrombin-hirudin complex in plasma with an enzyme-linked immunosorbent assay. Blood Coagulation and Fibrinolysis 1991; 02: 129-33.
    CrossrefPubMedGoogle Scholar
  • 5 Briiggener E, Walsmann P, Markwardt F. Neutralization of hirudin anticoagulant action by DIP-thrombin. Pharmazie 1989; 44: 648-9.
    PubMedGoogle Scholar
  • 6 Courtney M, Loison G, Lemoine Y, Riehl Bellon N, Degryse E, Brown SW, Cazenave J-P, Defreyn G, Delebassee D, Bernat A, Maffrand JP, Roitsch C. Production and evaluation of recombinant hirudin. Semin Thromb Hemost 1989; 15: 288-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Courtney M, Loison G, Riehl-Bellon N, Tolstoshev E, Degryse E, Marquet M, Brown S, Lemoine Y, Roitsch C. The production and evaluation of recombinant hirudin. Thromb Res 1987; Suppl VII: 30 (Abstract)
    PubMedGoogle Scholar
  • 8 Dodt J, Schmitz T, Schäfer T, Bergmann C. Expression, secretion and processing of hirudin in E. coli using the alkaline phosphatase signal sequence. FEBS Lett 1986; 202: 373-7.
    PubMedGoogle Scholar
  • 9 Doutremepuich C, Deharo E, Guyot M, Lalanne MC, Walenga J, Fareed J. Antithrombotic activity of recombinant hirudin in the rat: A comparative study with heparin. Thromb Res 1989; 54: 435-45.
    CrossrefPubMedGoogle Scholar
  • 10 Fareed J, Walenga JM. Do we need to neutralize hirudin’s anticoagulant effects to minimize bleeding?. Fed Proc. 1989 03. A328..
    PubMedGoogle Scholar
  • 11 Freund M, Cazenave J-P, Courtney M, Degryse E, Roitsch C, Bernat A, Delebassee D, Defreyn G, Maffrand J-P. Inhibition by recombinant hirudins of experimental venous thrombosis and disseminated intra- vascular coagulation induced by tissue-fac- tor in rats. Thromb Haemost 1990; 63: 187-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Fortkamp E, Rieger M, Heisterberg-Moutses G, Schweitzer S, Sommer R. Cloning and expression in Escherichia coli of a synthetic DNA for hirudin, the blood coagulation inhibitor in the leech. DNA 1986; 05: 511-7.
    CrossrefPubMedGoogle Scholar
  • 13 Glusa E, Urban U. Studies on platelet functions in hirudin plasma. Folia Haematol 1988; 115: 88-93.
    PubMedGoogle Scholar
  • 14 Glusa E, Wolfram U. The contractile response of vascular smooth muscle to thrombin and its inhibition by thrombin inhibitors. Folia Haematol 1988; 115: 94-100.
    PubMedGoogle Scholar
  • 15 Harvey RP, Degryse E, Stefani L, Schamber F, Cazenave J-P, Cortney M, Tolstoshev P, Lecocq JP. Cloning and expression of a c-DNA coding for the anticoagulant hirudin from the blood-sucking leech, Hirudo medicinalis. Proc Natl Acad Sei 1986; 83: 1084-8.
    CrossrefPubMedGoogle Scholar
  • 16 Hoffmann H, Siebeck M, Spannagl M, Weis M, Geiger R, Jochum M, Fritz H. Effect of recombinant hirudin, a specific inhibitor of thrombin, on endotoxin-induced intravascu- lar coagulation and acute lung injury in pigs. Am Rev Respir Dis 1990; 142: 782-8.
    CrossrefPubMedGoogle Scholar
  • 17 Hubbard T, Oliver T, Bacher P, Walenga JM, Galal H. Use of recombinant hirudin to increase the patency rate of microanastomosis in rabbit model. Blood Coagulation and Fibrinolysis 1991; 02: 101-3.
