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DOI: 10.1055/s-0038-1653834
Antithrombotic Activity in vivo of SDZ 217-766, a Low-molecular Weight Thrombin Inhibitor in Comparison to Heparin
Publikationsverlauf
Received 23. Juni 1994
Accepted after resubmission 14. Dezember 1994
Publikationsdatum:
09. Juli 2018 (online)
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Summary
Antithrombotic potency of SDZ 217-766, a potent inhibitor of thrombin and other trypsin-like serine proteases, was studied in comparison with heparin in rat models of thrombin induced lung platelet accumulation, of thrombosis in arterio-venous shunt, and of venous thrombosis induced by tissue factor. Thrombin-induced platelet accumulation in the lung was inhibited dose-dependently by SDZ 217-766 following intravenous (i.v.) administration of 0.03 mg/kg to 0.3 mg/kg as well as by intraduodenal (i.d.) administration of 3 mg/kg and 10 mg/kg. Comparable inhibitory effects were observed with heparin at 30 IU/kg and 100 IU/kg. In the rat arterio-venous shunt, following i.v. administration of SDZ 217-766, thrombus formation was inhibited by 40% at 0.1 mg/kg, by 60% at 0.3 mg/kg and was abolished at 1.0 mg/kg whilst APTT was prolonged 1.1 fold over the control value at 0.1 mg/kg and 2.7 fold at 1.0 mg/kg. Similar inhibitory effects were observed following i.d. administration of 10 and 30 mg/kg with only marginal (1.2 to 1.8 fold) APTT elevation. In the same model, heparin administered either i.v., 30-300 IU/kg, or subcutaneously, 100 and 300 IU/kg, inhibited thrombus formation dose dependently but in contrast to SDZ 217-766, the inhibitory effect was paralleled by 5-to >10 fold APTT elevation over baseline. In the venous thrombosis model, SDZ 217-766 infused at 10 μg/kg/min and 20 pg/kg/min, reduced thrombus formation by 35% and 70%, respectively. In comparison, thrombus formation was decreased by 22% when heparin was infused at 1 IU/kg/min, and abolished at 3 IU/kg/min. At the doses tested, APTT was prolonged much less with SDZ 217-766 (1.6 to 2.7 fold over baseline) than with heparin (2.8 to >10 fold over baseline).
The ability of SDZ 217-766, compared with heparin, to prevent thrombus formation with a minimum degree of anticoagulation together with its potential oral bioavailability make SDZ 217-766 an interesting candidate for the use in thrombosis prevention. For the use in thrombosis treatment, however, the restricted selectivity profile of SDZ 217-766 for thrombin over other serine proteases may limit its therapeutic potential.
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References
- 1 Berliner LJ. Thrombin: Structure and Function. Plenum; New York, USA: 1992
- 2 Cannon CP. The pharmacology of anticoagulation. In: Anticoagulation,hemostasis,and blood preservation in cardiovascular surgery. Pifarre R. ed Hanley & Belfus, Inc; Philadelphia, USA: 1993. pp 1-21
- 3 Weitz JI, Huboda M, Massel D, Maraganore J, Hirsch 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: 385-389
- 4 Agnelli G, Renga C, Weitz JI, Nenci GG, Hirsh J. Sustained antithrombotic activity of hirudin after its plasma clearance: Comparison with heparin. Blood 1992; 80: 960-965
- 5 Tapparelli C, Metternich R, Ehrhardt C, Cook NS. Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile. Trends Pharmacol Sei 1993; 14: 366-376
- 6 Tapparelli C, Powling M, Gfeller P, Metternich R. Novel boron containing thrombin inhibitor SDZ 217-766: in vitro and in vivo evaluation. Thromb Haemost 1991; 65: 774
- 7 Tapparelli C, Metternich R. Antithrombotic effects of Boc-D-TMSal-Pro- boroarginine-C10Hl6in arterial and venous thrombosis rat models. Thromb Haemostas 1993; 69: 668
- 8 Metternich R. European Patent Application 0471651, 19.02.1992
- 9 Tapparelli C, Metternich R, Ehrhardt C, Zurini M, Claeson G, Scully MF, Stone SR. In vitro and in vivo characterization of a neutral boron-containing thrombin inhibitor. J Biol Chem 1993; 268: 4734-4741
- 10 Morrison JF, Walsh CT. Adv Enzymol Relat Areas Mol Biol 1988; 61: 201-301
- 11 Ardlie NG, Packham MA, Mustard JF. Adenosine diphosphate-induced platelet aggregation in suspension of washed rabbit platelets. Br J Pharmacol 1970; 19: 7-17
- 12 Smith JR, White AM. Fibrin, red cell and platelet interactions in an experimental model of thrombosis. Br J Pharmacol 1982; 77: 29-38
- 13 Peters RF, Lees CM, Mitchell KA, Tweed MF, Talbot MD, Wallis RB. The characterisation of thrombus development in an improved model of arterio-venous shunt thrombosis in the rat and the effects of recombinant desulphatohirudin (CGP 39393),heparin,and iloprost. Thromb Haemost 1991; 65: 268-274
