Comparison of in vitro and in vivo properties of rhirudin (HBW 023) and a synthetic analogous peptide.
Recombinant hirudin and a shortened synthetic analogue, with the amino acid sequence of D-Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-Glu- Glu-Ile-Pro-Glu-Glu-Tyr-Leu, are specific thrombin inhibitors which in a concentration-dependent manner inhibit thrombus formation as well as clot propagation both in vitro and in vivo. In comparison to the analogue, lower molar concentrations of rhirudin affected doubling of aPTT and TT as well as inhibition of thrombin amidolytic activity or thrombin-induced platelet aggregation in vitro. In the rat wire coil-induced thrombosis model, a 50% thromboprotective effect may be brought about with doses of 0.043 mumol/kg of rhirudin and 1.43 mumol/kg of the synthetic peptide. However, doubling of bleeding times is caused, on average, by dosages of between 0.143 and 0.43 mumol/kg rhirudin or approximately 0.143 mumol/kg of the analogue. Treatment groups included animals revealing significant prolongation of bleeding times as well as nonresponders. Despite the 10-fold longer impact on aPTT after application of rhirudin, the extent of mean bleeding time prolongation is identical to that of the analogue.
Römisch
J
J
Research Laboratories of Behringwerke AG, Marburg/Lahn, FRG.
Diehl
K H
KH
Hoffmann
D
D
Krahl-Mateblowski
U
U
Reers
M
M
Stüber
W
W
Pâques
E P
EP
D000595:Amino Acid Sequence; D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013927:Thrombosis / Q000517:prevention & control*
D006629:Hirudins; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; C074619:bivalirudin; C083544:lepirudin