Pharmacokinetics and Anticoagulant Effect of Hirudin in Man

Markwardt, Fritz; Nowak, G; Stürzebecher, Jörg; Grießbach, Uta; Walsmann, P; Vogel, Günther

doi:10.1055/s-0038-1661163

Cited by 141 publications

(78 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PAR-1 activation can be blocked by hirudin, a highly specific noncovalent thrombin inhibitor produced by the salivary glands of the leech Hirudo medicinalis (23). One of the limiting factors for its therapeutic use is its rapid elimination from the circulation with a plasmatic half-life of about 1 hour (24). Polyethyleneglycolhirudin (PEG-hirudin), a recombinant hirudin covalently bound to two PEG-5,000 residues exhibits a significantly prolonged half-life (8-9 hour) with no loss of potency or specificity (25,26).…”

Section: Introductionmentioning

confidence: 99%

Amelioration of collagen-induced arthritis by thrombin inhibition

Marty¹,

Péclat²,

Kirdaitė³

et al. 2001

J. Clin. Invest.

108

View full text Add to dashboard Cite

The deleterious role of fibrin deposition in arthritic joints prompted us to explore the effect of the thrombin inhibition on the course of collagen-induced arthritis (CIA) in the mouse. CIA was induced in male DBA/1J mice using native chicken type II collagen. The thrombin inhibitor polyethyleneglycol-hirudin (PEG-hirudin) was given for 16 days, starting 20 days after the first immunization (preventive treatment) or at the onset of clinical signs of arthritis (curative treatment). All the mice treated with PEG-hirudin had a significantly prolonged clotting time compared with control mice. PEG-hirudin, administered in a preventive way, led to significantly reduced incidence and severity of CIA during most of the treatment period, as assessed by clinical scoring. Accordingly, histological features showed a significant diminution of synovial hyperplasia in PEG-hirudin-treated mice compared with untreated mice. There was also a significant downmodulation of the synovial proinflammatory IL-1β and IL-12p35 cytokine mRNAs in treated mice. Intra-articular fibrin, evaluated by immunohistochemistry, was significantly reduced in treated mice compared with control mice and correlated with both clinical and histological scorings. Most importantly, once arthritis was established, PEG-hirudin also showed a curative effect. In conclusion, PEG-hirudin can both prevent the onset of CIA in a dose-dependent manner and ameliorate established arthritis, suggesting that thrombin inhibition may offer a new therapeutic approach in arthritis.

show abstract

Section: Introductionmentioning

confidence: 99%

Amelioration of collagen-induced arthritis by thrombin inhibition

Marty¹,

Péclat²,

Kirdaitė³

et al. 2001

J. Clin. Invest.

108

View full text Add to dashboard Cite

show abstract

“…Experimental phar macological studies have shown that it is a highly active anticoagulant [1][2][3][4]. Recombi nant technology has made hirudins avail able.…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic Effects of Three Thrombin Inhibitors in a Rat Model of Laser-Induced Thrombosis

Krupiński

Breddin²,

Markwardt³

et al. 1989

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

The antithrombotic effects of three thrombin inhibitors (hirudin, NAPAP and argidipine) were investigated in an experimental thrombosis model using laser lesions of rat mesenteric venules. Furthermore, their in vitro anticoagulant activity (partial thromboplastin time, thrombin time, Heptest, inhibition of factor Xa and factor Xa) in human platelet poor plasma (PPP) and their in vitro and ex vivo activities were studied in rat plasma. All three thrombin inhibitors showed significant and dose-dependent antithrombotic effects after intravenous injection, if venules were damaged, which lasted for more than 4 but less than 8 h. The anticoagulant effect observed in vitro did not differ much between human and rat PPP. The two synthetic thrombin inhibitors NAPAP and argidipine were about as effective as hirudin in vitro; however, the ex vivo effect after intravenous injection of hirudin in rats was more pronounced than that observed with the two synthetic thrombin inhibitors. The antithrombotic effect of all three thrombin inhibitors in the laser model lasted much longer than the anticoagulant activity. This fact needs further investigations in the future.

