PMID- 17362226
OWN - NLM
STAT- MEDLINE
DCOM- 20070720
LR  - 20230829
IS  - 1538-7933 (Print)
IS  - 1538-7836 (Linking)
VI  - 5
IP  - 6
DP  - 2007 Jun
TI  - Antithrombotic and anticoagulant effects of the direct thrombin inhibitor 
      dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of 
      venous thrombosis.
PG  - 1237-42
AB  - BACKGROUND: Oral anticoagulant therapies targeted at thrombin are being developed 
      to overcome limitations associated with current standard therapies. OBJECTIVES: 
      This study was undertaken to assess and compare the antithrombotic and 
      anticoagulant effects of the novel, selective and reversible, direct thrombin 
      inhibitor (DTI), dabigatran, and its oral prodrug dabigatran etexilate, to that 
      of unfractionated heparin (UFH), hirudin and melagatran using a rabbit model of 
      venous thrombosis. METHODS: A rabbit model of venous thrombosis consisting of 
      endothelial damage with blood flow reduction was used with minor modifications. 
      RESULTS: All compounds demonstrated a dose-dependent reduction in thrombus 
      formation following i.v. administration with complete or almost complete 
      inhibition at the highest doses. Dabigatran (in the dose range 0.03-0.5 mg 
      kg(-1)) had a 50% effective dose of 0.066 mg kg(-1). By comparison, UFH (5-50 U 
      kg(-1)), hirudin (0.01-0.05 mg kg(-1)) and melagatran (0.01-0.3 mg kg(-1)) had a 
      50% effective dose of 9.8 U kg(-1), 0.016 mg kg(-1) and 0.058 mg kg(-1), 
      respectively. Similarly, oral dabigatran etexilate (1-20 mg kg(-1)) inhibited 
      thrombus formation in a dose-dependent manner. Maximum inhibition was achieved 
      within 1 h of administration, suggesting a rapid onset of action. For both routes 
      of administration, inhibition of thrombus formation directly correlated with 
      prolongation of the activated partial thromboplastin time. CONCLUSIONS: These 
      findings demonstrate the potent anticoagulant and antithrombotic activity of 
      dabigatran as a selective thrombin inhibitor in a rabbit model of venous 
      thrombosis. Notably, dose-dependent and long-lasting antithrombotic efficacy was 
      observed after application of its oral form dabigatran etexilate, which is 
      currently undergoing phase III clinical development.
FAU - Wienen, W
AU  - Wienen W
AD  - Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH and Co KG, 
      Biberach, Germany. wolfgang.wienen@bc.boehringer-ingelheim.com
FAU - Stassen, J-M
AU  - Stassen JM
FAU - Priepke, H
AU  - Priepke H
FAU - Ries, U J
AU  - Ries UJ
FAU - Hauel, N
AU  - Hauel N
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Anticoagulants)
RN  - 0 (Azetidines)
RN  - 0 (Benzimidazoles)
RN  - 0 (Benzylamines)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Prodrugs)
RN  - 0 (Pyridines)
RN  - 2A9QP32MD4 (melagatran)
RN  - 9005-49-6 (Heparin)
RN  - I0VM4M70GC (Dabigatran)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Anticoagulants/administration & dosage/*therapeutic use
MH  - Azetidines/administration & dosage/therapeutic use
MH  - Benzimidazoles/administration & dosage/*therapeutic use
MH  - Benzylamines/administration & dosage/therapeutic use
MH  - Dabigatran
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Fibrinolytic Agents/administration & dosage/*therapeutic use
MH  - Heparin/therapeutic use
MH  - Hirudin Therapy
MH  - Injections, Intravenous
MH  - Male
MH  - Partial Thromboplastin Time
MH  - Prodrugs/administration & dosage/*therapeutic use
MH  - Pyridines/administration & dosage/*therapeutic use
MH  - Rabbits
MH  - Venous Thrombosis/blood/*drug therapy
EDAT- 2007/03/17 09:00
MHDA- 2007/07/21 09:00
CRDT- 2007/03/17 09:00
PHST- 2007/03/17 09:00 [pubmed]
PHST- 2007/07/21 09:00 [medline]
PHST- 2007/03/17 09:00 [entrez]
AID - S1538-7836(22)10205-9 [pii]
AID - 10.1111/j.1538-7836.2007.02526.x [doi]
PST - ppublish
SO  - J Thromb Haemost. 2007 Jun;5(6):1237-42. doi: 10.1111/j.1538-7836.2007.02526.x.