HEPARINA POR VIA ORAL




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HEPARINA POR VIA ORAL

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Este estudio demuestra la efectividad de la heparina administrada por vía oral, lo que abre nuevas perspectivas terapéuticas en cuanto a su uso, aunque esto debe confirmarse con otros estudios a largo plazo.
hiebert9.jpg Autor:
Hiebert, Linda
Columnista Experto de SIIC

Institución:
Western College of Veterinary Medicine University of Saskatchewan Saskatchewan, Canada


Artículos publicados por Hiebert, Linda
Recepción del artículo
28 de Junio, 2004
Aprobación
30 de Junio, 2004
Primera edición
9 de Marzo, 2005
Segunda edición, ampliada y corregida
7 de Junio, 2021

Resumen
Las heparinas son drogas antitrombóticas de administración parenteral. Se cree que éstas no se absorben cuando son administradas oralmente, hecho sustentado por las escasas o nulas pruebas de la presencia de heparina en el plasma. No obstante, en nuestro laboratorio se demostró que tanto las heparinas no fraccionadas (HNF) como heparinas de bajo peso molecular (HBPM) se recuperan del endotelio cuando son administradas a ratas a través de una sonda gástrica. La concentración de la heparina en el endotelio de la aorta fue, a las 4 horas, de 1 000 a 10 000 veces mayor que la plasmática cuando se administraron 60 mg/kg. Es más, se demostró un efecto antitrombótico tras la administración oral de heparina. Se constató una disminución dependiente de la dosis en la incidencia de trombosis en el modelo de la vena yugular de rata tras la administración oral de HNF (bovina o porcina) o HBPM (reviparina, tinzaparina). Las HBPM son eficaces en menores dosis que las HNF con 50% de reducción de la incidencia de trombosis observada con 0.025 mg/kg de revirapina y 0.1 mg/kg de tinzaparina en comparación con 7.5 mg/kg de HNF. Los efectos antitrombóticos fueron además observados en los modelos de estasis venosa y arterial carotídeo de las ratas. Por lo tanto, las heparinas de administración oral son agentes antitrombóticos efectivos a pesar de sus bajos niveles plasmáticos. Las heparinas químicas y las radiomarcadas son recuperadas de tejidos no digestivos y de la orina cuando se administra HNF, tinzaparina o heparinas marcadas con 14C. Estos estudios avalan el trabajo de otros autores que demostraron cambios sistémicos cuantificados tras la administración oral de heparina o polianiones como el pentosan polisulfato o el condroitín sulfato. Estos resultados indican que se requieren investigaciones ulteriores sobre la eficacia oral de la heparina.

Palabras clave
Heparinas, oral, heparinas de bajo peso molecular, endotelio, trombosis


Artículo completo

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Extensión:  +/-12.01 páginas impresas en papel A4
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Abstract
Heparins are parenterally administered antithrombotic drugs. Administration of heparins by mouth would be more suitable for long term administration, often required for the prevention of thrombosis and for many additional proposed uses. It is believed that heparin is not absorbed when administered by the oral route, a belief supported by little or no heparin recovered from plasma. However, our laboratory has shown that heparin is recovered from endothelium when unfractionated (UFH) and low molecular weight heparins (LMWH) are given to rats by stomach tube. Heparin concentrations in aortic endothelium were on the order of 1 000 to 10 000 times greater than in plasma at 4 h when 60 mg/kg are given by stomach tube. Furthermore, an antithrombotic effect is evident after oral administration. A dose-dependent decrease in thrombosis incidence is seen in a rat jugular vein model following single oral doses of UFH (bovine and porcine) or LMWHs (reviparin, tinzaparin). LMWHs were effective at lower doses than UFH where a fifty percent reduction in thrombosis was observed with 0.025 mg/kg reviparin, 0.1 mg/kg tinzaparin versus 7.5 mg/kg for UFHs. Similar antithrombotic effects were seen in a rat venous stasis model and a rat carotid arterial model. Thus orally administered heparins are effective antithrombotic agents despite low plasma levels. Chemical heparins and radiolabel are recovered from non-gut tissue and from urine when UFH, tinzaparin or 14C labelled heparins are administered. These studies support the work of others demonstrating measurable systemic changes following oral administration of heparin or polyanions such as pentosan polysulphate and chondroitin sulphate. These results indicate that further investigation on the efficacy of oral heparin is required.