    CrossrefPubMedGoogle Scholar
  • 18 Ibbotson SH, Grant PJ, Kerry R, Findlay VS, Prentice CMR. The influence of infusions of l-Desamino-8-D-Arginine Vasopressin (DDAVP) in vivo on the anticoagulant effect of recombinant hirudin (CGP 39393) in vitro. Thromb Haemost 1991; 65: 64-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Kaiser B, Markwardt F. Antithrombotic and hemorrhagic effects of synthetic and naturally occurring thrombin inhibitors. Thromb Res 1986; 43: 613-20.
    CrossrefPubMedGoogle Scholar
  • 20 Kaiser B, Markwardt F. Experimental studies on antithrombotic effect of the naturally occurring thrombin inhibitor hirudin. Thromb Res 1987; Suppl VII: 41.
    PubMedGoogle Scholar
  • 21 Kaiser B, Markwardt F. Antithrombotic and haemorrhagic effects of the naturally occurring thrombin inhibitor hirudin. Folia Haematol 1988; 115: 41-6.
    PubMedGoogle Scholar
  • 22 Klöcking H-P, Dornheim G, Schulze-Rie-wald H. Influence of inhibitors on the thrombogenicity and toxicity of prothrombin complex concentrates. Arch Toxicol (Suppl) 1987; 11: 313-5.
    PubMedGoogle Scholar
  • 23 Klöcking H-P, Güttner J, Fink F. Toxicolo- gical studies with recombinant hirudin. Folia Haematol 1988; 115: 75-82.
    PubMedGoogle Scholar
  • 24 Klöcking H-P, Güttner J, Fink E. Toxicolo- gical studies with recombinant hirudin. Thromb Res 1987; Suppl VII: 39 (Abstract)
    PubMedGoogle Scholar
  • 25 Klöcking H-P, Güttner J, Fink E, Markwardt F. Studies in toxicity of recombinant hirudin. Blut 1990; 60: 129 (Abstract)
    PubMedGoogle Scholar
  • 26 Klöcking H-P, Güttner J, Fink E, Markwardt F. Subchronic toxicity studies with recombinant hirudin. Z Versuchstierkd. (in press)
    PubMedGoogle Scholar
  • 27 Klöcking H-P, Markwardt F. Influence of recombinant hirudin on the thrombogenicity of prothrombin complex concentrates. Pharmazie 1989; 44: 341-2.
    PubMedGoogle Scholar
  • 28 Klöcking H-P, Schulze-Riewald H, Markwardt F. Inhibitory effect of hirudin on thrombosis induced by prothrombin complex concentrates. Folia Haematol 1988; 115: 106-9.
    PubMedGoogle Scholar
  • 29 Kloss T, Lorenz W, Meyer U, Mittmann U, Neugebauer E, Saggau W. Gerinnungshemmung durch selektive Thrombinblockade mit Hirudin. Langenbecks Arch Chir 1978; Suppl: 143-8.
    PubMedGoogle Scholar
  • 30 Lindhout T, Blezer R, Hemker HC. The anticoagulant mechanism of action of recombinant hirudin (CGP - 39393) in plasma. Thromb Haemost 1990; 64: 464-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Maffrand JP, Bernat A, Delebassee D, Courtney M, Roitsch C, Defreyn G. Antithrombotic and haemorrhagic effects of rHV2-Lys47 hirudin compared with standard heparin in rabbits. Thromb Haemost 1989; 62: 1395 (Abstract)
    PubMedGoogle Scholar
  • 32 Markwardt F. Die Isolierung und chemische Charakterisierung des Hirudins. Hoppe- Seyler’s Z pyhsiol Chem 1957; 308: 147-56.
    PubMedGoogle Scholar
  • 33 Markwardt F. Versuche zur pharmakologischen Charakterisierung des Hirudins. Nau- nyn-Schmiedebergs Arch Pharmacol 1958; 234: 516-29.
    PubMedGoogle Scholar
  • 34 Markwardt F. Der blutgerinnungshemmende Wirkstoff des medizinischen Blutegels. Blut 1958; 04: 161-70.
    CrossrefPubMedGoogle Scholar
  • 35 Markwardt F. Die antagonistische Wirkung des Hirudins gegen Thrombin in vivo. Naturwissenschaften 1956; 43: 111.
