2-(2-Br-phenyl)-8-methoxy-benzoxazinone (HPW-RX2), a direct thrombin inhibitor with a suppressive effect on thromboxane formation in platelets

SummaryHirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.In all phases of the study, hirulog administration was generally well-tolerated.Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.

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Immediate high-dose intravenous immunoglobulins followed by direct thrombin-inhibitor treatment is crucial for survival in Sars-Covid-19-adenoviral vector vaccine-induced immune thrombotic thrombocytopenia VITT with cerebral sinus venous and portal vein thrombosis

Journal of Neurology ◽

10.1007/s00415-021-10599-2 ◽

2021 ◽

Author(s):

Tilmann Graf ◽

Thomas Thiele ◽

Randolf Klingebiel ◽

Andreas Greinacher ◽

Wolf-Rüdiger Schäbitz ◽

...

Keyword(s):

Portal Vein ◽

Adenoviral Vector ◽

Intravenous Immunoglobulins ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

High Dose ◽

Vector Vaccine ◽

Vein Thrombosis ◽

Cerebral Sinus ◽

Inhibitor Treatment

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Safety and Efficacy of Argatroban in the Management of Heparin-Induced Thrombocytopenia

Clinical medicine Blood disorders ◽

10.4137/cmbd.s5118 ◽

2011 ◽

Vol 4 ◽

pp. CMBD.S5118 ◽

Cited By ~ 1

Author(s):

Bernd Saugel ◽

Roland M. Schmid ◽

Wolfgang Huber

Keyword(s):

Arterial Thrombosis ◽

Pharmacokinetic Profile ◽

The United States ◽

Heparin Therapy ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

Heparin Induced Thrombocytopenia ◽

Safety And Efficacy ◽

Increased Risk ◽

Life Threatening

Heparin-induced thrombocytopenia (HIT) is a life-threatening adverse reaction to heparin therapy that is characterized by thrombocytopenia and an increased risk of venous and arterial thrombosis. According to guidelines, in patients with strongly suspected or confirmed HIT all sources of heparin have to be discontinued and an alternative, nonheparin anticoagulant for HIT treatment must immediately be started. For both the prophylaxis of thrombembolic events in HIT and the treatment of HIT with thrombosis the direct thrombin inhibitor argatroban is approved in the United States. The objective of this review is to describe the mechanism of action and the pharmacokinetic profile of argatroban, to characterize argatroban regarding its safety and therapeutic efficacy and to discuss its place in therapy in HIT.

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Effects of the direct thrombin inhibitor melagatran in rats with endotoxin-induced sepsis

European Journal of Anaesthesiology ◽

10.1097/00003643-200606001-00288 ◽

2006 ◽

Vol 23 (Supplement 37) ◽

pp. 81

Author(s):

N. Nitescu ◽

E. Grimberg ◽

S.-E. Ricksten ◽

G. Guron

Keyword(s):

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor

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Alternative parenteral anticoagulation with argatroban, a direct thrombin inhibitor

Expert Review of Cardiovascular Therapy ◽

10.1586/14779072.3.1.31 ◽

2005 ◽

Vol 3 (1) ◽

pp. 31-41 ◽

Cited By ~ 13

Author(s):

Marian P LaMonte ◽

Philip M Brown ◽

Marcie J Hursting

Keyword(s):

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor

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185 The new direct thrombin inhibitor S 18326 does not compromise fibrinolysis in the rabbit jugular vein model

Fibrinolysis and Proteolysis ◽

10.1016/s0268-9499(96)80272-4 ◽

1996 ◽

Vol 10 ◽

pp. 55

Keyword(s):

Jugular Vein ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor

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Argatroban and Renal Replacement Therapy in Patients with Heparin-Induced Thrombocytopenia

Annals of Pharmacotherapy ◽

10.1345/aph.1e480 ◽

2005 ◽

Vol 39 (2) ◽

pp. 231-236 ◽

Cited By ~ 60

Author(s):

Ignatius Y Tang ◽

Donna S Cox ◽

Kruti Patel ◽

Bharathi V Reddy ◽

Linda Nahlik ◽

...

Keyword(s):

At Risk ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

Systemic Clearance ◽

Recovery Method ◽

P Values ◽

Heparin Induced Thrombocytopenia ◽

Alternative Anticoagulation

BACKGROUND: Argatroban, a direct thrombin inhibitor, is an effective anticoagulant for patients who have heparin-induced thrombocytopenia (HIT). Anticoagulation is usually required for renal replacement therapy (RRT). OBJECTIVE: To prospectively evaluate the pharmacokinetics, pharmacodynamics, and safety of argatroban during RRT in hospitalized patients with or at risk for HIT. METHODS: Five patients with known or suspected HIT underwent hemodialysis (n = 4) or continuous venovenous hemofiltration (CVVH, n = 1), while receiving a continuous infusion of argatroban 0.5–2 μg/kg/min. Activated partial thromboplastin times (aPTTs), activated clotting times (ACTs), argatroban concentrations (plasma, dialysate, CVVH effluent), and safety were assessed before, during, and after a 4-hour session of RRT. Systemic and dialytic argatroban clearances were calculated. RESULTS: Among the 4 hemodialysis patients, aPTT, ACT, and plasma argatroban concentrations remained stable during RRT, with respective mean ± SD values of 74.3 ± 34.2 seconds, 198 ± 23 seconds, and 499 ± 353 ng/mL before RRT, and 70.6 ± 21.4 seconds, 181 ± 12 seconds, and 453 ± 295 ng/mL 2 hours after starting RRT (p values NS). Systemic clearance was 17.7 ± 12.8 L/h before hemodialysis and 17.0 ± 9.5 L/h during hemodialysis (n = 2). The dialyzer clearance (dialysate recovery method) was 1.5 ± 0.4 L/h (n = 4). Generally similar responses occurred in the CVVH patient: systemic argatroban clearance was 4.8 L/h before CVVH and 4 L/h during CVVH. The hemofilter argatroban clearance was 0.9 L/h. No bleeding or thrombosis occurred. CONCLUSIONS: Argatroban provides effective alternative anticoagulation in patients with or at risk for HIT during RRT. Argatroban clearance by high-flux membranes during hemodialysis and CVVH is clinically insignificant, necessitating no dose adjustment.

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