Key words
Heparins, oral, low molecular weight heparins, endothelium, thrombosis


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Clasificación en siicsalud
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página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Cardiología, Cuidados Intensivos, Hematología
Relacionadas: Bioquímica, Cardiología, Cuidados Intensivos, Farmacología, Hematología, Medicina Farmacéutica, Medicina Interna, Pediatría



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Enviar correspondencia a:
Hiebert, Linda
Patrocinio y reconocimiento:
Reconocimiento. Quiero expresar mi agradecimiento a Sandra Wice y Tilly Ping por la asistencia técnica relacionada con muchos de los estudios mencionados. Este trabajo fue financiado por la Heart & Stroke Foundation of Saskatchewan
Bibliografía del artículo
  1. Fareed J, Hoppenstead D,Bick RL. An update on heparins at the beginning of the new millenium. Semin Thromb Hemost 2000;26:5-21.
  2. Schulman S. Unresolved issues in anticoagulant therapy. J Thromb Haemost 2003;1:1464-1470.
  3. Engelberg H. Actions of heparin in the atherosclerotic process. Pharmacol Rev 1996;48:327-352.
  4. Zacharski LR, Loynes JT. Low-molecular-weight heparin in oncology. Anticancer Res 2003;23:2789-2793.
  5. Engelberg H. Actions of heparin that may affect the malignant process. Cancer 1999;85(2):257-272.
  6. Gorski A, Wasik M, Nowaczyk M et al. Immunomodulating activity of heparin. FASEB J 1991;5:2287-2291.
  7. Hopfner M, Alban S, Schumacher G et al. Selectin-blocking semisynthetic sulfated polysaccharides as promising anti-inflammatory agents. J Pharm Pharmacol 2003;55:697-706.
  8. Bagasra O, Lischner HW. Activity of dextran sulfate and other polyanionic polysaccharides against human immunodeficiency virus. J Infect Dis 1988;158:1084-1087.
  9. Howell AL, Taylor TH, Miller JD et al. Inhibition of HIV-1 infectivity by low molecular weight heparin. Results of in vitro studies and a pilot clinical trial in patients with advanced AIDS. Int J Clin Lab Res 1996;26:124-131.
  10. Folkman J, Weisz PB, Joullie MM et al. Control of angiogenesis with synthetic heparin substitutes. Science 1989;243:1490-1493.
  11. Mandal AK, Lyden T,Saklayen MG. Heparin lowers blood pressure:Biological and clinical perspectives. Kidney Int 1995;47:1017-1022.
  12. Berg D, Berg LH, Couvaras J et al. Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis. Blood Coagul Fibrinolysis 1999;10:435-438.
  13. Bergamaschini L, Rossi E, Storini C et al. Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease. J Neurosci 2004;24:4181-4186.
  14. Prajapati DN, Newcomer JR, Emmons J et al. Successful treatment of an acute flare of steroid-resistant Crohn's colitis during pregnancy with unfractionated heparin. Inflamm Bowel Dis 2002;8:192-195.
  15. Baert FJ, Rutgeerts PJ. Medical therapies for ulcerative colitis and Crohn's disease. Curr Gastroenterol Rep 2000;2:446-450.
  16. Matsui NM, Varki A,Embury SH. Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin. Blood 2002;100:3790-3796.
  17. Linhardt RJ, Loganathan D. Heparin, Heparinoids and Heparin oligosaccharides: Structure and biological activities. Biomimetic Polymers 1990;135-173.
  18. Ma Q, Cornelli U, Hanin I et al. Heparin and heparin-dervied oligosaccharides: A developmental perspective. In Vossoughi, J., Fareed, J., Mousa, S. A., and Karanian, J. W. Thrombosis Research and Treatment Bench to Bedside. Washington, DC: Medical and Engineering Publishers, Inc. 2004:287-334.
  19. Young E, Wells P, Holloway S et al. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994;71:300-304.
  20. Palm M, Wu H, Mattsson C et al. Pharmacokinetic properties of size-homogenous heparin oligosaccharides. Thromb Res 1990;59:799-805.
  21. Samama MM, Gerotziafas GT. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux). Thromb Res 2003;109:1-11.
