A comparison of the beta-D-xyloside, odiparcil, to warfarin in a rat model of venous thrombosis.
BACKGROUND
A significant need exists for new chronic oral anticoagulation therapies to replace warfarin. Previous studies have shown that beta-D-xylosides, which prime glycosaminoglycan (GAG) synthesis, have antithrombin and antithrombotic activity. In the following report, a new orally active beta-D-xyloside (odiparcil) has been characterized in a rat model of venous thrombosis and its efficacy and bleeding liability compared to warfarin. Additionally, studies were conducted to investigate odiparcil's ex vivo antithrombin and antiplatelet activity, and also to explore the potential utility of protamine sulfate as a neutralizing agent.


RESULTS
In vivo thrombosis studies were conducted in a rat inferior vena cava model, and bleeding studies in a rat tail transection model. Following oral dosing, warfarin and odiparcil produced dose-related suppression of thrombus formation. A therapeutically relevant dose of warfarin in this model (international normalized ratio; INR 3.0) achieved approximately 65% inhibition of thrombus formation. Warfarin caused dose-related significant increases in bleeding indices. Odiparcil antithrombotic activity was limited by its mechanism to a maximum suppression of thrombus formation of 65-70%, and did not prolong bleeding indices. Additionally, odiparcil-induced heparin cofactor II (HCII)-dependent antithrombin activity was shown to be a function of dermatan sulfate-like GAG production. Other than thrombin-related effects, no odiparcil effects on platelet function were observed. In antidote studies, it was demonstrated that odiparcil-induced antithrombotic activity could be partially neutralized by protamine sulfate.


CONCLUSIONS
These experiments suggest that an antithrombotic approach based upon xyloside induction of circulating GAGs may have the potential to approximate the efficacy of warfarin and yet with a reduced risk to hemostasis.
Toomey
J R
JR
Cardiovascular and Urogenital Diseases Center of Excellence, GlaxoSmithKline, King of Prussia, PA, USA. john.r.toomey@gsk.com
Abboud
M A
MA
Valocik
R E
RE
Koster
P F
PF
Burns-Kurtis
C L
CL
Pillarisetti
K
K
Danoff
T M
TM
Erhardt
J A
JA
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006025:Glycosaminoglycans / Q000097:blood; D006027:Glycosides / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced; D015844:Heparin Cofactor II; D011479:Protamines / Q000627:therapeutic use; D051381:Rats; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis / Q000188:drug therapy*; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D006025:Glycosaminoglycans; D006027:Glycosides; D011479:Protamines; C010807:xylosides; D014859:Warfarin; D015844:Heparin Cofactor II; C514804:odiparcil