| Reference | 1. J Clin Pharmacol. 2008 Oct;48(10):1158-70. doi: 10.1177/0091270008323751. Epub
2008 Aug 29.
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Characterization of total plasma glycosaminoglycan levels in healthy volunteers
following oral administration of a novel antithrombotic odiparcil with aspirin or
enoxaparin.
<br><br>
Myers AL(1), Upreti VV, Khurana M, Eddington ND.
<br><br>
Author information: <br>
(1)Pharmacokinetics/Biopharmaceutics Laboratory, School of Pharmacy, University
of Maryland, Baltimore, Maryland, USA.
<br><br>
Odiparcil is a novel, orally active beta-d-thioxyloside analog with
antithrombotic activity associated with a reduced risk of adverse bleeding
events. Its unique mechanism of action is postulated by means of an elevation in
circulating endogenous chondroitin sulfate-related glycosaminoglycans (GAGs)
levels. The purpose of these 2 separate clinical studies was to evaluate plasma
GAG levels in healthy subjects administered odiparcil with either aspirin (ASA)
or enoxaparin. Clinical plasma samples were processed and analyzed using
validated HPLC bioassays that indirectly estimate GAG levels based on the
simultaneous detection of the chondroitin disaccharide derivatives. The
concomitant administration of odiparcil with or without ASA resulted in a
significant elevation in GAG levels over baseline for both treatment groups. In
the other clinical study, the concomitant administration of odiparcil with or
without enoxaparin displayed significant increases in plasma DeltaDi-OS,
DeltaDi-4S, and total disaccharide levels versus control group. Neither plasma
GAG levels nor odiparcil plasma levels were correlated with a rise in hepatic
transaminases, an adverse drug event observed in several subjects; and plasma
odiparcil levels were indirectly correlated with plasma GAG levels. These
clinical studies were proof of concept of preclinical rat studies indicating that
chronic odiparcil treatment elevates endogenous GAG levels in human subjects.
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2. J Thromb Haemost. 2006 Sep;4(9):1989-96.
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A comparison of the beta-D-xyloside, odiparcil, to warfarin in a rat model of
venous thrombosis.
<br><br>
Toomey JR(1), Abboud MA, Valocik RE, Koster PF, Burns-Kurtis CL, Pillarisetti K,
Danoff TM, Erhardt JA.
<br><br>
Author information: <br>
(1)Cardiovascular and Urogenital Diseases Center of Excellence, GlaxoSmithKline,
King of Prussia, PA, USA. [email protected]
<br><br>
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.<br>
METHODS AND 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.<br>
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.
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