  22. Bjork I, Olson ST, Shore JD. Moleculr mechanisms of the accelerating effect of heparin on the reactions between antithrombin and clotting proteinases. In Lane, D. A. and Lindahl, U. Heparin Chemical and Biological Properties and Clinical Applications. Boca Raton,Florida: CRC Press,Inc. 1989:229-255.
  23. Toida T, Chaidedgumjorn A,Linhardt R.J. Structure and activity of sulfated polysaccharides. Trends in Glycoscience and Glycotechnology 2004;15:29-46.
  24. Morris T. Heparin and low molecular weight heparin: background and pharmacology. Clin Chest Med 2003;24:39-47.
  25. Bara L, Planes A,Samama MM. Occurence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery. Br J Haematol 1999;104:230-240.
  26. Hiebert LM, McDuffie NM. The intracellular uptake and protracted release of exogenous heparins by cultured endothelial cells. Artery 1989;16:208-222.
  27. Glimelius B, Busch C,Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1978;12:773-782.
  28. Barzu T, Molho P, Tobelem G et al. Binding and endocytosis of heparin by human endothelial cells in culture. Biochim Biophys Acta 1985;845:196-203.
  29. Barzu T, Molho P, Toblelem G et al. Binding of Heparin and low molecular weight heparin fragments to human vascular endothelial cells in culture. Nouv Rev Fr Hematol 1984;26:243-247.
  30. Van Rijn JLML, Trillou M, Mardiguian J et al. Selective binding of heparins to human endothelial cells. Implications for pharmacokinetics. Thromb Res 1987;45:211-222.
  31. Vannucchi S, Pasquali F, Chiarugi V et al. Internalization and metabolism of endogenous heparin by cultured endothelial cells. Biochem Bioph Res Co 1986;140:294-301.
  32. Hiebert LM, Jaques LB. Heparin uptake on endothelium. Artery 1976;2,1:26-37.
  33. Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976;8:195-204.
  34. Hiebert LM. Heparin and Endothelium. In McDuffie, N. M. Heparin, Structure, Cellular Functions and Clinical Applications. New York: Academic Press 1979:289-297.
  35. Jaques LB, Hiebert LM,Wice SM. Evidence from endothelium of gastric absorption of heparin and of dextran sulfates 8000. J Lab Clin Med 1991;117,2.:122-130.
  36. Hiebert LM, Wice SM, McDuffie NM et al. The heparin target organ - the endothelium. Studies in a rat model. Quart J Med 1993;86:341-348.
  37. Dawes J, Pepper D. Human vascular endothelial cells catabolise exogenous glycosaminoglycans by a novel route. Thromb Haemost 1992;67,4:468-472.
  38. Vannucchi S, Pasquali F, Porciatti F et al. Binding, internalization and degradation of heparin and heparin fragments by cultured endothelial cells. Thromb Res 1988;49:373-383.
  39. Barzu T, van Rijn JLML, Petitou M et al. Heparin degradation in endothelial cells. Thromb Res 1987;47:601-609.
  40. Hiebert LM, McDuffie NM. The internalization and release of heparins by cultured endothelial cells: The process is cell source, heparin source, time and concentration dependent. Artery 1990;17:107-118.
  41. Watanabe J, Haba M,Yuasa H. Uptake of fractionated 3H-heparin by isolated rat kuppfer cells. Pharm Res 1995;12,7:1092-1095.
  42. Araki H, Muramoto J, Nishi K et al. Heparin adheres to the damaged arterial wall and inhibits its thrombogenicity. Circ Res 1992;71,3:577-884.
  43. Norrby K. Heparin and angiogenesis:A low-molecular weight fraction inhibits and a high-molecular weight fraction stimulates angiogenesis systemically. Haemostasis 1993;23,Supp1:141-149.
  44. Robinson-White A, Baylin SB, Olivecrona T et al. Binding of diamine oxidase activity to rat and guinea pig microvascular endothelial cells. J Clin Invest 1985;76:93-100.
  45. Stins MF, Maxfield FR,Goldberg IJ. Polarized binding of lipoprotein lipase to endothelial cells. Arterioscler Thromb 1992;12:1437-1446.
  46. Kojima H, Omoto Y, Hidaka H et al. Increased plasma post-heparin diamine oxidase activity and plant sterol levels in streptozotocin diabetic rat. Biochem Bioph Res Co 1992;186,1:398-404.
  47. Oyanagui Y, Sato S. Heparin, a potent releasing agent of extracellular superoxide dismutase (EC-SOD C), suppersses ischaemic paw oedema in mice. Free Radic Res Commun 1990;9:87-99.
