Download PDF
Thromb Haemost 1994; 72(06): 874-879
DOI: 10.1055/s-0038-1648977
Original Article
Schattauer GmbH Stuttgart

The Venous Antithrombotic Profile of Naroparcil in the Rabbit

Jean Millet
Research and Development, Fournier S.C.A. Laboratories, Daix, France
,
Jocelyne Theveniaux
Research and Development, Fournier S.C.A. Laboratories, Daix, France
,
Neil L Brown
Research and Development, Fournier S.C.A. Laboratories, Daix, France
› Author Affiliations
Further Information

Publication History

Received 14 July 1994

Accepted after revision 05 September 1994

Publication Date:
06 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

The venous antithrombotic profile of naroparcil or (4-[4-cyanoben-zoyl]-phenyl)-1.5-dithio-β-D-xylopyranoside was investigated in the rabbit following single i. v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i. v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i. v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same doses of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human a-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay. The results suggest that naroparcil could have a safe venous antithrombotic profile following oral administration (antithrombotic effect compared to bleeding risk). It is probable that part of the mechanism of action of the β-D-xyloside, naroparcil, is due to the induction of chondroitin sulfate-like glycosaminoglycan biosynthesis, this material being detectable in the plasma.

 

  • References

  • 1 Ofosu FA, Gray E. Mechanisms of action of heparin: applications to the development of derivatives of heparins and heparinoids with antithrombotic properties. Semin Thromb Hemost 1988; 14: 9-17
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Morris GK. Prevention of venous thromboembolism: a survey of methods used in general and orthopaedic surgery. Lancet 1980; 1: 572-574
    PubMedGoogle Scholar
  • 3 Leyvraz PF, Bachmann F, Hoek J, Buller HR, Postel M, Samama M, Van-denbroek MC. Prevention of deep vein thrombosis after hip replacement: randomized comparison between unfractionated heparin and low molecular weight heparin. Br Med J 1991; 303: 543-548
    CrossrefPubMedGoogle Scholar
  • 4 Levine MN, Hirsh J, Gent M, Turpie AG, Leclerc J, Powers PJ, Jay RM, Neemeh J. Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Int Med 1991; 114: 545-551
    CrossrefPubMedGoogle Scholar
  • 5 Agnelli G, Cosmi B, Di Filippo P, Ranucci V, Veschi F, Longetti M, Ren-ga C, Barzi F, Gianese F, Lupatteli L, Rinonapoli E, Nenci GG. A randomized double-blind, placebo-controlled trial of dermatan sulfate for prevention of deep vein thrombosis in hip fracture. Thromb Haemost 1992; 67: 203-208
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Cade JF, Wood M, Magnani HN, Weslake GW. Early clinical experience of a new heparinoid Org 10172, in prevention of deep vein thrombosis. Thromb Res 1987; 45: 497-503
    CrossrefPubMedGoogle Scholar
  • 7 ten Cate JW. Prevention of deep vein thrombosis following total hip replacement surgery by Orgaran. Haemostasis 1992; 22: 109-111
    PubMedGoogle Scholar
  • 8 Furie B, Furie BC. Molecular basis of vitamin K-dependentγ-carboxyla-tion. Blood 1990; 75: 1753-1756
    PubMedGoogle Scholar
  • 9 Poller L. Oral anticoagulant therapy. In: Haemostasis and Thrombosis Bloom AI, Thomas DP. (ed). Edinburgh, London, New York: Churchill Livingstone; 1987: 870-885
  • 10 Sevitt S, Callagher NG. Prevention of venous thrombosis and pulmonary embolism in injured patients: a trial of anticoagulant prophlaxis with phen-indione in middle-aged and elderly patients with fractured necks of femur. Lancet 1959; 2: 981-989
