PMID- 15085465
OWN - NLM
STAT- MEDLINE
DCOM- 20050331
LR  - 20181130
IS  - 0094-6176 (Print)
IS  - 0094-6176 (Linking)
VI  - 30 Suppl 1
DP  - 2004 Feb
TI  - Pharmacodynamic considerations in the selection of dosage of tinzaparin for 
      various indications: experimental studies in primates.
PG  - 41-7
AB  - Like unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs) are 
      polypharmacologic agents that can modulate the hemostatic system at multiple 
      points. Thus, to select an optimal dose of LMWH for a given indication, it is 
      necessary to consider multiple actions of the drug. In this study, nonhuman 
      primates were treated with intravenous or subcutaneous boluses of the LMWH 
      tinzaparin or UFH. Doses were selected on the basis of the expected prophylactic 
      (75 U/kg) and therapeutic (175 U/kg) dosing of tinzaparin. Blood samples were 
      drawn periodically up to 24 hours after administration. Circulating anti-Xa and 
      anti-thrombin (anti-IIa) activities determined using amidolytic assays were used 
      to estimate plasma tinzaparin (heparin) concentrations. In addition, total tissue 
      factor pathway inhibitor (TFPI) levels were measured in these primates. 
      Subcutaneous administration of 75 U/kg tinzaparin resulted in plasma levels of 
      approximately 0.2 to 0.3 U/mL, concentrations sufficient for DVT prophylaxis. 
      Such drug levels were not associated with a significant release of TFPI. 
      Intravenous administration of the same dose resulted in a peak drug level of 
      approximately 1.5 anti-Xa U/mL. The elimination half-life was approximately 1 
      hour. Thus, intravenously administered tinzaparin may be useful for providing 
      anticoagulation during coronary interventions. Subcutaneous administration of 175 
      U/kg resulted in tinzaparin levels of approximately 0.7 anti-Xa U/mL and a 
      significant increase in TFPI levels. Interestingly, the increase in TFPI levels 
      occurred over a different time frame than anticoagulant activity. Intravenous 
      administration of 175 U/kg resulted in peak drug concentrations of almost 5 
      anti-Xa U/mL. The pharmacokinetic behavior of intravenously administered 
      tinzaparin was comparable to that of UFH. The data show that the pharmacokinetic 
      and pharmacodynamic effects measured using different assays widely differ. For a 
      proper pharmacodynamic analysis, multiple assays should be considered, given that 
      both UFH and LMWHs are polycomponent in nature.
FAU - Jeske, Walter
AU  - Jeske W
AD  - Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinois, 
      USA. wjeske@lumc.edu
FAU - Fareed, Jawed
AU  - Fareed J
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Semin Thromb Hemost
JT  - Seminars in thrombosis and hemostasis
JID - 0431155
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Heparin, Low-Molecular-Weight)
RN  - 7UQ7X4Y489 (Tinzaparin)
RN  - 9001-26-7 (Prothrombin)
RN  - 9002-04-4 (Factor IIa)
SB  - IM
MH  - Animals
MH  - Biological Availability
MH  - Factor Xa Inhibitors
MH  - Female
MH  - Heparin, Low-Molecular-Weight/*administration & dosage/*pharmacokinetics
MH  - Macaca mulatta
MH  - Male
MH  - Pharmacokinetics
MH  - Prothrombin/antagonists & inhibitors
MH  - Tinzaparin
EDAT- 2004/04/16 05:00
MHDA- 2005/04/01 09:00
CRDT- 2004/04/16 05:00
PHST- 2004/04/16 05:00 [pubmed]
PHST- 2005/04/01 09:00 [medline]
PHST- 2004/04/16 05:00 [entrez]
AID - 10.1055/s-2004-823002 [doi]
PST - ppublish
SO  - Semin Thromb Hemost. 2004 Feb;30 Suppl 1:41-7. doi: 10.1055/s-2004-823002.