  48. Yasuba H, Chihara J, Kino T et al. Increased releasability of platelet products and reduced heparin- induced platelet factor 4 release from endothelial cells in bronchial asthma. J Lipid Mediator 1991;4:5-22.
  49. Hoppensteadt D, Walenga J, Fasanella A et al. TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated and a low molecular weight heparin. Thromb Res 1995;77,2:175-185.
  50. Hiebert LM, Liu J. Heparin protects cultured endothelial cells from damage by toxic oxygen metabolites. Atherosclerosis 1990;83:47-51.
  51. Hiebert LM, Ping T. Protective effect of dextran sulfate and heparin on adult rat cardiomyocytes damaged by free radicals. J Mol Cell Cardiol 1997;29:229-235.
  52. Hiebert LM, Liu J. Protective action of polyelectrolytes on endothelium. Semin Thromb Hemost 1991;17(Supp 1):42-46.
  53. Black SC, Gralinski MR, Friedrichs GS et al. Cardioprotective effects of heparin or N-acetylheparin in an in vivo model of myocardial ischaemic and reperfusion injury. Cardiovasc Res 1995;29:629-636.
  54. Emanuele RM, Fareed J. Effects of molecular weight on the bioavailability of heparin. Thromb Res 1987;48:591-596.
  55. Windsor E, Cronkeim GE. Gastro-intestinal absorption of heparin and synthetic heparinoids. Nature 1961;4772:263-264.
  56. Gibaldi M, Feldman S. Mechanisms of surfactant effects on drug absorption. J Pharm Sc 1970;59,5:579-589.
  57. Guarini S, Ferrari W. Sodium deoxycholate promotes the absorption of heparin administered orally, probably by acting on gastro-intestinal mucosa in rats. Experientia 1983;41:350-352.
  58. Santiago N, Rivera T, Mayer E et al. Proteinoid microspheres for the oral delivery of heparin. Proc Intern Symp Control Rel Bioact Mater 1991;19:514-515.
  59. Jiao Y, Ubrich N, Marchand-Arvier M et al. In vitro and in vivo evaluation of oral heparin-loaded polymeric nanoparticles in rabbits. Circulation 2002;105:230-235.
  60. Zoppetti G, Caramazza I, Murakami Y et al. Structural requirements for duodenal permeability of heparin- diamine complexes. Biochim Biophys Acta 1992;1156:92-98.
  61. Engel RH, Riggi SJ. Effect of sulfated and sulfonated surfactants on the intestinal absorption of heparin. Proc Soc Exp Biol Med 1969;130:879-879.
  62. Lee Y, Kim SH,Byun Y. Oral delivery of new heparin derivatives in rats. Pharm Res 2000;17:1259-1264.
  63. Guarini S, Ferrari W. Structural restiction in bile acids and non-ionic detergents for the promotion of heparin absorption from rat gastro-intestinal tract. Arch Int Pharmacodyn 1984;271:4-4.
  64. Jaques LB, Sue TK. Mobilization of chondroitin sulphate by nitrilotriacetic acid. Toxicol Appl Pharmacol 1975;34:521-524.
  65. Andriuoli G, Caramazza I, Galimberti G et al. Intraduodenal absorption in the rabbit of a novel heparin salt. Haemostasis 1992;22,3:113-116.
  66. Rivera TM, Leone BA, Paton DR et al. Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate: pharmacological considerations. Pharm Res 1997;14:1830-1834.
  67. Baughman RA, Kapoor SC, Agarwal RK et al. Oral delivery of anticoagulant doses of heparin: A randomized, double-blind, controlled study in humans. Circulation 1998;98:1610-1615.
  68. Gonze MD, Manord JD, Leone BA et al. Orally administered heparin for preventing deep venous thrombosis. Am J Surg 1998;176:176-178.
  69. Berkowitz SD, Marder VJ, Kosutic G et al. Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. J Thromb Haemost 2003;1:1914-1919.
  70. Salartash K, Lepore M, Gonze MD et al. Treatment of experimentally induced caval thrombosis with oral low molecular weight heparin and delivery agent in a porcine model of deep venous thrombosis. Ann Surg 2000;231:789-794.
  71. Jandik KA, Kruep D, Cartier M et al. Accelerated stability studies of heparin. J Pharm Sc 1996;85,1:45-51.
  72. Dryjski M, Schneider DE, Mojaverian P et al. Investigations on plasma activity of low molecular weight heparin after intravenous and oral administrations. Br J Clin Pharm 1989;28:188-192.