    PubMedGoogle Scholar
  • 11 Hull R, Delmore T, Carter C, Hirsh J, Genton E, Gent M, Turpie G, McLaughlin D. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: 189-194
    CrossrefPubMedGoogle Scholar
  • 12 Millenson MM, Bauer KA, Kistler JP, Barzegar S, Tulin L, Rosenberg RD. Monitoring “mini-intensity”anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin F1+2 levels. Blood 1992; 79: 2034-2038
    PubMedGoogle Scholar
  • 13 Millet J, Theveniaux J, Brown NL. The venous antithrombotic effect of LF 1351 in the rat following oral administration. Thromb Haemost 1992; 67: 176-179
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Bellamy F, Horton D, Millet J, Prcard F, Samreth S, Chazan FB. Glycosylated derivatives of benzophenone benzhydrol, N. benzhydril as potential venous antithrombotic agents. J Med Chem 1993; 36: 898-903
    CrossrefPubMedGoogle Scholar
  • 15 Millet J, Theveniaux J, Vaillot M, Brown NL. Oral venous antithrombotic activity of naroparcil (LF 9.0055) in experimental thrombosis. Thromb Res 1992; 65: S158
    PubMedGoogle Scholar
  • 16 Wessler S, Reimer M, Sheps M. Biologic assay of thrombosis inducing activity in human serum. J Appl Physiol 1957; 14: 943-946
    PubMedGoogle Scholar
  • 17 Fareed J, Walenga JM, Kumar A, Rock A. A modified stasis thrombosis model to study the antithrombotic action of heparin and its fractions. Semin Thromb Hemost 1985; 11: 155-175
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the haemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-1245
    PubMedGoogle Scholar
  • 19 Doutremepuich C, Toulemonde F, Bousquet F, Bonini F. Comparison of the haemorrhagic effects of unfractionated heparin and a low molecular weight heparin fraction (CV 216) in rabbits. Thromb Res 1986; 43: 691-695
    CrossrefPubMedGoogle Scholar
  • 20 Ofosu FA, Modi GJ, Smith LM, Cerskus AL, Hirsh J, Blajchman MA. Heparan sulfate and dermatan sulfate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood 1984; 64: 742-747
    PubMedGoogle Scholar
  • 21 Hemker HC, Willems GM, Béguin S. .A computer assisted method to obtain the prothrombin activation velocity in whole plasma independent of thrombin decay processes. Thromb Haemost 1986; 56: 9-17
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Fernandez FA, Buchanan MR, Hirsh J, Fenton JW, Ofosu FA. Catalaysis of thrombin inhibition provides an index for estimating the antithrombotic potential of glycosaminoglycans in rabbits. Thromb Haemost 1987; 57: 286-293
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Jandrot-Perrus M, Didry D, Guillin MC, Nurden AT. Cross-linking of alpha and gamma-thrombin to distinct binding sites on human platelets. Eur J Biochem 1988; 174: 359-367
    CrossrefPubMedGoogle Scholar
  • 24 Dupouy D, Sié P, Dol F, Boneu B. A simple method to measure dermatan sulfate at submicrogram concentrations in plasma. Thromb Haemost 1988; 60: 236-239
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Sié P, Dupouy D, Dol F, Boneu B. Determination of plasma dermatan sulfate at relevant pharmacological concentrations. Sem Thromb Haemost 1922; 17: 181-185
    PubMedGoogle Scholar
  • 26 Gitel SN, Wessler S. Dose-dependent antithrombotic effect of warfarin in rabbits. Blood 1983; 61: 435-438
    CrossrefPubMedGoogle Scholar
  • 27 Van Ryn-McKenna J, Gray E, Weber E, Ofosu FA, Buchanan MR. Effects of sulfated polysaccharides on inhibition of thrombus formation initiated by different stimuli. Thromb Haemos 1989; 61: 7-9