- 14 Freund M, Cazenave J, Courtney M, Degryse E, Roitsch C, Bemat A, Delebassee D, Defreyn G, Maffrand J. Inhibition by recombinant hirudins of experimental venous thrombosis and disseminated intravascular coagulation induced by tissue factor in rats. Thromb Haemostas 1990; 63: 187-192
- 15 Wessler S, Reimer SM, Sheps MC. Biologic assay of a thrombosis-inducing activity in human serum. J Appl Physiol 1959; 14: 943-946
- 16 Reyers I, Mussoni L, Donati MB, De Gaetano G. Failure of aspirin at different doses to modify experimental thrombosis in rats. Thromb Res 1980; 18: 669-674
- 17 Kettner C, Mersinger L, Knabb R. The selective inhibition of thrombin by peptides of boroarginine. J Biol Chem 1990; 265: 18289-18289
- 18 Kaiser B, Hauptmann J. Pharmacology of synthetic thrombin inhibitors of. the tripeptide type Cardiovasc Drug Rev 1992; 10: 71-87
- 19 Hussain M, Knabb R, Aungst BJ, Kettner C. Anticoagulant activity of a peptide boronic acid thrombin inhibitor by various routes of administration in rats. Peptides 1991; 12: 1153-1154
- 20 Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 1-23
- 21 Fox I, Dawson A, Loynds P, Eisner J, Findlen K, Levin E, Hanson D, Mant T, Wagner J, Maraganore J. Anticoagulant activity of hirulog,a direct thrombin inhibitor,in humans. Thromb Haemost 1993; 69: 157-163
- 22 Schechter I, Berger A. On the size of the active site in proteases.I.Papain. Biochem Biophys Res Comm 1967; 27: 157-162
- 23 Bode W, Turk D, Stürzebecher J. Eur J Biochem 1990; 193: 175-178
- 24 Gilboa N, Villanueva GB, Fenton JW. Inhibition of fibrinolytic enzymes by thrombin inhibitors. Enzyme 1988; 40: 144-148
- 25 Shuman RT, Rothenberger RB, Campbell CS, Smith GF, Gifford-Moore DS, Gesellchen PD. Highly selective tripeptide thrombin inhibitors. J Med Chem 1993; 36: 314-319
- 26 Chiu AT, Mousa SA, Pease LJ, Roscoe WA, Bozarth JM, Reilly TM, Smith RD, Timmermans P. Inhibition of the thrombin-platelet reactions by DuP 714. Biochem Biophys Res Comm 1991; 179: 1500-1508
- 27 Stone SR, Hofsteenge J. Kinetics of the inhibition of thrombin by hirudin. Biochemistry 1986; 25: 4622-4628
- 28 Glusa E. Hirudin and Platelets. Sem Thromb Hemost 1991; 17: 122-125
- 29 Stone SR, Tapparelli C. Thrombin inhibitors as antithrombotic agents: The importance of rapid inhibition. J Enzyme Inhibition 1995; 9: 3-15
- 30 Jackman MP, Parry MA A, Hofsteenge J, Stone SR. Intrinsic fluorescence changes and rapid kinetics of the reactions of thrombin with hirudin. J Biol Chem 1992; 267: 15375-15383
- 31 Callas D, Bacher P, Iqbal O, Hoppensteadt D, Fareed J. Fibrinolytic compromise by simultaneous administration of site-directed inhibitors of thrombin. Thromb Res 1994; 74: 193-205
- 32 Tapparelli C, Metternich R, Menninger K, Fozard J. Pharmacological in vitro and in vivo profile of a novel thrombin inhibitor, SDZ MTH 958,a potent new antithrombotic agent. Can J Physiol Pharmacol 1994; 72: 87
- 33 Heras M, Chesebro JH, Webster MW I, Mruk JS, Grill DE, Penny WJ, Bowie EJ W, Badimon L, Fuster V. Hirudin, heparin, and placebo during deep arterial injury in the pig. Circulation 1990; 82: 1476-1478
- 34 Marbet GA, Verstraete M, Kienast J, Graf P, Hoet B, Tsakiris DA, SillingEngelhardt G, Close P. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers. J Cardiovasc Pharmacol 1993; 22: 364-372
- 35 Verstraete M, Nurmohamed M, Kienast J, Siebeck M, Silling-Engelhardt G, Bueller H, Hoet B, Bichler J, Close P. Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. J Am Coll Cardiol 1993; 22: 1080-1088
- 36 Cannon CP, McCabe CH, Henry TD, Schweiger MJ, Gibson RS, Mueller HS, Becker RC, Kleinman NS, Haugland JM, Anderson JL, Sharaf BL, Edwards SJ, Rogers WJ, Williams DO, Braunwald E. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue- type plasminogen activator and aspirin for acute myocardial infarction: Results on the thrombolysis in myocardial infarction (TIMI) 5 trial. J Am Coll Cardiol 1994; 23: 993-103
- 37 Antman EA. For the TIMI 9 A investigators. Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A trial Circulation 1994; 90: 1624-1630
- 38 GUSTO IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90: 1631-1637
- 39 Neuhaus KL, Von Essen R, Tebbe U, Jessel A, Heinrichs H, Maeurer W, Doering W, Harmjanz D, Koetter V, Kalhammer E, Simon H, Horacek T. Safety observations from the pilot phase of the randomized r-Hirudin for improvement of thrombolysis (HIT-III) study. Circulation 1994; 90: 1638-1642