PMID- 23768448
OWN - NLM
STAT- MEDLINE
DCOM- 20140617
LR  - 20161125
IS  - 1879-2472 (Electronic)
IS  - 0049-3848 (Linking)
VI  - 132
IP  - 2
DP  - 2013 Aug
TI  - Comparison of antithrombotic and hemorrhagic effects of edoxaban, a novel factor 
      Xa inhibitor, with unfractionated heparin, dalteparin, lepirudin and warfarin in 
      rats.
PG  - 234-9
LID - S0049-3848(13)00212-0 [pii]
LID - 10.1016/j.thromres.2013.05.020 [doi]
AB  - BACKGROUND: Edoxaban is a novel, potent and orally active direct Factor Xa (FXa) 
      inhibitor under development for prophylaxis and treatment of thromboembolic 
      diseases. Properties of dose response and margin of safety of anticoagulants are 
      the key factors for a positive risk/benefit of novel oral anticoagulants. 
      OBJECTIVES: To compare the dose response of antithrombotic effect and margin of 
      safety between antithrombotic and hemorrhagic effects of edoxaban with 
      conventional anticoagulants, unfractionated heparin (UFH), dalteparin (low 
      molecular weight heparin), lepirudin, and warfarin in rat models of thrombosis 
      and hemorrhage. METHODS: Rats were treated with edoxaban, UFH, dalteparin, and 
      lepirudin by continuous intravenous (iv) infusion, or with oral warfarin for 4 
      days before inducing thrombosis or bleeding. Thrombosis was induced by inserting 
      a platinum wire into the inferior vena cava for 60 minutes. Tail template 
      bleeding time was measured after making an incision on the tail. RESULTS: In 
      rats, iv infusion of edoxaban inhibited venous thrombosis in a dose-dependent 
      manner. The other anticoagulants also exerted dose-dependent antithrombotic 
      effects. The slopes of the dose-response curves of edoxaban were significantly 
      shallower than the slopes of UFH, dalteparin, and warfarin. At supratherapeutic 
      doses, edoxaban prolonged bleeding time in a rat tail bleeding model. To 
      determine bleeding risk, the margins between antithrombotic and bleeding-time 
      prolongation were compared. The margins of safety of edoxaban were wider than 
      those of UFH, dalteparin, lepirudin, and warfarin. CONCLUSIONS: These results 
      suggest that edoxaban may be more easily controlled and has the potential for a 
      more positive risk/benefit ratio compared to conventional anticoagulants.
CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
FAU - Morishima, Yoshiyuki
AU  - Morishima Y
AD  - Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd. 
      Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
FAU - Honda, Yuko
AU  - Honda Y
FAU - Kamisato, Chikako
AU  - Kamisato C
FAU - Shibano, Toshiro
AU  - Shibano T
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20130612
PL  - United States
TA  - Thromb Res
JT  - Thrombosis research
JID - 0326377
RN  - 0 (Anticoagulants)
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Hirudins)
RN  - 0 (Pyridines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Thiazoles)
RN  - 5Q7ZVV76EI (Warfarin)
RN  - 9005-49-6 (Heparin)
RN  - NDU3J18APO (edoxaban)
RN  - Y43GF64R34 (lepirudin)
SB  - IM
MH  - Animals
MH  - Anticoagulants/*pharmacology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - *Factor Xa Inhibitors
MH  - Heparin/*pharmacology
MH  - Hirudins/*pharmacology
MH  - Male
MH  - Pyridines/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Recombinant Proteins/pharmacology
MH  - Thiazoles/*pharmacology
MH  - Thromboembolism/drug therapy
MH  - Warfarin/*pharmacology
OTO - NOTNLM
OT  - APTT
OT  - Anticoagulant
OT  - Antithrombotic effect
OT  - BT2
OT  - Bleeding
OT  - CI
OT  - Dose response
OT  - ED(50)
OT  - Edoxaban
OT  - FXa
OT  - INR
OT  - LMWH
OT  - Margin of safety
OT  - PT
OT  - SEM
OT  - UFH
OT  - VTE
OT  - activated partial thromboplastin time
OT  - confidence interval
OT  - dose required for 50% inhibition of thrombus formation
OT  - dose required to double bleeding time
OT  - factor Xa
OT  - international normalization ratio
OT  - intravenous
OT  - iv
OT  - low molecular weight heparin
OT  - oral administration
OT  - po
OT  - prothrombin time
OT  - standard error of mean
OT  - unfractionated heparin
OT  - venous thromboembolism
EDAT- 2013/06/19 06:00
MHDA- 2014/06/18 06:00
CRDT- 2013/06/18 06:00
PHST- 2013/02/21 00:00 [received]
PHST- 2013/05/17 00:00 [revised]
PHST- 2013/05/21 00:00 [accepted]
PHST- 2013/06/18 06:00 [entrez]
PHST- 2013/06/19 06:00 [pubmed]
PHST- 2014/06/18 06:00 [medline]
AID - S0049-3848(13)00212-0 [pii]
AID - 10.1016/j.thromres.2013.05.020 [doi]
PST - ppublish
SO  - Thromb Res. 2013 Aug;132(2):234-9. doi: 10.1016/j.thromres.2013.05.020. Epub 2013 
      Jun 12.