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Pharmacokinetic and antithrombotic properties of two pentasaccharides with
high affinity to antithrombin III in the rabbit: comparison with CY216
D Carrie, C Caranobe, S Saivin, G Houin, M Petitou, JC Lormeau, C Van Boeckel, D Meuleman and B Boneu
Laboratoire d'Hemostase, Centre de Transfusion, Toulouse, France.
This study compares the pharmacokinetic and the antithrombotic properties
of two pentasaccharides with high affinity to antithrombin III with those
of a conventional low molecular weight heparin, CY216, in the rabbit. On a
weight basis, SR 90107A/ORG 31540 (natural pentasaccharide [NPS]) and SR
80027A/ORG 31550 (sulfated pentasaccharide [SPS]) were, respectively, 4.7
and 26 times more potent antifactor Xa inhibitory agents than CY216. They
were devoid of antithrombin activity, whereas the antifactor
Xa/antithrombin ratio of CY216 was 3.8. After bolus intravenous
administration, the clearance (mL/kg/h) of CY216 decreased from 91 +/- 27
for the dose of 12.5 U/kg to 49 +/- 14 for the dose of 50 U/kg and then
remained constant up to the highest dose tested (500 U/kg). The clearance
of NPS was unrelated to the dose and comparable to that of CY216 over 50
U/kg, whereas that of SPS was 10 times lower. Consistent results were
observed after continuous intravenous infusions for 9 hours and
subcutaneous administration. The duration of the antithrombotic effect was
compared after a single subcutaneous injection of 250 U/kg of either
compound in the stasis-Wessler model using human serum as thrombogenic
stimulus. Two hours after the injection, the three compounds provided a
thrombus prevention of greater than 95% and mean plasma activities of 0.8,
0.9, and 1.9 U/mL for CY216, NPS, and SPS, respectively. Twelve hours after
injection, the antithrombotic effects of CY216 and NPS had totally
vanished, whereas that of SPS was 68%. At that time, the plasma anti-Xa
activities were less than 0.06 U/mL for CY216 and NPS, but 1.1 U/mL for
SPS. For the latter compound, significant antithrombotic effects and
detectable anti-Xa activities were still recorded 48 hours after the
injection. The antithrombotic potency of the three compounds was also
compared as their ability to inhibit the growth of a standardized venous
thrombosis during 4 hours. The lowest total doses providing the maximum
inhibitory effect were 3,125, 1,428, and 62 micrograms/kg for CY216, NPS,
and SPS, respectively. These doses generated mean steady state antifactor
Xa activities of 1.06, 1.5, and 1.2 anti-Xa U/mL, respectively. These
observations indicate that the amplification mechanisms triggered by
thrombin bound to fibrin and leading to the generation of new thrombin are
essential to ensure venous thrombosis growth and that these mechanisms may
be efficiently inhibited by pure antifactor Xa targeting agents.
Volume 84,
Issue 8,
pp. 2571-2577,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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J. P. Hérault, A. Bernat, A. M. Pflieger, J. C. Lormeau, and J. M. Herbert
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J.M. Herbert, J.P. Herault, A. Bernat, R.G.M. van Amsterdam, G.M.T. Vogel, J.C. Lormeau, M. Petitou, and D.G. Meuleman
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