show abstract

“…Hirudin acts differently, directly and highly specifically to bind thrombin without inhibition of other proteases.10-14 Because hirudin reacts stoichiometrically in a 1:1 ratio with thrombin with a very low dissociation constant, the amount of drug needed to prevent thrombosis should be an indirect measure of the amount of thrombin generated. [10][11][12] The aims of the current study, in a deep arterial injury model, were to test whether 1) a conventional dosage of heparin will reduce platelet deposition and the incidence of mural thrombosis compared with placebo, 2) hirudin will produce a dose-dependent reduction in quantitative platelet and fibrinogen deposition and the incidence of mural thrombosis; the lowest effective activated partial thromboplastin time (APTT) prolongation for the prevention of arterial thrombosis can be established, 3) the APTT during hirudin therapy will correlate inversely with the platelet and fibrinogen deposition, and the incidence of mural thrombosis; the APTT and the thrombin time will provide a direct measure of hirudin blood levels; and 4) doses of heparin and hirudin sufficient to inhibit platelet aggregation to thrombin and prolong the bleeding time will reduce platelet deposition and mural thrombosis compared with placebo. were randomly allocated to one of five treatment groups: placebo (0.9% saline), sodium heparin at 50 units/kg (from porcine intestine that contained 1,000 USP units/ml) or recombinant desulfato hirudin (CGP 39393; sequence of hirudin variant 1 but lacks sulfate on tyrosine 63; specific activity, 11,496 ATU/ mg; known as hirudin in the text) at 0.3, 0.7, or 1.0 mg/kg.…”

mentioning

confidence: 99%

Hirudin, heparin, and placebo during deep arterial injury in the pig. The in vivo role of thrombin in platelet-mediated thrombosis.

et al. 1990

View full text Add to dashboard Cite

Three dosages (0.3, 0.7, and 1.0 mg/kg) of recombinant hirudin, a specific inhibitor of thrombin, were compared with heparin (50 units/kg) and placebo for reducing thrombus formation in the carotid arteries of 50 pigs after deep injury by balloon dilatation. Each drug was administered as a bolus followed immediately by a continuous infusion of the same dose per hour. Major end points were quantitative indium-111-labeled platelet and iodine-125-labeled fibrinogen deposition and the incidence of mural thrombosis. This study showed that heparin, at a dose that prolonged the activated partial thromboplastin time (APTT) to twice the control time, did not prevent mural thrombosis or significantly reduce platelet deposition compared with placebo but did reduce fibrinogen deposition. Recombinant hirudin markedly reduced platelet and fibrinogen deposition in a dose-related manner and totally eliminated mural thrombosis at an APTT of two to three times that of control. Platelet deposition (x 16/cm2, mean±SEM) in areas of deep arterial injury for the placebo, heparin, and 0.3, 0.7, and 1.0 mg/kg hirudin groups was 54+±21, 33+9, 22+f6, 8±1, and 7±1, respectively; electron microscopy showed a single layer (or less) of platelets at the two highest hirudin dosages. The incidence of macroscopic mural thrombosis was 76% with placebo, 57% with heparin, 46% with 0.3 mg/kg hirudin; there were no thrombi with 0.7 or 1.0 mg/kg hirudin (p<0.01). The APTT is a valuable index of the plasma hirudin concentration (r=0.89, p<0.001) and correlated inversely with quantitative platelet (r= -0.67, p<0.0001) and fibrinogen deposition (r= -0.42, p=0.005). The thrombin time is overly sensitive and plays no role in monitoring heparin or hirudin therapy for arterial thrombosis. Heparin and all dosages of hirudin abolished platelet aggregation to thrombin and prolonged the bleeding time to a similar degree; neither test reflects the in vivo antithrombotic efficacy of heparin or hirudin. Thrombin plays a critical role in arterial thrombosis. Heparin in conventional doses does not significantly reduce arterial platelet thrombosis. Hirudin produces a dose-dependent reduction in platelet and fibrinogenfibrin deposition, which correlates with the prolongation of the APTT and the hirudin plasma level. Hirudin totally eliminates macroscopic mural thrombus formation at dosages that prolong the APTT to at least twice control and is a promising therapeutic agent for platelet-rich arterial thrombi. (Circulation 1990;82:1476-1484 Ba alloon dilatation produces mechanical disruption of the arterial wall with injury into the media that releases tissue thromboplastin (tissue factor) and exposes very thrombogenic deep arterial structures (mainly smooth muscle cells and

show abstract

Pharmacokinetics and Anticoagulant Effect of Hirudin in Man

Cited by 141 publications

References 9 publications

Amelioration of collagen-induced arthritis by thrombin inhibition

Amelioration of collagen-induced arthritis by thrombin inhibition

Antithrombotic Effects of Three Thrombin Inhibitors in a Rat Model of Laser-Induced Thrombosis

Hirudin, heparin, and placebo during deep arterial injury in the pig. The in vivo role of thrombin in platelet-mediated thrombosis.

Contact Info

Product

Resources

About