    PubMedGoogle Scholar
  • 28 Hladovec J. The rational basis of thrombosis models. In: Antithrombotic drugs in thrombosis models Hladovec J. (ed). Boca Raton, Florida: CRC Press; 1989: 3-37
  • 29 Wessler S. The issue of animal models of thrombosis. In: Heparin and related polysaccharides: structure and activities Ofosu FA, Danishefksu I, Hirsh J. (eds). Ann NY Acad Sc. 1989. 556 366-370
  • 30 Cade JF, Buchanan MR, Boneu B, Ockelford P, Carter CJ, Cerskus AL, Hirsh J. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight fractions: the influence of the method of preparation. Thromb Res 1984; 35: 613-625
    CrossrefPubMedGoogle Scholar
  • 31 Hoppensteadt D, Walenga JM, Fareed J. Comparative antithrombotic and haemorrhagic effects of dermatan sulfate, heparan sulfate and heparin. Thromb Res 1990; 60: 191-200
    CrossrefPubMedGoogle Scholar
  • 32 Buchanan MR, Ofosu FA, Fernandez F, Van Ryn J. Lack of relationship between enhanced bleeding induced by heparin and other sulfated polysaccharides and enhanced catalysis of thrombin inhibition. Sem Thromb Haemost 1986; 12: 324-327
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Ockelford PA, Carter CJ, Hirsh J. In vivo activity of a new heparinoid. Pathology 1985; 17: 78-81
    CrossrefPubMedGoogle Scholar
  • 34 Okayama M, Kimata K, Suzuki S. The influence of P-nitrophenyl (3-D-xy-loside on the synthesis of proteochondroitin sulfate by slices of embryonic chick cartilage. J Biochem 1973; 74: 1069-1073
    PubMedGoogle Scholar
  • 35 Robinson JA, Robinson HC. Control of chondroitin sulfate biosynthesis. Biochem J 1981; 194: 839-846
    CrossrefPubMedGoogle Scholar
  • 36 Sobue M, Habuchi H, Ito K, Yonekura H, Oguri K, Sakurai K, Kamohara S, Ueno Y, Noyori R, Suzuki S. (3-D-xylosides and their analogues as artificial initiators of glycosaminoglycan chain synthesis. Aglycone-related variation in their effectiveness in vitro and in ovo. Biochem J 1987; 241: 591-601
    CrossrefPubMedGoogle Scholar
  • 37 Cöster J, Harnnäs J, Malmstrom A. Biosynthesis of dermatan sulfate proteoglycans. The effect of β-D-xyloside addition on the polymer-modifica-tion process in fibroblast cultures. Biochem J 1991; 276: 533-539
    CrossrefPubMedGoogle Scholar
  • 38 Robinson HC, Brett MJ, Tralaggan PJ, Lowther DA, Okayama M. The effect of D-xylose, β-D-xylosides and β-D-galactosides on chondroitin sulfate biosynthesis in embryonic chicken cartilage. Biochem J 1975; 148: 575-586
    PubMedGoogle Scholar
  • 39 Lohmander LS, Hascall VC, Caplan AI. Effects of 4-methylumbelliferyl-p-D-xylopyranoside on chondrogenesis and proteolgycan synthesis in chick limb bud mesenchymal cell cultures. J Biol Cheni 1979; 254: 10551-10561
    PubMedGoogle Scholar
  • 40 Ofosu FA, Fernandez F, Anvari N, Caranobe C, Dol F, Cadroy Y, Petitou M, Mardiguan J, Sié P, Boneu B. Further studies on the mechanisms for the antithrombotic effects of sulfated polysaccharides in rabbits. Thromb Haemost 1988; 60: 188-192
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Shimada K, Ozawa T. Modulation of glycosaminoglycan production and antithrombin III binding by cultured aortic endothelial cells treated with 4-methylumbelliferyl-β-D-xyloside. Arteriosclerosis 1987; 7: 627-636
    CrossrefPubMedGoogle Scholar
  • 42 Parkinson JF, Garcia JGN, Bang NU. Decreased thrombin affinity of cell surface thrombomodulin following treatment of cultured endothelial cells with β-D-xyloside. Biochem Biophys Res Comm 1990; 169: 177-183
    CrossrefPubMedGoogle Scholar