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A recombinant hirudin (IK-HIR02) in healthy volunteers. I. Effects on coagulation parameters and bleeding time.

Abstract
The pharmacodynamic effects of different intravenous and subcutaneous doses of a recombinant hirudin (r-hirudin; IK-HIR02) on clotting parameters and bleeding time were investigated in 24 healthy volunteers in a bicenter study. Single intravenous bolus injections of 0.1, 0.2 and 0.3 mg/ kg IK-HIR02 caused a prolongation of thrombin time (TT) and aPTT in a dose-dependent manner and led to an increase in hirudin plasma levels > 6 micrograms/ml. The plasma half-life of IK-HIR02 was calculated as 1.3 h. A continuous infusion of 0.03 mg/kg/h of IK-HIR02 for 4 h significantly prolonged TT and aPTT. At the end of the hirudin infusion, a mean plasma level of 0.19 +/- 0.13 microgram/ml was measured. Single subcutaneous doses of 0.1, 0.25 and 0.5 mg/kg markedly prolonged the coagulation tests. The highest increase in hirudin plasma levels was found 2 h after injection. At this time the aPTT was doubled after 0.5 mg/kg. After repeat subcutaneous injections of 0.3 mg/kg b.i.d., aPTT was doubled, and TT increased to about 200 s, 2 h after the injections. At this time the mean plasma level was 0.5-0.6 microgram/ml. There was no cumulative effect after multiple injections. Bleeding time was not changed after the 4-hour intravenous infusion and after repeat subcutaneous injections of 0.3 mg/kg IK-HIR02. Bleeding time was moderately but significantly prolonged after the highest single intravenous and subcutaneous hirudin doses tested. Other than very minor local bleeding in some volunteers, IK-HIR02 was well tolerated. Biochemical blood and urine parameters did not change. In conclusion, r-hirudin (IK-HIR02) obtained by a new technique was well tolerated in healthy volunteers after single intravenous and subcutaneous injections, after repeat subcutaneous doses and during continuous intravenous infusion. Measurement of aPTT and anti-IIa activity, using a chromogenic substrate test, can be used to monitor hirudin effects if doses similar to those tested here are administered.
AuthorsJ F Schenk, E Glusa, P Radziwon, A Butti, F Markwardt, H K Breddin
JournalHaemostasis (Haemostasis) 1996 May-Jun Vol. 26 Issue 3 Pg. 140-9 ISSN: 0301-0147 [Print] Switzerland
PMID8738588 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Multicenter Study)
Chemical References
  • Antithrombins
  • Hirudins
  • Recombinant Proteins
  • desirudin
Topics
  • Adult
  • Antithrombins (adverse effects, pharmacology)
  • Bleeding Time
  • Blood Coagulation (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Evaluation
  • Female
  • Hirudins (adverse effects, analogs & derivatives, pharmacology)
  • Humans
  • Infusions, Intravenous
  • Injections, Subcutaneous
  • Male
  • Recombinant Proteins (adverse effects, pharmacology)

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