    PubMedGoogle Scholar
  • 36 Markwardt F. Pharmacology of hirudin: One hundred years after the first report of the anticoagulant agent in medicinal leeches. Biomed Biochim Acta 1985; 44: 1007-13.
    PubMedGoogle Scholar
  • 37 Markwardt F. Pharmacological approaches to thrombin regulation. Ann NY Acad Sei 1986; 485: 204-14.
    CrossrefPubMedGoogle Scholar
  • 38 Markwardt F. Development of hirudin as an antithrombotic agent. Semin Thromb He- most 1989; 15: 269-82.
    PubMedGoogle Scholar
  • 39 Markwardt F. Hirudin als potentielles Anti- koagulans zur Prävention der Rethrombo- sierung nach intrakoronarer Lyse und Angioplastie. Hämostaseologie 1989; 09: 204-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Markwardt F, Fink E, Kaiser B, Klöcking H-P, Nowak G, Richter M, Stürzebecher J. Pharmacological survey of recombinant hirudin. Pharmazie 1988; 43: 202-7.
    PubMedGoogle Scholar
  • 41 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: 226-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Markwardt F, Kaiser B, Nowak G. Studies on antithrombotic effects of recombinant hirudin. Thromb Res 1989; 54: 377-88.
    CrossrefPubMedGoogle Scholar
  • 43 Markwardt F, Nowak G. Stürzebecher J, Grießbach U, Walsmann P, Vogel G. Pharmacokinetics and anticoagulant effect of hirudin in man. Thromb Haemost 1984; 52: 160-3.
    PubMedGoogle Scholar
  • 44 Markwardt F, Nowak G. Stürzebecher J, Vogel G. Clinico-pharmacological studies with recombinant hirudin. Thromb Res 1988; 52: 393-400.
    PubMedGoogle Scholar
  • 45 Markwardt F, Schäfer G, Töpfer H, Walsmann P. Die Isolierung des Hirudins aus medizinischen Blutegeln. Pharmazie 1967; 22: 239-41.
    PubMedGoogle Scholar
  • 46 Nowak G, Markwardt F. Influence of hirudin on endotoxin-induced disseminated in- travascular coagulation (DIC) in weaned pigs. Exp Pathol 1980; 18: 438-43.
    PubMedGoogle Scholar
  • 47 Nowak G, Markwart F, Fink E. Pharmacokinetic studies with recombinant hirudin in dogs. Folia Hematol 1988; 115: 70-4.
    PubMedGoogle Scholar
  • 48 Seemüller U, Dodt J, Fink E, Fritz H. Proteinase inhibitor of the leech Hirudo medicinalis (hirudins, bdellins, eglins). In: Barrett AJ. (ed) Proteinase inhibitors. Amsterdam; Elsevier: 1986: 337-59.
    Google Scholar
  • 49 Siebeck M, Hoffmann H, Weipert J, Spannagl M, Weis M, Bichler J. Hirudin verhindert die intravaskuläre Gerinnung im Endotoxinschock des Schweins. In: Schriefers KH et al. (Hrsg) Chirurgisches Forum 88 für experimentelle und klinische Forschung. Berlin; Heidelberg: Springer: 1988: 297-300.
    Google Scholar
  • 50 Spinner S, Stöffler G, Fink E. Quantitative enzyme-linked immunosorbent assay (ELISA for hirudin). J Immunol Meth 1986; 87: 79-83.
    CrossrefPubMedGoogle Scholar
  • 51 Walenga JM, Pifarre R, Hoppensteadt DA, Fareed J. Development of recombinant hirudin as a therapeutic anticoagulant and antithrombotic agent. Some objective considerations. Semin Thromb Hemost 1989; 15: 316-33.
    PubMedGoogle Scholar
  • 52 Walsmann P. Biochemische und pharmakologische Aspekte des Thrombininhibitors Hirudin. Pharmazie 1981; 36: 653-60.
    PubMedGoogle Scholar
  • 53 Walsmann P. Untersuchung zur Affinitätschromatographie an trägerfixiertem Thrombin. Pharmazie 1981; 36: 860-1.
    PubMedGoogle Scholar