  73. Jaques LB, Wice SM,Hiebert LM. Determination of absolute amounts of heparin and of dextran sulfate in plasma in microgram quantities. J Lab Clin Med 1990;115,4:422-432.
  74. Hiebert LM, Wice SM,Jaques LB. Antithrombotic activity of oral unfractionated heparin. J Cardiovasc Pharmacol 1996;28:26-29.
  75. Hiebert LM, Wice SM, Ping T et al. Tissue distribution and antithrombotic activity of unlabeled or 14C-labeled porcine intestinal mucosal heparin following administration to rats by the oral route. Can J Physiol Pharm 2000;78:307-320.
  76. Hiebert LM, Ping T,Wice SM. Antithrombotic activity of orally administered low molecular weight heparin (logiparin) in a rat model. Haemostasis 2000;30:196-203.
  77. Hiebert LM, Wice SM,Ping T. Tissue distribution of the low molecular weight heparin, tinzaparin, following administration to rats by the oral route. Biomed Pharmacother 2004;
  78. Hiebert LM, Wice SM, Ping T et al. Antithrombotic efficacy in a rat model of the low molecular weight heparin, reviparin sodium, administered by the oral route. Thromb Haemost 2001;85:114-118.
  79. Hiebert LM. Oral heparins. Clin Lab 2002;48:111-116.
  80. Hiebert LM. Evidence that orally administered heparins are absorbed. In Vossoughi, J., Fareed, J, Mousa, S. A., and Karanian, J. W. Thrombosis Research and Treatment. Bench to Bedside. Washington DC: Medical and Engineering Publishers, Inc. 2004:553-563.
  81. Pinel C, Wice SM,Hiebert LM. Orally administered heparins prevent arterila thrombosis in a rat model. Thromb Haemost 2004;
  82. Vasdev S, Sampson CA, Longerich L et al. Oral heparin normalizes blood pressure and elevated cytosolic calcium in hypertensive rats. Artery 1992;19,3:124-146.
  83. Vasdev S, Ford C, Longerich L et al. Oral treatment with low molecular weight heparin normalizes blood pressure in hypertensive rats. Artery 1994;21,1:1-28.
  84. Gorski A, Lagodzinski Z. Oral heparin prolongs survival of skin allografts. Arch Immunol Ther Exp 1991;39:557-562.
  85. Johnson WTM, Roberts B, Horwitz O et al. Pilot studies of oral vs subcutaneous heparin: heparin powder in a gelatin capsule. FASEB J 1994;8 (4):A455-A455.
  86. Engelberg H. Orally ingested heparin is absorbed in humans. Clin Appl Thrombosis/Hemostasis 1995;1(4):283-285.
  87. Lualdi P. Bioavailability of oral chondroitin sulfate. Rheumatol Int 1993;13:39-40.
  88. Ofosu F. Pharmacological Actions of Sulodexide. Semin Thromb Hemost 1998;24:127-138.
  89. Gambaro G, Kinalska I, Oksa A et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patieints: the Di.N.A.S. randomized trial. J Am Soc Nephrol 2002;13:1615-1625.
  90. Ninomiya K, Saito F, Hideaki M et al. Effect of oral administration of dextran sulfate on endogenous plasma lipoprotein lipase and hepatic lipase activities in healthy men. J Clin Biochem Nutr 1988;5:59-66.
  91. Lorentsen KJ, Hendrix CW, Collins JM et al. Dextran sulfate is poorly absorbed after oral administration. Ann Int Med 1989;111:561-566.
  92. Hartman N, Johns D,Mitsuya H. Pharmacokinetic analysis of dextran sulfate in rats as pertains to its clinical usefulness for therapy of HIV infection. AIDS Res Hum Retroviruses 1990;6,6:805-812.
  93. Hiebert LM, Wice SM, Jaques LB et al. Orally administered dextran sulfate is absorbed in HIV-positive individuals. J Lab Clin Med 1999;133:161-170.
  94. Hiebert LM, Wice SM, Ping T et al. Tissue distribution of [14C] sucrose octasulfate following oral administration to rats. Pharm Res 2002;19:838-844.
  95. Nickel JC, Johnston B, Downey J et al. Pentosan polysulfate therapy for chronic nonbacterial prostatitis (chronic pelvic pain syndrome category IIIA): a prospective multicenter clinical trial. Urology 2000;56:413-417.
  96. Duda B, Cornelli U, Lee JM et al. Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Abeta(25-35)-induced abnormal tau protein immunoreactivity in rat brain. Neurobiol Aging 2002;23:97-104.

 
 
 
 
 
 
 
 
 
 
 
 
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