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Thromb Haemost 1984; 51(02): 248-253
DOI: 10.1055/s-0038-1661069
Original Article
Schattauer GmbH Stuttgart

Acyl-Enzymes as Thrombolytic Agents in Dog Models of Venous Thrombosis and Pulmonary Embolism

R J Dupe
The Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey, U. K.
,
P D English
The Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey, U. K.
,
R A G Smith
The Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey, U. K.
,
J Green
The Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey, U. K.
› Author Affiliations
Further Information

Publication History

Received 08 August 1983

Accepted 20 February 1984

Publication Date:
19 July 2018 (online)

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Summary

A quantitative model of venous thrombosis in the beagle dog is described. The model was adapted to permit ageing of isolated experimental clots in vivo. A model of acute pulmonary embolism in this species is also described. In the venous thrombosis model, infusion of streptokinase (SK) or SK-activated human plasmin gave significant lysis but bolus doses of SK. plasmin complex were ineffective. Active site anisoylated derivatives of SK. plasminogen complex, SK-activated plasmin and activator-free plasmin were all active when given as bolus doses in both models. At lytic doses, the acyl-enzymes caused fewer side-effects attributable to plasminaemia than the corresponding unmodified enzymes.

Keywords

Thrombolysis - Venous thrombosis - Pulmonary embolism - Dogs - Acylated enzymes
 

  • References

  • 1 Smith RA G, Dupe RJ, English PD, Green J. Fibrinolysis with acyl-enzymes: a new approach to thrombolytic therapy. Nature 1981; 290: 505-508
    CrossrefPubMedGoogle Scholar
  • 2 Dupe RJ, English PD, Smith RA G, Green J. The evaluation of plasmin and streptokinase activator complexes in a new rabbit model of venous thrombosis. Thromb Haemostas 1981; 46: 528-534
    PubMedGoogle Scholar
  • 3 Smith RA G, Dupe RJ, English PD, Green J. Acyl-enzymes as thrombolytic agents in a rabbit model of venous thrombosis. Thromb Haemostas 1982; 47: 269-274
    PubMedGoogle Scholar
  • 4 Dupe RJ, English PD, Smith RA G, Green J. The activity of acylated streptokinase. Plasminogen complex (BRL 26921) in dog models of thrombosis In Progress in Fibrinolysis. Davidson JF, Bachmann F, Bouvier CA, Kruithof EK O. (Eds) Churchill Livingstone; 1983. VI p 240-244
    Google Scholar
  • 5 Duckert F. Urokinase. In Fibrinolytics and Antifibrinolytics. Markwardt F. (Ed) Springer-Verlag; 1978. p 222-229
    Google Scholar
  • 6 Nowak A, Gurewich V. Thrombolysis with streptokinase in rabbits - dose-response, fibrin-clot specificity and laboratory evaluation of fibrinolytic effect. Thrombos Diathes Haemorrh 1974; 31: 265-272
    PubMedGoogle Scholar
  • 7 English PD, Smith RA G, Dupe RJ, Green J, Hibbs MJ. The thrombolytic activity of streptokinase in the rabbit. Thromb Haemostas 1981; 46: 535-537
    PubMedGoogle Scholar
  • 8 Klöcking H-P. Pharmacology of streptokinase. In Fibrinolytics and Antifibrinolytics. Markwardt F. (Ed) Springer-Verlag; 1978. p 151-177
    Google Scholar
  • 9 Henry RL. Methods for the experimental study of intravascular thrombus formation. In Thrombosis and Bleeding Disorders. Bang UL, Beller FK, Deutsch E, Mammen EF. (Eds) Georg Thieme Verlag; 1971. p 498-513
    Google Scholar
  • 10 Wessler S. Experimental intravascular thrombosis induced by serum fractions containing serum prothrombin conversion accelerator (SPCA). Fed Proc 1953; 12: 152-153
    PubMedGoogle Scholar
  • 11 Ambrus JL, Back N, Mihalyi E, Ambrus CM. Quantitative method for the in vivo testing of fibrinolytic agents: effect of intravenous trypsin on radioactivity thrombi and emboli. Circulation Res 1956; 4: 430-439
    CrossrefPubMedGoogle Scholar
  • 12 Sherry S, Titchener A, Gottesman L, Wasserman P, Troll W. The enzymatic dissolution of experimental arterial thrombi in the dog by trypsin, chymotrypsin and plasminogen activators. J Clin Invest 1954; 33: 1303-1313
    CrossrefPubMedGoogle Scholar
  • 13 Tsapogas MJ, Flute PT. Experimental thrombolysis with streptokinase and urokinase. Br Med Bull 1964; 20: 223-227
    CrossrefPubMedGoogle Scholar
  • 14 Hume M. Lysis of the experimental radioactive pulmonary embolus induced by streptokinase and SK-activated plasmin. Thrombos Diathes Haemorrh 1964; 11: 99-107
    PubMedGoogle Scholar
  • 15 Hume M. Urokinase evaluated with the experimental radioactive embolus. Thrombos Diathes Haemorrh 1967; 17: 405-411
    PubMedGoogle Scholar
  • 16 Korninger C, Matsuo O, Suy R, Stassen JM, Collen D. Thrombolysis with human extrinsic (tissue-type) plasminogen activator in dogs with femoral vein thrombosis. J celin Invest 1982; 69: 573-580
    PubMedGoogle Scholar
  • 17 Friberger P, Knös M, Gustavsson S, Aurell L, Claeson G. Methods for the determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978; 7: 138-145
    PubMedGoogle Scholar
  • 18 Gottlob R, El Nashef B, Donas P, Piza F, Kolb R. Studies on thrombolysis with streptokinase. IV. Immunofluorescent investigations on the fibrin pattern and the content of plasminogen and of plasma-plasmin inhibitors in clots and thrombi of various age. Thrombos Diathes Haemorrh 1973; 29: 393-407
    PubMedGoogle Scholar
  • 19 Matsuo O, Rijken DC, Collen D. Comparison of the relative fibrinogenolytic, fibrinolytic and thrombolytic properties of tissue plasminogen activator and urokinase in vitro. Thromb Haemostas 1981; 45: 225-229
    PubMedGoogle Scholar