Antithrombotic Activity of a Novel C-Terminal Hirudin Analog in Experimental Animals

R J Broersma; L W Kutcher; E F Heminger; J L Krstenansky; F N Marshall

doi:10.1055/s-0038-1648156

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1991; 65(04): 377-381
DOI: 10.1055/s-0038-1648156

Original Article

Schattauer GmbH Stuttgart

Antithrombotic Activity of a Novel C-Terminal Hirudin Analog in Experimental Animals

R J Broersma

Merrell Dow Research Institute, Indianapolis, IN, USA

,

L W Kutcher

Merrell Dow Research Institute, Indianapolis, IN, USA

,

E F Heminger

Merrell Dow Research Institute, Indianapolis, IN, USA

,

J L Krstenansky

^*Merrell Dow Research Institute, Cincinnati, OH, USA

,

F N Marshall

Merrell Dow Research Institute, Indianapolis, IN, USA

› Author Affiliations

Abstract

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Summary

A synthetic hirudinsgs_55-65 C-terminal fragment analog was evaluated for anticoagulant activity and in models of experimental thrombosis in mice and rats. Intravenous injection caused doserelated inhibition of thrombin and anticoagulation in rat blood samples, protection from thromboembolism in mice and inhibition of stasis-induced venous thrombosis in rats. Antithrombotic effectiveness corresponded with anticoagulant activity. Anephric animals exhibited longer duration of activity than normal animals suggesting the kidney as a major route of elimination.

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References

References
1 Hauptmann J, Kaiser B, Markwardt R, Nowak G. Anticoagulant and antithrombotic action of novel specific inhibitors of thrombin. Thromb Haemostas 1980; 43: 118-123
2 Kaiser B, Markwardt F. Experimental studies on the antithrombotic action of a highly effective synthetic thrombin inhibitor. Thromb Haemostas 1986; 55: 194-196
3 Markwardt I, Nowak G, Hoffman J. Comparative studies on thrombin inhibitors in experimental microthrombosis. Thromb Haemostas 1983; 49: 235-237
4 Stone SR, Hofsteenge J. Kinetics of the inhibition of thrombin by hirudin. Biochemistry 1986; 25: 4622-4628
5 Markwardt R, Hauptman J, Nowak G, Klessen Ch, Walsmann p. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemostas 1982; 47: 226-229
6 Krstenansky JL, Mao SJT. Antithrombin properties of C-terminus of hirudin using synthetic unsulfated N^th-acetyl-hirudinls os. FEBS Lett 1987; 211: 10-16
7 Krstenansky JL, Mao SJT. Comparison of hirudin and hirudin PA Cterminal fragments and related analogs as antithrombin agents. Thromb Res 1988; 52: 137-141
8 Krstenansky JL, Broersma RI, owen J, payne MH, yates MT, Mao SJT. Development of MDL 28,050, a small stable anticoagulant based on a functional domain of the leech antithrombin, hirudin. Thromb Haemostas 1990; 63: 208-214
9 Dodt J, Muller H-P, Seemuller y, Chang J-y. The complete amino acid sequence of hirudin, a thrombin specific inhibitor. FEBS Lett 1984; 165: 180-184
10 Wessler S, Reimer SM, Sheps MC. Biologic assay of a thrombosisinducing activity in human serum. J Appl physiol 1959; 14: 943-946
11 Nowak G, Markwardt E. Pharmacokinetic studies with hirudin. Thromb Res 1987; Suppl VII 45-36
12 Henschen A, Markwardt R, Walsmann P. Identification by HPLC analysis of the unaltered forms of hirudin and desulfated hirudin after kidney passage. Thromb Res 1987; Suppl VII 45-37